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This book aims to educate nurses and advanced practice providers (APP’s) about known mutations, availability of targeted
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Anti-angiogenesis Strategies in Cancer Therapeutics provides a detailed look at the current status and future directions
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Table of contents :
2: Introduction to Mutation Testing
2.1 Introduction/Lung Cancer Statistics/Histology
2.2 Types of Lung Cancer Mutations
2.2.6 ERBB2 (HER2)
2.3 Mechanism of Resistant Mutations
2.4 Patient Selection for Molecular Testing
2.5 Role of Nursing and Advanced Practice Providers (APP) and Team Approach to Molecular Testing
3: Nursing Considerations with EGFR Inhibitors in NSCLC
3.1 The Epidermal Growth Factor Receptor Mutation
3.1.1 The EGFR Inhibitors
3.2 Toxicities of EGFR Inhibitors
4: Nursing Considerations with ALK and ROS1 Inhibitors in NSCLC
4.2 ALK Positive NSCLC
4.3 ROS1 Positive NSCLC
4.3.2 Other Treatments
4.4 Toxicities and Management of ALK/ROS1 Inhibitors
4.4.3 Visual Disturbances
4.4.4 GI Toxicities
4.4.5 Cardiovascular Toxicities
4.4.6 Laboratory Abnormalities
5: BRAF in NSCLC
5.1 Overview and Mechanism of Action of BRAF Mutations in NSCLC
5.2 Data for BRAF
5.3 Toxicities and Management
5.3.1 Previously Treated Patients
5.3.2 Melanoma Patients
5.3.4 Cutaneous Skin Reactions
5.3.7 QTc Prolongation
5.3.8 Ocular Toxicities
6: Mechanisms of Acquired Resistance to Targeted Therapy in NSCLC: Role of Repeat Biopsy and Nursing Considerations
6.2 Utility of Repeat Biopsy: Tissue Testing
6.3 Utility of Repeat Biopsy: Liquid Biopsy
6.4 Mechanisms of Acquired Resistance
6.4.1 EGFR Acquired Resistance Mutations
126.96.36.199 Primary Resistance
188.8.131.52 Acquired Resistance
184.108.40.206 Secondary Resistance
220.127.116.11 Tertiary Resistance
6.4.2 ALK Acquired Resistance Mutations
7: The Impact and Toxicity of Checkpoint Inhibitors in Management of Lung Cancer
7.1.1 Immune Checkpoint Inhibitor Agents
7.2 Mechanism of Action
7.3 Patient Selection
7.4 Results of Clinical Trials
7.4.1 Metastatic Disease: First-Line Therapy
18.104.22.168 Pembrolizumab Monotherapy
22.214.171.124 Pembrolizumab Plus Chemotherapy
126.96.36.199 Atezolizumab Plus Chemotherapy
7.4.2 Metastatic Disease: Second-Line Monotherapy
188.8.131.52 Combination Checkpoint Inhibitors
184.108.40.206 Combinations with Radiation
220.127.116.11 Consolidation Therapy
18.104.22.168 Small Cell Lung Cancer
22.214.171.124 Mesothelioma: Second and Third Line
7.5 Management of Immune-Related Adverse Events
7.5.1 Management of Select irAEs
7.6 Patient Education
7.7 Supportive Care
7.8 Future Developments
8: The Role of Anti-Angiogenic Agents (VEGF)
8.2 Tumor Angiogenesis
8.3 Vascular Endothelial Growth Factor (VEGF)
8.6 Bevacizumab Toxicities
8.6.2 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
8.6.5 GI Perforation (GIP)
8.9 Ramucirumab Administration, Precautions, and Monitoring Parameters
8.10 Nursing Management of Common Adverse Effects
8.10.3 Epistaxis and Hemoptysis
9: Nursing Considerations for Patients Treated with Targeted Therapies
9.1 Preparing Patients for Treatment on Targeted Therapies: Nursing Considerations
9.1.1 Access to Therapy
9.2 Treatment Initiation and Monitoring
9.2.1 Nursing Assessment
9.2.2 Telephone Triage
9.2.4 Multidisciplinary Approach
Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners Marianne Davies Beth Eaby-Sandy Editors
Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners
Marianne Davies • Beth Eaby-Sandy Editors
Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners
Editors Marianne Davies Yale Comprehensive Cancer Center Yale University School of Nursing New Haven, CT USA
Beth Eaby-Sandy Abramson Cancer Center University of Pennsylvania Philadelphia, PA USA
ISBN 978-3-030-16549-9 ISBN 978-3-030-16550-5 (eBook) https://doi.org/10.1007/978-3-030-16550-5 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
1 Introduction������������������������������������������������������������������������������������������������ 1 Beth Eaby-Sandy 2 Introduction to Mutation Testing ������������������������������������������������������������ 3 Vanna Dest and Kathryn Medow 3 Nursing Considerations with EGFR Inhibitors in NSCLC ������������������ 17 Michelle M. Turner and Beth Eaby-Sandy 4 Nursing Considerations with ALK and ROS1 Inhibitors in NSCLC���������������������������������������������������������������������������������������������������� 27 Beth Eaby-Sandy 5 BRAF in NSCLC���������������������������������������������������������������������������������������� 39 Helen Shih 6 Mechanisms of Acquired Resistance to Targeted Therapy in NSCLC: Role of Repeat Biopsy and Nursing Considerations���������� 51 Emily Duffield 7 The Impact and Toxicity of Checkpoint Inhibitors in Management of Lung Cancer�������������������������������������������������������������� 65 Stephanie Crawford Andrews and Marianne Davies 8 The Role of Anti-Angiogenic Agents (VEGF)������������������������������������������ 85 Melinda Oliver and Elizabeth S. Waxman 9 Nursing Considerations for Patients Treated with Targeted Therapies���������������������������������������������������������������������������� 105 Kelly E. Goodwin and Marianne Davies
Introduction Beth Eaby-Sandy
Lung cancer is the second most common type of cancer diagnosed in men after prostate cancer, and the second most common type of cancer diagnosed in women after breast cancer. There are an estimated 228,150 new cases of lung cancer to be diagnosed in 2019 . While lung cancer is prevalent, it is also deadly, resulting in an estimated 142,670 deaths in 2019, which is more than breast, colon, and prostate cancers combined and accounts for approximately 25% of all cancer deaths in the United States (US) . There are two main categories of lung cancer, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC is the most common type of lung cancer, resulting in 83% of cases in the US, and is the most common type of lung cancer diagnosed in patients who are never or light smokers. SCLC accounts for the other 17% of cases and is strongly associated with heavy cigarette smoking. As smoking rates decline in the US, there has been a slow decline in the incidence of SCLC as well . Within the realm of NSCLC, there are two predominant histologic subtypes: adenocarcinoma and squamous cell carcinoma. See Fig. 1.1 for the breakdown of histologic subtypes of lung cancer. Adenocarcinoma is the most common histologic subtype and the most common type in patients with light or no smoking history. Over the past 15 years, researchers have found that within the adenocarcinoma histology, several molecular biomarkers have emerged such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and many others, which will be further discussed in this book. The diagnosis and detection of these biomarkers in NSCLC lead to the development of several targeted therapies to treat NSCLC which harbor one of these mutations or gene alterations. Given their different mechanisms of action and side effect B. Eaby-Sandy (*) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 M. Davies, B. Eaby-Sandy (eds.), Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners, https://doi.org/10.1007/978-3-030-16550-5_1
Fig. 1.1 Histologic subtypes of lung cancer (www.onclive.com)
Lung Cancer 5% Adenocarcinoma
Squamous cell 20%
Small cell Carcinoid/large cell/large cell neuroendocrine
profiles, it has been a challenge for oncology nurses to effectively educate patients about the drugs and their toxicities. This book will focus on providing a thorough understanding of the different techniques used to detect these biomarkers and populations of lung cancer patients who may be more likely to display certain biomarkers. The National Comprehensive Cancer Network (NCCN) guidelines recommend testing for EGFR, ALK, ROS1, BRAF, and PD-L1 in all patients with a non-squamous histology and consideration in patients with squamous cell carcinoma who exhibit certain clinical characteristics such as never smoking . Following detection and diagnosis, the book aims to educate nurses and healthcare providers with the rationale for use of these targeted therapies as well as an in-depth look at potential toxicities and management strategies. Nurses, whether in the clinic, infusion room, or triaging phone calls, are often charged with identifying these toxicities. Nurses remain a constant first point of contact for most oncology patients who are experiencing toxicities due to their cancer treatments. In this ever-changing landscape of oncology, specifically lung cancer, there is a huge need for oncology nurses and other oncology healthcare providers to stay up to date and educated on the indications, mechanisms of action, and the toxicity profiles. Management strategies differ depending on the drug and the toxicity. While some toxicities may be minimal, others are life threatening at times. This book will review each of these targeted therapies, their toxicities, and strategies for nursing management.
References 1. American Cancer Society Facts & Figures. https://www.acs.org. Accessed June 20, 2019. 2. Wang S, Tang J, Sun T, Zheng X, Li J, Sun H, Zhou X, Zhou C, Zhang H, Cheng Z, Ma H, Sun H. Survival changes in patients with small cell lung cancer and disparities between different sexes, socioeconomic statuses and ages. Sci Rep. 2017;7:1339. https://doi.org/10.1038/ s41598-017-01571-0. 3. National Comprehensive Cancer Network. www.NCCN.org. Accessed 29 Nov 2018.
Introduction to Mutation Testing Vanna Dest and Kathryn Medow
Introduction/Lung Cancer Statistics/Histology
Lung cancer remains the leading cause of cancer related mortality in the United States, with 142,670 deaths anticipated in 2019 . Lung cancer incidence continues to decline with 228,150 estimated new cases in 2019. The decline in lung cancer in males is twice the number compared to females, which may be related to tobacco consumption and smoking cessation . Mortality rates from lung cancer remain substantial despite significant advances in the field of cancer treatment in recent years. Historically, chemotherapy has been the cornerstone of treatment for NSCLC, with treatment decisions based empirically on tumor histology. The World Health Organization (WHO) identified two classifications of lung cancer, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) [3–5]. SCLC accounts for approximately 10–15% of all lung cancers and is directly related to tobacco smoking . NSCLC accounts for approximately 85% of lung cancer cases with associated histologies that include adenocarcinoma, squamous cell, and large cell carcinoma . Over 50% of NSCLC are adenocarcinoma in histology . In 2015, the World Health Organization (WHO) updated the lung cancer classification based upon molecular profiles and genetic alterations. It is recommended that pathologists categorize lung cancer into adenocarcinoma and squamous cell carcinoma secondary to targetable driver genetic alterations. Adenocarcinoma markers include TTF-1 and Napsin 1. Squamous cell carcinoma markers include p40, CK5/6, and p63. Adenocarcinoma is classified by the extent of invasiveness. There are also variants of invasive carcinoma including invasive mucinous adenocarcinoma (IMA), which replaced mucinous bronchi alveolar carcinoma (BAC). Squamous cell carcinomas are classified into keratinizing, non-keratinizing, and basaloid [3–5]. V. Dest · K. Medow (*) Smilow Cancer Hospital at Yale-New Haven, New Haven, CT, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2019 M. Davies, B. Eaby-Sandy (eds.), Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners, https://doi.org/10.1007/978-3-030-16550-5_2
V. Dest and K. Medow
The treatment of lung cancer with cytotoxic chemotherapeutic agents has led to improved overall survival, however survival rates remain low and patients often incur significant treatment related toxicity, thus driving the need for novel therapies and treatment strategies. The role of molecular testing for NSCLC has grown rapidly, leading to the discovery of a number of molecular markers that are now being used to determine treatment plan, and often to predict potential response to treatment. Recent evidence suggests that lung cancer is a histologically and molecularly heterogeneous disease [3–5]. The result has been a clear shift toward targeted and histologically directed therapies. The distinction between squamous and non-squamous histology remains the first step in delivering personalized therapeutic options to patients with NSCLC. More recent molecular studies have demonstrated that subsets of NSCLC can be further defined at the molecular level, with a significant proportion of adenocarcinomas harboring distinct genomic alterations. These alterations are commonly referred to as “driver mutations,” as their role is implicated in driving the development and proliferation of lung cancer through the activation of mutant signaling proteins that induce and sustain tumorigenesis. Driver mutations are somatic genome alterations that can help to promote cancer through a number of different mechanisms. They are often transformative, initiating the change from a noncancerous cell to a malignant one, or preventing normal cellular mechanisms such as regular cell growth, differentiation, and cell death . The Lung Cancer Mutation Consortium has identified one or more of such mutations in approximately two-thirds of patients diagnosed with Stage IV NSCLC . Driver mutations can be found in all NSCLC histologies, though are far more commonly seen in adenocarcinoma. Similarly, they are found in current, former and never smokers . There are currently a number of targeted small molecule inhibitors available or being developed to treat these specific, molecularly defined subsets of patients. These agents show improved efficacy with superior survival rates as compared to chemotherapy when given to the appropriate patient with the corresponding driver mutation [10, 11]. Several biomarkers have been identified as predictive and/or prognostic markers for NSCLC; predictive markers indicate therapeutic efficacy when there is a direct interaction between the mutation and the therapy on the patient’s outcome. Prognostic markers indicate innate tumor behavior (i.e., aggressiveness), independent of the treatment that the patient receives. Testing for these mutations continues to become more efficient and affordable, resulting in a rapid rise in the use of genomic sequencing which will undoubtedly continue to affect routine clinical practice. In turn, this will further expand our knowledge of these markers and thus influence potential treatment recommendations in routine clinical practice, allowing providers to identify patients who are most likely to benefit from a specific drug. It is paramount that molecular profiling is obtained at the time of diagnosis for all patients with advanced stage NSCLC so that the full armament of treatment options can be tailored to their particular cancer with the goal of providing efficacious targeted therapies, as well as avoiding therapies unlikely to provide clinical benefit. Increased utilization of personalized therapies has shown clear promise for the future of lung cancer treatment, with a necessary shift from the “one size fits all”
2 Introduction to Mutation Testing
treatment paradigm of chemotherapy, to allowing for specific recommendations for individual patients based on the presence of specific genetic alterations. In the past decade, the United States FDA has approved numerous new medications to treat patients with these mutations . This, along with the increasing use of immunotherapy in NSCLC, has greatly expanded the catalog of treatment options.
Types of Lung Cancer Mutations
The most common driver mutations found in lung cancer are EGFR mutations, ALK gene rearrangements, and KRAS mutations , though several others have been identified (HER2, MET, BRAF, FGFR4, PIK3CA, ROS1, and RET). Figure 2.1 depicts the incidence rate of these mutations. Actionable mutations are classified as those that are potentially targetable with an FDA-approved anti-cancer drug. They are found in roughly 20–25% of the non- squamous population .
2.2.1 EGFR EGFR (epidermal growth factor receptor) is a trans-membrane ligand-binding receptor normally found on the surface of epithelial cells, and has a significant role in cellular proliferation and differentiation. When ligands bind to the extracellular
Fig. 2.1 Incidence of molecular etiologies in NSCLC in the United States. Adapted from 
FGFR4 2% BRAF 2%
V. Dest and K. Medow
receptor, auto-phosphorylation occurs, initiating an intracellular cascade of downstream signals that result in normal cell growth, differentiation, and cell death. In malignant cells, there is dysregulation of the intracellular activity of EGFR, caused by EGFR protein overexpression or EGFR gene mutations resulting in uncontrolled cellular proliferation, invasion, and inhibition of apoptosis . EGFR mutations are the most commonly found actionable driver mutations, occurring in 15% of Caucasian and African American patients with NSCLC, and in 30–50% of those with Asian ethnicity [3, 7, 8]. They are associated with adenocarcinoma histology, female gender, and nonsmoking status [3, 7, 8]. Within the category of EGFR mutations, there are four subcategories of mutations that exist in the first four exons (exons 18 through 21) of the tyrosine kinase domain of EGFR. The most commonly described EGFR mutations are: 1. Insertions/deletions in exon 19–45% of EGFR mutations. They are sensitive to oral EGFR TKIs. These mutations include in-frame deletions L747 and E749. 2. Point mutations in exon 21–40% of EGFR mutations. They are sensitive to EGFR TKIs. The most common point mutation for exon 21 is L858R [3, 7, 8, 12]. Some, less common mutations in EGFR are associated with lack of responsiveness to EGFR TKIs, including most EGFR exon 20 mutations (4–5% of EGFR mutations). The T790M mutation is most commonly associated with cancer recurrence following initial treatment with an EGFR TKI, however if this mutation is identified prior to initial TKI exposure, genetic counseling should be considered, as a germ line T790M mutation is associated with familial lung cancer predisposition. Multiple phase 3 studies of treatment naïve EGFR mutated lung cancer have shown improved efficacy in the first line setting for patients with EGFR mutated NSCLC who receive EGFR TKIs as compared to chemotherapy (platinum doublet) with regard to progression free survival and response rate [8, 10]. Thus, these should be used as first line systemic therapy in patients with documented sensitizing EGFR mutations. EGFR TKIs approved for first line treatment of EGFR mutated NSCLC include osimertinib, afatinib, erlotinib, gefitinib, and dacomitinib .
2.2.2 ALK ALK (anaplastic lymphoma kinase) is a receptor tyrosine kinase not normally expressed in the lung. However, when the ALK gene fuses with another gene (most commonly EMLA4, echinoderm microtubule-associated protein-like4) it can become rearranged, causing dysregulation and inappropriate signaling through the ALK kinase domain resulting in uncontrolled cell growth and proliferation [12, 13]. ALK gene rearrangements are the second most commonly identified actionable driver mutation in NSCLC. These activating mutations are found in approximately 3–7% of patients with NSCLC. They are associated with male patients of younger age and adenocarcinoma histology . Rates are higher in patients who have never smoked (defined as less than 100 cigarettes in their lifetime) or who are “ever smokers” (less than a 15-pack year history) . ALK-positive tumors are sensitive to
2 Introduction to Mutation Testing
treatment with TKIs that inhibit ALK rearrangements (alectinib, crizotinib, ceritinib, brigatinib, and lorlatinib).
2.2.3 ROS1 ROS1 is a receptor tyrosine kinase within the insulin receptor family. A rearrangement of ROS1 causes dysregulation and inappropriate activation of other intracellular pathways through the ROS1 kinase domain, resulting in promotion of cell survival and proliferation. These mutations are found in 1–2% of patients with NSCLC, and are associated with younger age, never smokers, Asian ethnicity, and advanced stage disease [7, 13]. They are most commonly found with adenocarcinoma histology, however are also seen in both large cell and squamous cell etiologies. ROS1 rearrangements occur more frequently in those who are negative for EGFR mutations, KRAS mutations, and ALK gene rearrangements. Presence of ROS1 rearrangement is associated with responsiveness to oral ROS1 TKIs. Crizotinib is currently the only FDA-approved therapies for ROS1 positive patients, with crizotinib preferred given its substantial response rates of 70–80% .
2.2.4 BRAF BRAF is a serine tyrosine kinase enzyme that links cell signaling between RAS GTPases and the enzymes of the MAPK family, which work to control cell proliferation. While these mutations are well documented in melanomas, they are also seen in 1–3% of adenocarcinomas of the lung. They are more likely to occur in former or current smokers . When this mutation results in a change in amino acid position 600 (p.V600E), disease may respond to combined therapy with oral inhibitors of BRAF and MEK; the combination of dabrafenib and trametinib is recommended for patients with vBRAF 600E mutations . A number of other mutations that occur in NSCLC have shown response to medications that are approved for other cancers, but have yet to be approved for lung cancer.
2.2.5 KRAS KRAS proto-oncogene point mutations are activating mutations that result in unregulated signaling through the MAP/ERK pathway. In the United States, activating KRAS mutations are found in approximately 15–20% of all patients with NSCLC, and approximately 30–50% of patients with adenocarcinoma histology . These mutations are commonly associated with a significant smoking history, as well as larger tumor size . KRAS mutations are correlated with decreased survival . Additionally, KRAS-positive tumors have demonstrated lack of therapeutic response to EGFR TKIs. While there are currently no available therapies to target the
V. Dest and K. Medow
KRAS-mutant variant, there is suggestion that KRAS mutations may sensitize tumors to antifolates such as pemetrexed , as well as immune-checkpoint inhibitors .
2.2.6 ERBB2 (HER2) HER2 status is reported in about 2% of NSCLC, with increased frequency in women, never smokers, and patients of Asian origin. It is also more commonly associated with adenocarcinoma histology .
2.2.7 MET The MET gene is located on chromosome 7q21-q31 and encodes for the hepatocyte growth factor receptor. MET amplifications occur in 2–4% of NSCLC, and can be found in both squamous and adenocarcinoma histologies. They are associated with poor prognosis . Crizotinib is approved as treatment for patients with MET exon 14 alterations.
2.2.8 NTRK NTRK gene fusions act as oncogenic drivers, and are linked with a diverse range of solid tumors including lung, salivary gland, thyroid, and sarcoma. They are rare in NSCLC, occurring only in 0.2% of patients, and do not generally overlap with other oncogenic drives such as EGFR, ALK, or ROS1. Larotrectinib is a TRK inhibitor that has shown efficacy across a diverse range of solid tumors in patients with TRK gene-fusion positive disease .
2.2.9 Other Other non-actionable driver mutations that have been seen in lung cancer are FGFR1, MEK1, RET, PIK3CA, and PTEN. Targeted therapies for these mutations are currently in clinical development. See Table 2.1 for more details on molecular alterations in NSCLC. While it is not traditionally considered a driver mutation, it is important to also discuss PDL1 as an actionable target for patients with NSCLC. PDL1, programmed cell death ligand 1, is a coregulatory molecule that can be expressed on tumor cells, and works to inhibit T-cell mediated cell death, thus allowing cancer cells to avoid destruction. A number of human immune-checkpoint inhibitor antibodies have been created to block the PD-1 and PD-L1 interaction, thus freeing cytotoxic t-cells to mediate the killing of cancer cells that express PDL1. Monoclonal antibodies that are currently approved and utilized include nivolumab and pembrolizumab, which inhibit PD-1 receptors, and atezolizumab and durvalumab, which
2 Introduction to Mutation Testing
Table 2.1 Molecular alterations in NSCLC Genetic alteration EGFR mutation
Frequency in NSCLC (%) 25
Major clinicopathologic correlates Asian, female, never smoker, adenocarcinoma
KRAS mutation ALK translocation
Younger, male, never smoker, adenocarcinoma
HER2 mutation MET amplification BRAF mutation FGFR4 amplification PIC3CA mutation ROS1 translocation
Never smoker, female, Asian, adenocarcinoma EGFR-mutant tumors
Younger, never smoker, Asian, advanced stage disease, adenocarcinoma
Potential therapeutic agent Osimertinib, erlotinib, gefitinib, afatinib, dacomitinib None Alectinib, crizotinib, brigatinib, ceritinib, lorlatinib Afatinib, lapatinib Crizotinib
Adapted from Kiel et al.  and Lovly et al. . Preferred Agent FDA-Approved Approved in other Cancer Types
inhibit PD-L1 . Finally, tumor mutational burden (TMB) is a measurement of the overall quantity of mutations carried by tumors cells. It is an emerging, predictive biomarker that may be helpful in selecting patients who will respond to immunotherapy [7, 12].
Mechanism of Resistant Mutations
Unfortunately, almost all patients will eventually develop resistance to first- and second-generation EGFR TKIs within approximately 10–12 months. The most common mechanism of resistance is the acquired T790M mutation at the exon 20 of the EGFR gene. This accounts for approximately 50–60% of all cases of TKI resistance. After resistance has been identified, the quinazoline-based first generation EGFR TKIs can no longer bind to the ATP binding receptor, leading to inhibition of downstream signaling. The incidence of T790M mutations is similar amongst ethnicities and amongst EGFR TKI agents. Osimertinib was developed and FDA approved in November 2015 for patients with T790M mutation resistance to first or second-generation EGFR TKIs. Less common EGFR resistant mutations have been identified and include C797S, G769S/R, L792F/H, L718Q, and L844V . There are also other mechanisms of resistance that are heterogeneous and may include
V. Dest and K. Medow
Table 2.2 Possible resistance mechanisms in EGFR TKIs First and second generation: Erlotinib/Gefitinib/ Afatinib Primary resistance EGFR Exon 20 insertion modification BIM deletion Alternative pathway activation Acquired resistance EGFR T790M modification
Alternative pathway activation
Bypass MET amplification HGF overexpression AXL overexpression HER2 amplification Downstream PTEN loss PI3K mutation BRAF V600E SCLC transformation (RB loss) Epithelial- mesenchymal transition
Third generation: osimertinib
Third generation: rociletinib
C797S G769S/R L792F/H T790M loss Bypass MET amplification HER2 amplification Downstream BRAF V600E NRAS mutation
C797S L718Q L844V amplification
SCLC transformation Epithelial- mesenchymal transition
Third generation: WZ4002
C797S L718Q L844V Bypass IGF1R activation Downstream ERK1 and ERK2 activation
Adapted from IASLC Atlas of EGFR Testing in Lung Cancer 
HER2 and/or MET amplification, PIK3CA and/or BRAF mutation, and small cell transformation . See Table 2.2 for more details on resistant mutations.
Patient Selection for Molecular Testing
The initial guidelines for molecular testing were established in 2013 by the International Association for the Study of Lung Cancer (IASLC) and the Association of Molecular Pathology (AMP). In 2014, the American Society of Clinical Oncology (ASCO) and the NCCN endorsed these guidelines. In 2017, the guidelines were updated with input from all three organizations— College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and the Association of Molecular Pathology (AMP). The guidelines were updated as a response to the continuous, rapid influx of new evidence being published on new therapies, new biomarkers for targeted therapies, and advances in current and new technologies. Targetable driver mutations are most commonly found in adenocarcinoma. The recommendations for molecular testing are based upon cancer histology. See Table 2.3 for the 2017 Changes to EGFR Mutation Testing.
Updated recommendation: specimen processing Updated recommendation: performing EGFR testing
Updated recommendation: specimen testing for EGFR mutation
Statement Reaffirmed recommendation
Recommendation • Use molecular testing for the appropriate targets on either primary or metastatic lung lesions to guide initial therapy selection • Pathologists and laboratories should not use EGFR copy number analysis such as FISH or CISH, to select patients for EGFR-targeted TKI therapy • Use EGFR and ALK molecular testing for lung adenocarcinoma patients at the time of diagnosis for patients presenting with advanced stage disease or at progression in patients who originally presented with lower stage disease but were not previously tested • Pathologists may utilize either cell blocks or other cytological preparations as suitable specimens for lung cancer biomarker molecular testing • Laboratories should not use total EGFR expression by IHC testing to select patients for EGFR-targeted TKI therapy • Laboratories should not use EGFR mutation specific IHC testing to select patients for EGFR-targeted TKI therapy
Table 2.3 2017 recommendations for EGFR testing
• Laboratories should employ, or have available at an external reference laboratory, clinical lung cancer biomarker molecular testing assays that are able to detect molecular alterations in specimens with as little as 20% cancer cells
Expert consensus opinion • Molecular testing of tumors at diagnosis from patients presenting with early stage disease is encouraged
2 Introduction to Mutation Testing 11
Statement New recommendation: which new genes should be tested for in lung cancer patients?
Table 2.3 (continued)
Recommendation • ROS1 testing must be performed on all lung adenocarcinomas, irrespective of clinical characteristics
Expert consensus opinion • BRAF molecular testing is currently not indicated as a routine stand-alone assay outside the context of a clinical trial. It is appropriate to include BRAF as part of larger testing panels performed either initially or when routine EGFR, ALK, and ROS1 testing are negative • RET molecular testing is currently not indicated as a routine stand-alone assay outside the context of a clinical trial. It is appropriate to include RET as part of larger testing panels performed either initially or when routine EGFR, ALK, and ROS1 testing are negative • ERBB2 (HER2) molecular testing is not indicated as a routine stand-alone assay outside the context of a clinical trial. It is appropriate to include RET as part of larger testing panels performed either initially or when routine EGFR, ALK, and ROS1 testing are negative • KRAS molecular testing is not indicated as a routine stand-alone assay as a sole determinant of targeted therapy. It is appropriate to include KRAS as part of larger testing panels performed either initially or when routine EGFR, ALK, and ROS1 testing are negative • MET molecular testing is not indicated as a routine stand-alone assay outside the context of a clinical trial. It is appropriate to include MET as part of larger testing panels performed either initially or when routine EGFR, ALK, and ROS1 testing are negative
12 V. Dest and K. Medow
New recommendation: is molecular testing appropriate for lung cancers that do not have an adenocarcinoma component? New recommendation: what testing is indicated for patients with targetable mutations who have relapsed on targeted therapy?
New recommendation: what methods should be used to perform molecular testing?
• In lung adenocarcinoma patients who harbor sensitizing EGFR mutations and have progressed after treatment with an EGFR-targeted TKI, physicians must use EGFR T790M mutational testing when selecting patients for third generation EGFR-targeted therapy • Laboratories testing for T790M mutation in patients with secondary clinical resistance to EGFR TKIs should deploy assays capable of detecting EGFR T790M mutations in as little as 5% of viable cells • There is currently insufficient evidence to support a recommendation for or against routine testing for ALK mutational status for lung adenocarcinoma patients with sensitizing ALK mutations who have progressed after treatment with an ALK-targeted tyrosine kinase inhibitor
• Immunohistochemistry (IHC) is an equivalent alternative to FISH for ALK testing
• ROS1 IHC maybe used as a screening test in advanced stage lung adenocarcinoma patients. However, positive ROS1 IHC results should be confirmed by a molecular or cytogenetic method • Multiplexed genetic sequencing panels are preferred over multiple single-gene tests to identify their treatment options beyond EGFR, ALK, and ROS1 • Laboratories should ensure test results that are unexpected, discordant, equivocal, or otherwise low confidence are confirmed or resolved using an alternative method or sample • Use molecular biomarker testing in tumors with histologies other than adenocarcinoma when clinical features indicate a higher probability of an oncogenic driver
2 Introduction to Mutation Testing 13
Recommendation • There is currently insufficient evidence to support the use of circulating cell-free plasma DNA (cfDNA) molecular methods for the diagnosis of primary lung adenocarcinoma • In some clinical settings in which tissue is limited and/or insufficient for molecular testing, cell-free plasma DNA (cfDNA) assay may be used to identify EGFR mutations • There is currently insufficient evidence to support the use of circulating tumor cell (CTC) molecular analysis for the diagnosis of primary lung adenocarcinomas, the identification of EGFR or other mutations, or the identification of EGFR T790M mutations at the time of EGFR TKI resistance Expert consensus opinion • May use cell-free plasma DNA (cfDNA) methods to identify EGFR T790M mutations in lung adenocarcinoma patients with progression or secondary clinical resistance to EGFR-targeted TKI; Testing of the tumor sample is recommended if the plasma result is negative
Italic font: Strong recommendation; Normal font: Recommendation. Adapted from Lindeman et al. 
Statement New recommendation: what is the role of testing for circulating, cell-free DNA for lung cancer patients?
Table 2.3 (continued)
14 V. Dest and K. Medow
2 Introduction to Mutation Testing
ole of Nursing and Advanced Practice Providers (APP) R and Team Approach to Molecular Testing
The role of nursing and the advanced practice provider (APP) is pivotal in the care of the lung cancer patient undergoing molecular testing. As precision medicine and molecular profiling continue to be in the forefront of practice, practitioners must have a good understanding of genomics. In addition, they must be versed and comfortable in educating the patient and their family about the testing process, potential cost of testing, result interpretation, and subsequent treatment implications. The oncology APP needs to maintain current knowledge of evidence based guidelines regarding lung cancer histology, ordering of molecular profiling, and interpretation of the molecular testing results. They also need to have an understanding of the current limitations of testing and knowledge of ongoing clinical trials helping to address these issues. The process of molecular testing in lung cancer involves a multidisciplinary team, with each discipline having different responsibilities to ensure accurate and efficient delivery of results and interpretation of results leading to determination of the treatment plan. The medical oncologist or APP is responsible for ordering the molecular testing. Nurses are responsible for obtaining serum samples and buccal swabs for testing. Other key members in the molecular testing process include the physician performing the biopsy who in turn needs to deliver the sample to pathology. The pathologists oversee the testing process, assess if the sample is adequate, identify tumor cells through histology, make histopathologic diagnoses, and report the results to the ordering provider. Another important component of testing is insurance authorization and prior authorization, based on a patient’s health insurance. The APP works collaboratively with the medical oncologist to review test results, formulate the plan of care, and educate the patient and their family about recommended therapy.
References 1. American Cancer Society. Facts & figures 2019. Atlanta: American Cancer Society; 2019. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. https://doi.org/10.3322/caac.21551. 3. Kiel P, Cheng L, Livers-Ertel A, Durm G. The emerging role of molecular testing in non-small cell lung cancer. J Adv Pract Oncol. 2017;8:7–27. https://doi.org/10.6004/jadpro.2017.8.6.13. 4. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Gesisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243–60. https://doi.org/10.1097/JTO.0000000000000630. 5. Inamura K. Lung cancer: understanding its molecular pathology and the 2015 WHO classification. Front Oncol. 2017;7:1–7. https://doi.org/10.3389/fonc.2017.00193. 6. DiBardino DM, Rawson DW, Saqi A, Heymann JJ, Pagan CA, Bulman WA. Next- generation sequencing of non-small cell lung cancer using a customized, targeted sequencing panel: emphasis on small biopsy and cytology. Cytojournal. 2017;14:7. https://doi. org/10.4103/1742-6413.202602.
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7. Waxman E, Fossella F. Biomarkers/molecular targets, immunotherapy, and treatments for non-small cell lung cancer. J Adv Pract Oncol. 2016;7:514–24. https://doi.org/10.6004/ jadpro.206.754. 8. Vijayalakshmi R, Krishnamurthy A. Targetable “driver” mutations in non-small cell lung cancer. Indian J Surg Oncol. 2011;2(3):178–88. https://doi.org/10.1007/s13193-011-0108-0. 9. Lovly C, Horn L, & Pao W. Molecular profiling of lung cancer. My Cancer Genome. 2018. https://www.mycancergenome.org/content/disease/lung-cancer. Updated 16 Mar 2018. 10. Padda S, Harvey D. Navigating the landscape of molecular testing and targeted treatment of non-small cell lung cancer. J Adv Pract Oncol. 2016;7(3):299–301. https://doi.org/10.6004/ jadpro.2067310. 11. Zhu QG, Zhang SM, Ding XX, He B, Zhang HQ. Driver genes in non-small cell lung cancer: characteristics, detection methods, and targeted therapies. Oncotarget. 2017;8(34):57680–92. https://doi.org/10.18632/oncotarget.17016. 12. National Comprehensive Cancer Network. Non-small cell lung cancer (Version 3.2019). 2019. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 5 Feb 2019. 13. Davies M, Shih H. Diagnosis of lung cancer. J Adv Pract Oncol. 2017;8(Suppl 1):11–23. 14. Tsao MS, Wistuba IL, Yatabe Y. EGFR testing. In: Mok TS, Carbone DP, Hirsch FR, editors. International Association for the Study of Lung Cancer (IASLC) atlas of EGFR testing in lung cancer. North Fort Myers: Editorial Rx Press; 2017. p. 19–26. 15. Stewart EL, Tao SZ, Liu G, Tsao MS. Known and putative mechanism of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations—a review. Transl Lung Cancer Rev. 2015;4(1):67–81. 16. Yang J, Janne PA, Ahn MJ, Horn L. EGFR gene mutations. In: Mok TS, Carbone DP, Hirsch FR, editors. International Association for the Study of Lung Cancer (IASLC) atlas of EGFR testing in lung cancer. North Fort Myers: Editorial Rx Press; 2017. p. 33–41. 17. Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, Colasacco C, Dacic S, Hirsch FR, Kerr K, Kwiatkowski DJ, Ladanyi M, Nowak JA, Sholl L, Temple- Smolkin R, Solomon B, Soutdr LH, Thunnissen E, Tsao MS, Ventura CB, Wynes MW, Yatabe Y. Updated molecular testing guideline for the selection of lung cancer patients for treatment with the targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2017;13(3):323–58. https://doi.org/10.1016/j. jtho.2017.12.001. 18. Gazdar AF. Activating and resistance mutations of EGFR in non-small cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28(Suppl 1):S24–31. https://doi.org/10.1038/onc.2009.198. 19. Yu HA, Arcilia ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M, Riely GJ. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR mutant lung cancers. Clin Cancer Res. 2013;19(8):2240–7.
Nursing Considerations with EGFR Inhibitors in NSCLC Michelle M. Turner and Beth Eaby-Sandy
The Epidermal Growth Factor Receptor Mutation
Although great progress has been made in lung cancer over the past several years, it remains the leading cause of cancer death in 2019. Lung cancer continues to cause more deaths than breast, colorectal, and ovarian cancers combined annually . The oncology community has seen the treatment landscape change over the past decade with first, with the introduction of chemotherapy driven by pathologic subtype, and then to targeted agents treating certain identifiable receptors, making therapy more personalized for patients who express driver mutations. As with any new class of agents, comes additional responsibility for nurses and other healthcare providers to understand management of side effects. In cancer, cellular proliferation and differentiation begins at the growth factor receptors. Once a ligand, or growth factor, binds to this receptor it tells the cell to grow and divide. The epidermal growth factor receptor (EGFR) is a transmembrane receptor that occurs naturally throughout our body but can be overexpressed on lung cancer cells making it an attractive target for cancer drug development. EGFR is part of the HER family of receptors, sometimes also referred to as HER1 or erb1. There is an extracellular and intracellular binding domain and the EGFR inhibiting drugs can inhibit the tyrosine kinase domain and block downstream signaling which stops cell proliferation and metastases [2, 3]. The EGFR domain can be blocked either at the extracellular receptor by a monoclonal antibody or at the intracellular level at the tyrosine kinase domain .
M. M. Turner (*) Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, 21224 MD, USA e-mail: [email protected] B. Eaby-Sandy Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 M. Davies, B. Eaby-Sandy (eds.), Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners, https://doi.org/10.1007/978-3-030-16550-5_3
M. M. Turner and B. Eaby-Sandy
An EGFR mutation is most likely to be found in patients with the adenocarcinoma histology of non-small cell lung cancer (NSCLC). There are some cases where an EGFR mutation can be found in patients with squamous cell carcinoma of the lung, however, this is usually in patients who display clinical characteristics of an EGFR mutation. Clinical characteristics that patients with EGFR mutations often share are never-smoking history, Asian ethnicity, and females . However, there are certainly males, smokers, and patients of any race or ethnicity who can develop an EGFR mutation, thus per the NCCN guidelines, all patients with non-squamous histology, which is mainly adenocarcinoma, and any patient with squamous cell carcinoma who exhibits clinical characteristics of EGFR mutations should be tested . EGFR-mutant lung cancers are more likely to respond and have improved progression free survival (PFS) with drugs that target the EGFR mutation than traditional chemotherapy . There are currently 5 EGFR inhibitors approved in the United States used to treat EGFR-mutant lung cancer all with similar toxicities, though some more or less than others.
3.1.1 The EGFR Inhibitors Gefitinib is an oral, first-generation tyrosine kinase inhibitor (TKI) approved for the first-line treatment of metastatic adenocarcinoma of the lung that harbors specific gene mutations in exon 19 or exon 21 (also known as the L858R point mutation). It was approved based on a large randomized trial of East-Asian, never-smoking patients with NSCLC, given first-line treatment with either gefitinib given at 250 mg daily versus carboplatin/paclitaxel chemotherapy. Response rates and PFS were significantly improved in favor of gefitinib over the chemotherapy arm for patients found to have an EGFR mutation . Erlotinib is an oral, first-generation TKI approved as first-line therapy in patients with EGFR mutations in exon 19 or exon 21 metastatic adenocarcinoma of the lung. Originally erlotinib was approved as a second-line treatment for all patients with NSCLC, however, this indication has been discontinued and removed from the NCCN guidelines due to futility in this setting. Erlotinib was studied first-line versus standard first-line chemotherapy in patients who harbored an EGFR mutation. Patients receiving erlotinib had an improvement in PFS of 9.7 months versus 5.2 months for standard chemotherapy . Afatinib is an oral, second-generation irreversible-binding TKI approved for patients harboring EGFR mutations in exon 19 or 21, as well as other non-resistant mutations of EGFR such as L861Q, G719X, and S7681 . Approval was based on a large randomized trial of 345 patients in a 2:1 ratio to receive afatinib versus up to 6 cycles of cisplatin/pemetrexed chemotherapy as first-line therapy. Similar to the previous gefitinib and erlotinib studies, significant improvement was noted in PFS in favor of first-line afatinib . Osimertinib is an oral, third-generation TKI that has an indication for first-line use in EGFR-mutant lung cancers and is the “preferred” first-line treatment for EGFR-mutant lung cancer per the NCCN guidelines . It also has an indication for use after progression on a first-line EGFR inhibitor for lung cancers with the T790M EGFR resistance mutation. Osimertinib gained its approval and recommendation
3 Nursing Considerations with EGFR Inhibitors in NSCLC
for preferred use based on significant improvement in PFS of 18.9 months in comparison with the standard of care arm of either gefitinib or erlotinib with a PFS of 10.2 months . Dacomitinib is the most recent EGFR inhibitor to be approved, and the fifth drug in the United States approved for use in this class. Similar to the others, it is approved in the first-line setting for patients with exon 19 and 21 mutations . However, the toxicity profile is generally worse than the other EGFR inhibitors, so use of the drug may be limited. Icotinib is approved only in China at this time and is used as first-line therapy for those patients harboring EGFR mutations as well. See Table 3.1 for a list of EGFR inhibitors used in NSCLC and their dosing schedules.
Toxicities of EGFR Inhibitors
Side effects from EGFR inhibitors are quite similar across all generations but their intensity varies. It is important to understand the pathophysiology of EGFR inhibitors in order to appropriately understand the timing and treatment of their side effects. The role of the epidermal growth factor receptor is to stimulate the growth of the epidermis, inhibit differentiation, and accelerate wound healing. When this is inhibited there is a lack of cellular turnover leading to increased inflammation and dermal injury . The acneiform or papulopustular rash is seen in varying percentages of patients receiving EGFR inhibitors, but can be common and frequent depending on the drug. See Table 3.2 for a list of the drugs and the likelihood of rash development. The rash can occur between 2 days and up to 6 weeks post commencement of EGFR inhibitor therapy . As a result of the time interval most providers will follow up with patients approximately 2 weeks post treatment initiation to evaluate for any cutaneous toxicities. Table 3.1 EGFR inhibitors in NSCLC
EGFR inhibitor Gefitinib Erlotinib Afatinib Osimertinib Dacomitinib
Table 3.2 EGFR inhibitor rash [7, 8, 10, 11]
EGFR inhibitor Gefitinib Erlotinib Afatinib Osimertinib Dacomitiniba
Dose and schedule 250 mg daily with or without food 150 mg daily without food 40 mg daily without food 80 mg daily with or without food 45 mg daily with or without food
Any grade rash (%) 66 85 89 58 69
Package insert for dacomitinib
Grade 3/4 rash (%) 3 14 16 1 23
M. M. Turner and B. Eaby-Sandy
Table 3.3 CTCAE grading criteria for Rash  Grade 1 – Less than 10% of the body surface area is covered in papules or pustules (or both), which may or may not be associated with symptoms of tenderness or pruritus Grade 2 – Between 10% and 30% the body surface area is covered in papules or pustules (or both), which may or may not be associated with symptoms of tenderness or pruritus – Associated with psychosocial impact – Limits instrumental activities of daily living Grade 3 – More than 30% of the body surface area is covered in papules or pustules (or both) which may or may not be associated with symptoms of tenderness or pruritus – Associated with local superinfection, with oral antibiotics indicated. Limits self-care activities of daily living Grade 4 – Any percentage of the body surface is covered in papules or pustules (or both), which may or may not be associated with symptoms of tenderness or pruritus – Associated with extensive superinfection, with intravenous antibiotics indicated. Life-threatening consequences Grade 5 – Death
The rash induced by EGFR inhibitors can be pruritic, painful and can cover the whole body in some patients, however the majority of patients typically develop rash on the face, neck, upper chest, back, and scalp . Grading of the acneiform rash can be difficult due to the patient’s subjective analysis of the toxicity. As a result of this, the Common Toxicity Criteria Adverse Events (CTCAE) grading system can be helpful to appropriately grade the rash, thus leading to effective therapy, see Table 3.3. Examples of the various grades of rashes can be seen in Fig. 3.1. Management of the EGFR inhibitor acneiform rash can be challenging, however with close follow-up post initiation of therapy the severity of the toxicity can be significantly diminished. Due to increased dermal dryness, ensuring that the skin is well moisturized with thick, non-fragrant emollient creams is important. Photosensitivity can occur so avoidance of the sun and aggressive use of sunscreen and clothing covering the skin can be beneficial. Prevention of rash utilizing oral doxycycline and topical hydrocortisone at the onset of EGFR inhibitor therapy has been studied in colon cancer patients receiving the EGFR monoclonal antibody panitumumab. The study did show a decrease in the overall severity of rash and improvement in quality of life, however, did not decrease the incidence of developing rash . Also, there were several challenges with patient compliance using the pre-emptive topical therapy recommended by the study. There have been several rash management algorithms for treatment of EGFR inhibitor rash discussed in the literature. The Multinational Association for the Supportive Care in Cancer (MASCC) skin toxicity study group developed evidence- based and expert-based guidelines demonstrated in Table 3.4.
3 Nursing Considerations with EGFR Inhibitors in NSCLC Grade 2
21 Grade 3/4
Fig. 3.1 Images of varying grades of acneiform rash related to EGFR inhibitors. Photos courtesy of Beth Eaby-Sandy, MSN, CRNP. Abramson Cancer Center, University of Pennsylvania
Table 3.4 Adapted from the MASCC skin toxicity study group EGFR clinical practice guidelines treatment of rash  Topical
Recommended Alclometasone 0.05% cream Fluocinonide 0.05% cream twice daily Clindamycin 1% Doxycycline 100 mg twice daily Minocycline 100 mg daily Isotretinoin at low doses 20–30 mg/day
Not recommended Vitamin K1 cream
Photosensitizing agents Doxycycline is preferred in patients with renal impairment. Minocycline is less photosensitizing
In addition to the acneiform rash, other dermatologic side effects that can occur include but are not limited to paronychia and fissuring at the finger tips and toes, hair changes, xerosis, and mucositis. Many of these mentioned toxicities wax and wane and have variable times to onset. Paronychia, or swelling around the nail beds, occurs in about 6–12% of patients . It is usually not bacterial but rather inflammatory, and in the event there is an open wound, the practitioner can culture and treat any organism that may be growing. They can occur on the fingernails or toenails. Often, they occur on toenails when shoes are too tight or there is friction, see Fig. 3.2 for examples. Management of paronychia includes topical corticosteroids, topical calcineurin inhibitors, systemic steroids, and/or systemic antibiotics (tetracyclines). Bleach soaks at a 0.005% concentration (1/4–1/8 cup for 3–5 gallons of water) may help to prevent paronychia, and for more advanced cases that are resistant, silver nitrate cauterization or nail avulsion may be necessary . Fissures in the skin, mostly commonly fingertips and the heels, are cracks in the skin when it becomes very dry. Figure 3.3 is an example of a fissure in a patient
M. M. Turner and B. Eaby-Sandy
Fig. 3.2 Examples of paronychia on the toenails. Photographs courtesy of Beth Eaby-Sandy, MSN, CRNP. Abramson Cancer Center, University of Pennsylvania Fig. 3.3 Fissure. Photographs courtesy of Beth Eaby-Sandy, MSN, CRNP. Abramson Cancer Center, University of Pennsylvania
taking an EGFR inhibitor for lung cancer. Recommendations for management of fissuring would be thick moisturizing creams as well as products to seal the crack to avoid infection such as liquid glues. When applicable, the provider can also use steroid tapes, hydrocolloid dressings, topical antibiotics, and diluted bleach soaks (see paronychia recommendations for the ratio) . Xerosis and pruritus are also common toxicities of EGFR inhibitors which can be cumbersome to patients. Prevention is key to minimizing this. Avoiding hot showers, using bath oils instead of drying soaps, and using thick emollient creams are good prevention mechanisms. If the pruritus is interfering with quality of life, antihistamines and topical steroids can be employed . Several hair abnormalities can be associated with EGFR inhibitor therapy. One of the more common is hypertrichosis of the eyelashes, which is often a cosmetic
3 Nursing Considerations with EGFR Inhibitors in NSCLC
Fig. 3.4 Hypertrichosis of the eyelashes. Photographs courtesy of Beth Eaby- Sandy, MSN, CRNP. Abramson Cancer Center, University of Pennsylvania
interference, however should be managed due to the potential for ocular irritation. This side effect is typically seen after several months of being on EGFR inhibitor therapy, see Fig. 3.4. Trimming the eyelashes is recommended but should be done with extreme caution and referral to an ophthalmologist is often necessary. Aberrant hair growth on the face, thick and matted hair on the head, and scalp irritation are also common. For scalp irritation, selenium-based shampoos or steroidal shampoos may be recommended . Mucositis is a less common side effect and though it occurs in 2–36% of patients, it is often mild or moderate . Treatments may include topical steroid rinses and pain control with oral pain medications though there is little evidence to support these recommendations and they are widely based on radiation mucositis experience . Interstitial lung disease (ILD) or pneumonitis occurs rarely, in less than 5% of patients, however, it can be fatal and should be detected and managed quickly. It is a class effect of all EGFR TKIs and often presents with acute onset of shortness of breath and/or worsening constant dry cough. A computed tomography (CT) scan of the chest should be performed to evaluate for all causes of these symptoms. Patients should be educated to call immediately for new onset or worsening of existing shortness of breath and that it could be an ILD reaction to the EGFR inhibitor. If ILD occurs, the EGFR inhibitor must be immediately stopped and permanently discontinued, and the ILD treated accordingly, which is usually with high dose corticosteroids. Transaminitis, or elevated liver function tests, may occur and again, are a class effect of the TKIs. Dose reductions are uncommon with EGFR inhibitors due to transaminitis, however, refer to each drug’s package insert for recommendation of when you may need to hold drug. Often, holding drug and restarting at the same dose can be a reasonable management strategy. Remember to evaluate blood work periodically on patients receiving EGFR inhibitors. The most common non-dermatologic toxicity that can occur with EGFR inhibitors is diarrhea which can be significant and require dose modification. Table 3.5 gives the incidence of diarrhea of each EGFR inhibitor. Workup should rule out other causes such as checking a stool sample for Clostridium difficile when s uspected or any parasite if indicated based on patient history.
M. M. Turner and B. Eaby-Sandy
Table 3.5 Diarrhea incidence of EGFR inhibitors [7, 8, 10–12] Drug Gefitinib Erlotinib Afatinib Osimertinib Dacomitinib
Diarrhea all grades (%) 46 52 95 58 87
Diarrhea grade 3/4/5 (%) 3.8 5 14 2 9
Recommendations for management of diarrhea induced by EGFR inhibitors can vary based on the severity. For mild diarrhea : • drinking 8 oz. fluid/day (including but not limited to water, electrolyte drinks, chicken or beef broth) • intermittent loperamide or loperamide 4 mg, followed by 2 mg after every stool (or every 4 h in patients with a colostomy) until diarrhea-free for 12 h • consider holding EGFR therapy for several days (on case by case basis) until toxicity returns to baseline If diarrhea is severe or if diarrhea persists : • • • • •
give loperamide 2 mg every 2 h plus oral antibiotics hold EGFR therapy consider hospital admission consider Octreotide (subcutaneous short acting starting with 10–20 mg) intravenous fluids or intravenous antibiotics as indicated
To conclude, EGFR inhibitors are a mainstay of lung cancer treatment for those patients who harbor an EGFR mutation. These drugs have increased PFS that allows for patients to live a longer time with less symptoms due to their lung cancer as opposed to treatment with standard chemotherapy. Because the drugs are oral, there can be financial issues with copays, access issues with specialty pharmacies, and even compliance issues with forgetting to take the pills. Side effect profiles are similar throughout the different drugs approved, however, they vary in incidence, and choosing the right medication requires knowledge of their efficacy and side effect profiles. Nurses are often the first line of communication with patients experiencing side effects from cancer treatments, including EGFR inhibitors. Rash and diarrhea are the most common side effects of EGFR inhibitors, but there are several management strategies that may be recommended to mitigate these toxicities. With the proper knowledge base and resources, nurses can help patients stay on therapy and maintain a good quality of life on EGFR inhibitor therapy.
3 Nursing Considerations with EGFR Inhibitors in NSCLC
References 1. Cancer facts & figures 2019. American Cancer Society Web site. https://www.cancer.org/ content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf. Accessed 29 Jan 2019. 2. Melosky B. Supportive care treatments for toxicities of anti-EGFR and other targeted agents. Curr Oncol. 2012;19(Suppl 1):S59–63. https://doi.org/10.3747/co.19.1054. 3. Harari PM. Epidermal growth factor receptor inhibition strategies in oncology. Endocr Relat Cancer. 2004;11(4):689–708. 4. Tsao AS, Tang XM, Sabloff B, et al. Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer. J Thorac Oncol. 2006;1:231–9. 5. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. Version 2.2019. National comprehensive Cancer Network Web site. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Published 21 Nov 2018. Accessed 15 Jan 2019. 6. Kuan F-C, Kuo L-T, Chen M-C, et al. Overall survival benefits of first-line EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancers: a systematic review and meta- analysis. Br J Cancer. 2015;113:1519–28. 7. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:10. 8. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first- line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–46. 9. Yang JC-H, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-lung 2, LUX-lung 3, and LUX-lung 6. Lancet Oncol. 2015;16:830–8. 10. Sequist LV, Yang JC-H, Yamamoto N, et al. LUX-Lung 3: phase III study of afatinib or cisplatin plus pemetrexed in patients EGFR mutations. J Clin Oncol. 2013;31:3327–34. 11. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–25. 12. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHEL 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454–66. 13. Fabbrocini G, Panariello L, Caro G, Cacciapuoti S. Acneiform rash induced by EGFR inhibitors: review of the literature and new insights. Skin Appendage Disord. 2015;1:21–37. 14. United States, Department of Health and Human Services, National Institutes of Health, National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events (CTCAE). Ver. 4.03. Bethesda, MD. 2010. Available online at: http://evs.nci.nih.gov/ftp1/CTCAE/ CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf; cited 29 Apr 2012. 15. Hirsh V. Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced non-small- cell lung cancer. Curr Oncol. 2011;18:126–38. 16. Lacouture ME, Anadkat MJ, Bensadoun R-J, Bryce J, Chan A, Epstein JB, Eaby-Sandy B, Murphy BA. Clinical practice guidelines for the prevention and treatment of EGFR-associated dermatologic toxicities. Support Care Cancer. 2011;19:1079–95. 17. Lynch TJ, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12:610–21.
Nursing Considerations with ALK and ROS1 Inhibitors in NSCLC Beth Eaby-Sandy
Anaplastic lymphoma kinase (ALK) and the ROS1 gene are driver mutations that have been identified in non-small cell lung cancer (NSCLC) patients, almost exclusively in the adenocarcinoma histology subtype. They are most commonly found in patients with distant or never smoking histories. While they are generally uncommon, ALK+ NSCLC still accounts for more than 3500 new cases per year in the United States and ROS1+ NSCLC accounts for about 500–1000 new cases per year . The overall prognosis tends to be longer for these patients given the potential options for treatment that yield overall better outcomes than traditional treatments for metastatic NSCLC.
ALK Positive NSCLC
The echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion is a gene translocation found in about 4–6% of adenocarcinoma histology NSCLC cases . It is most common in patients with a never smoking history and tends to affect a generally younger population of patients than traditional NSCLC. In one study, patients with NSCLC, adenocarcinoma subtype, who were never smokers and did not have an epidermal growth factor receptor (EGFR) mutation, showed a frequency of 33% ALK positivity . The ALK mutation drives cancer growth. It is an inversion of chromosome 2 that contrasts the EML4 gene with the ALK gene resulting in the fusion oncogene EML4-ALK . For convenience, it is also often referred to as “ALK positive” B. Eaby-Sandy (*) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 M. Davies, B. Eaby-Sandy (eds.), Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners, https://doi.org/10.1007/978-3-030-16550-5_4
Table 4.1 ALK inhibitors Drug Crizotinib
Approved dose 250 mg twice a day
Ceritinib Alectinib Brigatinib
450 mg daily 600 mg twice a day 90 mg daily × 7 days, then 180 mg daily 100 mg once a day
Dose formulations 250 mg, 200 mg 150 mg 150 mg 180 mg, 90 mg, 30 mg 100 mg, 25 mg
Indication ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC after progression or intolerance to crizotinib ALK+ NSCLC after progression on crizotinib + another ALK inhibitor or after progression on ceritinib or alectinib
NSCLC. Testing for the EML4-ALK fusion can be performed using immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), DNA sequencing, as well as detection on liquid biopsy panels. Several ALK targeted treatments have emerged in the past 5–10 years and have dramatically improved survival in this population of patients. There are currently five approved drugs to treat ALK positive NSCLC. They are all oral tyrosine kinase inhibitors that act on the ALK gene to disrupt downstream signaling to promote cancer cell death. See Table 4.1 for a list of the drugs and their dosing schedules.
4.2.1 Crizotinib Crizotinib was the first drug to be approved for the treatment of ALK positive NSCLC. In 2010, the first major paper was published showing a 53% response rate and a 90% disease control rate (both response and stable disease), with a median duration of response of over 6 months . This was followed by two studies of crizotinib versus chemotherapy in ALK positive patients, one in the first-line treatment setting and one in the second-line setting after progression on chemotherapy. In both studies, crizotinib was significantly superior to standard chemotherapy [6, 7]. For many years crizotinib was the standard first-line treatment for ALK positive NSCLC, however, more recently, Alectinib has shown superiority in the first-line setting .
4.2.2 Ceritinib Ceritinib was the second ALK inhibitor to be approved in the United States for treatment of ALK positive NSCLC. Originally it was approved as a second-line treatment post failure of crizotinib, based on data from the ASCEND-1 and the ASCEND-5 studies. ASCEND-1 showed that after progression on crizotinib, 56%
4 Nursing Considerations with ALK and ROS1 Inhibitors in NSCLC
of patients had a response to the ceritinib . ASCEND-5 further confirmed this data in a randomized fashion of ceritinib versus chemotherapy in the setting of progression on crizotinib and platinum-based chemotherapy, showing superiority of ALK therapy with ceritinib over single agent chemotherapy . This was then followed by the ASCEND-4 study comparing first-line ceritinib to platinum-based chemotherapy in ALK positive NSCLC patients, which showed a benefit in favor of the ceritinib over chemotherapy with a progression free survival (PFS) of 16.6 months versus 8.1 months respectively . However, the approved dose of 750 mg per day on an empty stomach demonstrated significant gastrointestinal (GI) toxicities, namely diarrhea in 85% and vomiting in 66% of patients . Given the substantial toxicities with ceritinib, recently, a dose of 450 mg daily with food showed biosimilarity to the 750 mg daily dose, with much less GI toxicity, thus, this has now become the standard dosing.
4.2.3 Alectinib The third ALK inhibitor to gain approval in the United States is alectinib, which is currently considered the preferred first-line standard of care for ALK positive NSCLC. It was initially approved as a second-line treatment post crizotinib failure based on a 48% response rate in that setting . However, the groundbreaking ALEX trial looking at first-line alectinib versus crizotinib in ALK positive NSCLC showed a median PFS of 25.7 months versus 10.4 months in favor of the alectinib . Another provocative finding in the ALEX study was the response in central nervous system (CNS) metastases, with 81% of patients in the alectinib arm having shrinkage of CNS tumors, 8% with complete response in the CNS and the median duration of response lasting 17.3 months. This was significantly higher than the crizotinib arm and introduced the idea that this new generation ALK inhibitor had superior CNS penetration over those before it.
4.2.4 Brigatinib Brigatinib was the fourth ALK inhibitor to be approved in the ALK positive NSCLC disease state. This drug is currently approved in the second-line setting post failure of crizotinib, with a 54% response rate on the 180 mg dosing arm . Like alectinib, brigatinib also shows a significant intracranial response for patients with CNS metastases. The response rate in the CNS with brigatinib was 67% and the most recent follow-up data demonstrated a median 16.6 month duration of response . Studies are ongoing evaluating the use of brigatinib in the first-line ALK positive NSCLC setting. Due to higher than anticipated rates of pneumonitis within days of starting brigatinib, the drug is approved with a run-in dose of 90 mg daily for 7 days. If the patient does not develop pneumonitis, they can then escalate the dose to 180 mg going forward.
4.2.5 Lorlatinib Approved in November 2018 for ALK positive NSCLC, Lorlatinib in phase I studies showed promising data in patients who had already failed 2 or more ALK inhibitors, with a response rate of 42% in this heavily pretreated population . This was followed by a further study of lorlatinib in either first, second, or third line therapy for ALK positive NSCLC patients, showing consistently significant responses in all three cohorts as well as significant CNS penetration and responses in all 3 cohorts .
ROS1 Positive NSCLC
C-ros oncogene 1 (ROS1) encodes a receptor tyrosine kinase similar to the EML4- ALK gene rearrangement in NSCLC. The ROS1 rearrangement is a driver mutation found in about 1% of patients with NSCLC. It can become activated by a gene rearrangement that leads to fusion of ROS1 and other partner proteins, which then can drive cancer growth . ROS1 gene rearrangements are most commonly found in patients who are never or former distant smokers, are more common in women than men, and are found in a younger population than traditional NSCLC . ROS1 rearranged NSCLC is also less likely to spread outside of the lung, including less frequency of brain metastases as compared to traditional metastatic NSCLC . As with ALK positive patients, ROS1 patients are almost exclusively found in NSCLC patients with adenocarcinoma histology. Like ALK, testing can be performed using IHC, FISH, or DNA sequencing testing as well as liquid biopsy specimens. There is only one drug currently approved to target ROS1 positive NSCLC, however, there are several targeted therapies under evaluation in clinical trials, see Table 4.2. Table 4.2 Clinical trials for ROS1 positive NSCLC  Therapy Lorlatinib (PF-06463922) Crizotinib Ceritinib + Trametinib SBRT Cabozantinib AT13387 +/− Crizotinib Entrectinib (RXDX-101) DS-6051b TPX-0005 PF-02341066
Setting First or second line for metastatic disease Neoadjuvant Several lines of treatment for metastatic disease Metastatic Metastatic Metastatic, first line
Specifics Non-measurable CNS metastatic disease Prior to definitive surgery Phase I/II Adding SBRT to treatment Can already be on crizotinib
Second line Second line and beyond First line or after chemo/ immunotherapy Any line
Phase 1/first in human Phase I/II Phase I
4 Nursing Considerations with ALK and ROS1 Inhibitors in NSCLC
4.3.1 Crizotinib Crizotinib is the only approved treatment for ROS1 positive metastatic NSCLC. This is based on a study published in 2014 of 50 patients treated with crizotinib after testing positive for ROS1. Some patients had several lines of previous treatments, while only seven patients were treatment naïve. Response rates were 72% with a median PFS of 19.2 months . Based on these significant response rates and PFS, which are far superior to traditional chemotherapy in NSCLC, the drug was approved and is considered standard of care for first-line treatment of ROS1 rearranged NSCLC. Adverse events were similar to what had been seen in other clinical trials of crizotinib, with most common adverse events (AEs) being visual impairment, diarrhea, nausea, peripheral edema.
4.3.2 Other Treatments Resistance mutations have been identified in ROS1 rearranged patients who have failed crizotinib, though at this time, there are no approved agents to target these resistance mechanisms . Ceritinib has been studied in a phase II trial of patients with a ROS1 rearrangement. In 28 evaluable patients, after failure of either chemotherapy or crizotinib, 62% of patients had a response and an 81% disease control rate, only 2 patients had progressive disease . However, in more recent data, both ALK inhibitors ceritinib and brigatinib appear to only have limited activity in crizotinib-resistant ROS1 rearranged NSCLC .
Toxicities and Management of ALK/ROS1 Inhibitors
Unlike several other targeted therapies, where the majority of drugs in the same class have similar toxicity profiles, the ALK inhibitors tend to have unique toxicities individual to the respective drug. There are some toxicities that are similar across the approved agents, however, they can vary in incidence and grade.
4.4.1 Pneumonitis Pneumonitis is an inflammation of the lungs, often induced as a drug reaction or drug toxicity. It is also sometimes referred to as interstitial lung disease (ILD). This is a class effect of many of the tyrosine kinase inhibitors (TKIs) in NSCLC, whether ALK or EGFR inhibitors. Table 4.3 is a representation of the rates of pneumonitis by drug. While not the most common toxicity, it is the most life threatening, where 65% of reported cases were a grade 3/4 with up to a 9% mortality rate . It is very important to catch pneumonitis as early as possible and manage with high
32 Table 4.3 Rates of pneumonitis per package inserts
B. Eaby-Sandy Drug Crizotinib Ceritinib Alectinib Brigatinib Lorlatinib
Rate of pneumonitis (%) 2.9 2.4 0.4 9.1 1.5
Fig. 4.1 Image on the left is the baseline CT scan prior to starting crizotinib. Image on the right is a CT scan about 10 days after starting crizotinib therapy showing a grade three pneumonitis
dose corticosteroids and a prolonged taper schedule. Pneumonitis is a toxicity that is recommended to permanently discontinue the drug, with the caveat of brigatinib. In the brigatinib study  most pneumonitis occurred between days one through nine after starting drug. In this study, drug was held until pneumonitis resolved and the drug was able to be restarted successfully in half of these patients with a dose reduction. This is the reason for the run-in dosing schedule starting at 90 mg daily and then after 7 days, increasing to 180 mg daily for those patients who do not develop pneumonitis. Presentation of pneumonitis is usually an acute worsening in shortness of breath over a quick timeframe, usually over a couple of days. The patients are often hypoxic and have a frequent, dry, nagging cough. Any patient calling in with this symptom should be evaluated immediately in the office or emergency room. Workup would include vital signs with pulse oximetry followed by computed tomography (CT) chest. Chest X-ray will usually not show the diffuse pattern of pneumonitis. CT chest will often be ordered with contrast to rule out pulmonary embolism, however, pneumonitis can be seen with or without the contrast in a CT chest. Figure 4.1 is a typical radiographic presentation of drug-induced pneumonitis from a patient on crizotinib.
4 Nursing Considerations with ALK and ROS1 Inhibitors in NSCLC
Treatment for pneumonitis is immediate discontinuation of drug followed by management of symptoms, often requiring high dose corticosteroids in patients exhibiting shortness of breath or symptoms associated with the pneumonitis. Often, these patients require hospitalization for respiratory supportive care until they are stabilized.
4.4.2 Fatigue Fatigue is one of the most common side effects associated with the ALK inhibitors. The etiology is not exactly known, it generally does not correlate with lab abnormalities, such as anemia, or decrease in nutrition. Treatment can be centered around encouraging activity or exercise as well as physical therapy referrals for any physical deficits .
4.4.3 Visual Disturbances There is a unique side effect of crizotinib only. It is very common, occurring in 41–71% of patients in the registrational clinical trials [4, 5]. No patients required dose reduction or holding drug. It is described by patients as a difficulty accommodating to light when going from a dark to light room. They describe it as a trailing of light behind objects. It is important to educate patients that this is likely to happen, it is not causing damage to the eye, and it often resolves after several months on the drug. One caution for patients is that they may want to avoid driving at night due to the visual disturbance being exacerbated by oncoming headlights of another car. Of note, visual disturbances were also reported in brigatinib studies, however, it was rare, and described as blurred vision or diplopia. This is not to be confused with the common crizotinib phenomenon.
4.4.4 GI Toxicities Nausea is a common toxicity seen with the ALK inhibitors, more often than EGFR TKIs used in NSCLC. Ceritinib at its original approved dose of 750 mg daily had a high rate of nausea and vomiting, 83% and 61%, respectively . However, with the lower approved dose of 450 mg daily and the ability to take it with food has lowered the incidence of nausea and vomiting. Both crizotinib and ceritinib are listed in the NCCN guidelines as moderate to high potential for nausea and vomiting for oral anticancer agents. Treatment for nausea can be tricky with these agents given that they are dosed every day with no breaks in treatment. Using oral antiemetics should be based on the potential for drug interactions and side effects of the antiemetics, because the patient will likely need to take it daily. More study is needed in this area.
Diarrhea is also a common toxicity of the ALK inhibitors, though constipation is also reported. Neither is generally associated with dose reductions or dose delays, other than with ceritinib, where dose reductions were common for diarrhea. Again, as seen with nausea, ceritinib particularly has a very high rate of diarrhea, though less now with the lower dosing approved. Treatment is standard antidiarrheals such as loperamide, or in more severe or refractory cases, diphenoxylate/atropine.
4.4.5 Cardiovascular Toxicities Bradycardia is a common class effect that has been seen in most of the ALK inhibitors, though the mechanism is not well known. Practitioners should first search for other causes, such as co-administration of beta-blockers. While many patients may be asymptomatic, onco-cardiology evaluation should be considered to rule out complications such as heart block or prolonged QTc interval. If symptomatic, hold drug until HR rises above 60 beats per minute (BPM), then resume at a reduced dose . If a concomitant drug is contributing, and that drug can be modified or discontinued, you may consider resuming the dose of the ALK inhibitor at full dose. Hypertension was mostly seen in brigatinib clinical trials, where it occurred in about 21% of patients at the approved dosing schedule, with 5.9% grade three requiring a dose reduction. Most often, traditional antihypertensives can control the hypertension and patients can remain on ALK-directed therapy. Edema, more generalized than of cardiac origin, was mostly seen in patients receiving crizotinib, occurring in about 28–38% of patients, but extremely rare to cause dose reductions. Nurses should assess for and educate patients that this could be a side effect of their ALK inhibitor therapy. Cardiac causes such as heart failure should be ruled out. Otherwise, interventions such as elevation of lower extremities or compression stockings may be used to minimize the edema. Diuretics should be used sparingly as it is not generally cardiac related. QTc interval prolongation is commonly seen with many anticancer drugs and common with the TKIs in NSCLC. It has been reported in the ALK trials. As with other drugs, providers should check for concomitant medications that may be contributing and offer alternatives to the concomitant medication prior to dose reducing the ALK inhibitor. Ondansetron is a common offender in oncology patients. A general treatment strategy across the TKIs is that if the QTc interval is more than 500 ms, drug should be held until this interval measures less than 481 ms, in which drug can be restarted with a dose reduction .
4.4.6 Laboratory Abnormalities Transaminitis or liver function test (LFT) abnormalities are also a common toxicity across oral TKIs in NSCLC and have been reported in all ALK inhibitor trials. Patients are rarely symptomatic and often this is just picked up on routine blood
4 Nursing Considerations with ALK and ROS1 Inhibitors in NSCLC
tests. Grading of LFT abnormalities varies based on the actual test, but if a patient develops significant LFT abnormalities, drug should be held in concordance with the package insert and only resumed at either same dose or dose reduction once the levels return to grade one or lower. Creatinine phosphokinase (CPK) elevations were mostly reported in patients taking alectinib and brigatinib. Alectinib trials reported 26% of patients complaining of symptoms of myalgia or muscle pain. Actual CPK elevations occurred in 41% of patients, with 4% reported to be grade 3/4. In patients taking brigatinib, 48% developed elevated CPK and 4.5% required dose reductions. Nurses should advise patients to report muscle pain and weakness, however, many patients with elevated CPK levels do not experience symptoms, so routine blood monitoring is recommended. Hyperglycemia and pancreatitis are uncommon but reported across the ALK inhibitors. Both should be monitored for and tested in patients in particular who exhibit clinical symptoms. Hypercholesterolemia is uniquely reported in clinical trials with lorlatinib, and is one of the most common toxicities of this drug, occurring in 81% of patients, and 15% grade 3/4 . Management at this time is being explored, with considerations of diet modification, cholesterol-lowering medications, and dose reductions of the lorlatinib when needed.
4.4.7 Other There is a unique side effect to lorlatinib that manifests as changes in cognitive function, including hallucinations, mental status changes, and even suicidal ideations. Per the lorlatinib package insert, these cognitive effects occurred in 29% of patients, some of which required dose reductions, but rarely discontinuation of drug. Patients and caregivers especially should be warned about this potential side effect and discuss the severity with the provider and ability to maintain quality of life while on the drug.
ALK and ROS1 inhibitors for NSCLC have been approved at a rapid pace in the past 5–10 years. While it is a small population of patients, these drugs are highly targeted and active at treating patients who harbor these mutations with NSCLC. While they are generally well tolerated, there are certain important toxicities that can be life threatening, such as ILD. Nurses need to educate patients on these potential toxicities and how to contact their healthcare team. Since these drugs are also administered orally, nurses must provide patients with tools to remember to adhere to the medications, especially with many of the drugs requiring multiple tablets at multiple doses throughout a day. All healthcare providers must continue to aggressively seek continuing education to remain knowledgeable on the new drugs available for patients with NSCLC.
References 1. American Cancer Society Facts & Figures 2019. https://www.cancer.org/research/cancer-factsstatistics/all-cancer-facts-figures/cancer-facts-figures-2019.html. Accessed June 15, 2019. 2. Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer. 2013;82:179–89. 3. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcomes of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27(26):4247. 4. Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res. 2011;17(8):2081. 5. Kwak EL, Bang Y-J, Camidge R, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693–703. 6. Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77. 7. Shaw AT, Kim D-W, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK- positive lung cancer. N Engl J Med. 2013;368:2385–94. 8. Peters S, Camidge R, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377:829–38. 9. Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370(13):1189–97. 10. Shaw AT, Kim TM, Crino L, et al. Ceritinib versus chemotherapy in patients with ALK- rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;18:874–6. 11. Soria J-C, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open- label, phase 3 study. Lancet. 2017;389:917–29. 12. Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, non- small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet. 2016;17:234–42. 13. Kim D-W, Tisco M, Ahn M-J, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma-kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35:1–11. 14. Ou SHI, Tiseo M, Camidge DR, et al. Intracranial efficacy of brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase (AKL)-non-small cell lung cancer (NSCLC) and baseline CNS metastases. Poster presented at the Annual Congress of the European Society of Medical Oncology; 8–12, September 2017, Madrid. Poster 1345p. 15. Shaw AT, Felipe E, Bauer TM, Besse B, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18(12):1590–9. 16. Solomon BJ, Besse B, Bauer TM. Lorlatinib in patients with ALK-positive non-small cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654–67. 17. Lin JJ, Shaw A. Recent advances in targeting of ROS1 in lung cancer. J Thorac Oncol. 2017;12:161–1625. 18. Marchetti A, Barberis M, Di Lorito A, et al. ROS1 gene fusion in advanced lung cancer in women: a systematic analysis, review of the literature, and diagnostic algorithm. JCO Precis Oncol. 2017;1:1–9. 19. Gainor Justin F, et al. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer. JCO Precis Oncol. 2017;1:1–13.. https://doi. org/10.1200/PO.17.00063 20. Clinicaltrials.gov. Searched ROS1 rearrangement. Accessed 8 June 2018. 21. Shaw AT, Ou S-HI, Bang Y-J, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371(21):1963–71. 22. Lim SM, Kim HR, Lee J-S, et al. Open-label, multicenter, phase II study of ceritinib in patients with no-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol. 2017;35: 2613–8.
4 Nursing Considerations with ALK and ROS1 Inhibitors in NSCLC
23. Pellegrino B, Facchinetti F, Bordi P, Silva M, Gnetti L, Tiseo M. Lung toxicity in non-small- cell lung cancer patients exposed to ALK inhibitors: report of a peculiar case and systematic review of the literature. Clin Lung Cancer. 2018;19(2):e151–61.. https://doi.org/10.1016/j. cllc.2017.10.008 24. Jacky J, Baik C. Symptom management strategies for patients receiving anaplastic lymphoma kinase inhibitors for non-small cell lung cancer. J Adv Pract Oncol. 2017;8(7):729–35. 25. Kim D-W, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR, et al. Intracranial and whole-body response of ceritinib in ALK inhibitor-naïve and previously ALK inhibitor-treated patients with ALK-rearranged non-small-cell lung cancer (NSCLC): updated results from the phase 1, multicentre, open-label ASCEND-1 trial. Lancet Oncol. 2016;17(4):452–63. 26. Beardslee T, Lawson J. Alectinib and brigatinib: new second-generation ALK inhibitors for the treatment of non-small cell lung cancer. J Adv Pract Oncol. 2018;9(1):94–101. 27. Rothenstein JM, Letarte N. Managing treatment-related adverse events associated with ALK inhibitors. Curr Oncol. 2014;21(1):19–26.
BRAF in NSCLC Helen Shih
Abbreviations AEs CTCAE DOR IA IRC NSCLC PFS
Adverse events Common terminology criteria for adverse reactions Duration of response Investigator assessed Independent review committee Non-small cell lung cancer Progression free survival
verview and Mechanism of Action of BRAF O Mutations in NSCLC
The ability of our organs and tissues to maintain integrity is sustained by an elaborate network of genes that coordinate cellular proliferation, differentiation, and death. BRAF is a pathway that moderates cellular responses to growth signals. Mutations in this pathway can lead to cancer growth in NSCLC. BRAF in NSCLC is considered an oncogenic driver, which is almost always mutually exclusive from other activating mutations such as epidermal growth factor receptor (EGFR). The most common BRAF mutation, V600E (Val600Glu), is observed in 1–2% of lung adenocarcinomas. Half of BRAF mutations in NSCLC are BRAF V600E. BRAF inhibitors (BRAFi) plus MEK inhibitors (MEKi) are used for treatment in the first and second line settings in patients with BRAFV600E mutations in NSCLC. H. Shih (*) University of California, San Francisco, San Francisco, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 M. Davies, B. Eaby-Sandy (eds.), Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners, https://doi.org/10.1007/978-3-030-16550-5_5
More specifically, BRAF is an oncogenic driver mutation that results in the RAS- RAF- MEK-ERK-MAP (MAPK mitogen-activated protein kinase/ERK extracellular-signal-regulated kinase) pathway . Within the realm of molecular biology, the MAPK pathway is regarded as an original model for signal transduction. Many manifestations of MAPK are found in cells and have been examined thoroughly in a variety of organisms ranging from yeast to humans . RAS, RAF, MEK, ERK, and MAP are a chain of proteins that communicate by adding a phosphate group and then act as an “on” or “off” switch. When one of the proteins experiences a mutation (such as BRAF), the switch may become stuck in the on position, and the signal to enter the nucleus of the cell and transcription of DNA continues without a programmed stop . Phosphorylation occurs in response to a varied number of stimuli (i.e., cellular stress, cytokines, growth factors, neurotransmitters, and cell adherence). This pathway is critical to many vital cellular systems, encompassing cellular proliferation, differentiation, and death. It can also regulate the activities of enzymes, receptors, transporters, docking, and scaffolding proteins. BRAF encodes a well-sequenced serine/threonine kinase that mutates in the V600 position most common in melanoma, and other solid tumors (colon, thyroid, NSCLC) . The value of RAF inhibition in BRAF V600-mutant solid tumors has been well demonstrated in a study by Pratilas et al. This was studied in human cell lines in vitro . This MAPK pathway endorses one of the most standard signaling models found in a biological signal transduction. Namely this is a cycle that originates by a kinase which phosphorylates a target protein and then an opposing phosphatase that dephosphorylates the target .
Data for BRAF
Previously, studies in melanoma have found that the combination of dabrafenib, a BRAFi, plus trametinib, a MEKi, improves progression-free survival (PFS) and overall survival (OS) versus dabrafenib plus placebo in patients with BRAF V600E- mutant melanoma . In further randomized phase II and III trials in patients with BRAF V600E-mutant stage IIIC unresectable or stage IV metastatic melanoma , findings did confirm a benefit to PFS and OS. Though the majority of previous studies were based on melanoma findings, the mutational pathway functions in the same fashion, and results from melanoma were surmised to possibly apply to NSCLC and thus lead to study of this pathway in NSCLC. BRAFi and MEKi combinations have been researched as first line and second line treatments in patients with a BRAF V600E mutation in NSCLC. Prior to this, there had been few to no studies on the efficacy of combined BRAF and MEK inhibition in NSCLC [7, 8]. In Planchard et al. , all patients studied had been previously treated for their BRAFV600E metastatic NSCLC with chemotherapy. They received dabrafenib 150 mg twice a day and trametinib 2 mg once a day. This was a phase II, multicenter, non-randomized, open-label study, with pretreated metastatic stage IV BRAF V600E-mutant NSCLC. All participants had documented tumor progression
5 BRAF in NSCLC
after at least one previous platinum-based chemotherapy and had no more than three previous systemic anticancer therapies. Response was seen in 36 patients out of 57 evaluable patients. There were two patients that were able to achieve complete response and 34 with partial responses. Disease control, which was defined by (complete response/partial response/stable disease) was attained by 45 (78.9%) patients. No patients developed brain metastases over the course of the study. Median PFS was 9.7 months (range: 6.9–19.6). The safety profile documented in this study was equivocal to that for dabrafenib plus trametinib in patients with unresectable or metastatic melanoma. In a different, phase II study by Planchard et al. , patients with untreated metastatic BRAF V600E-mutant NSCLC received dabrafenib 150 mg twice a day, and trametinib 2 mg once daily. This trial was the first to examine the combination of BRAF and MEK inhibition in treatment naïve patients with BRAF V600E-mutant NSCLC. An overall response was seen in 23 patients (64%) including 2 patients (6%) who had a complete response. Four patients had stable disease, resulting in a 75% disease control rate. In light of these results, dabrafenib plus trametinib was FDA approved as a novel therapy for patients with BRAF V600E-mutant NSCLC, with substantial overall response rates, disease control rate, and manageable toxicity. This combination targeted therapy demonstrates superior response rates and disease control than standard chemotherapy in NSCLC, however, there is no head to head data for dabrafenib/ trametinib versus chemotherapy in BRAF mutated NSCLC. Future research will determine the sequencing of first line treatment with BRAF inhibitors and look at the combination targeted therapy plus or minus immunotherapy .
Toxicities and Management
The goal of targeted therapy in cancer is to prolong survival with minimal impairment of quality of life and avoid dose reduction or discontinuation. Drug related adverse events (AEs) require thorough and efficient management to ensure that patients elicit optimal benefit from therapy as well as safety. Of note, the combination of dabrafenib plus trametinib versus dabrafenib alone has been generally less toxic surprisingly. Proper management of drug-related AEs depends on an understanding of which AEs are most likely associated with BRAFi or MEKi, which can then lead to the correct dose modification of the appropriate drug . Additionally, the prevalence of some AEs differs depending on the single agent or combination being administered. The safety profiles of the regimen chosen may influence patient selection and monitoring .
5.3.1 Previously Treated Patients In Planchard et al.  study, there was permanent discontinuation in seven patients (12%), dose interruption or delay in 35 (61%), and dose reduction in 20 (35%).
Table 5.1 AEs in previously treated dabrafenib and trametinib  Pyrexia Nausea Vomiting Diarrhea Decreased appetite Asthenia Dry skin Peripheral edema Chills Cough Rash Arthralgia Constipation
Grade 1–2 (%) 25 (44) 23 (40) 20 (35) 18 (32) 17 (30) 16 (28) 14 (25) 13 (23) 12 (21) 12 (21) 11 (19) 11 (19) 10 (18)
Grade 3 (%) 1 (2) 0 0 1 (2) 0 2 (4) 1 (2) 0 1 (2) 0 1 (2) 1 (2) 0
Grade 4 0 0 0 0 0 0 0 0 0 0 0 0 0
Grade 5 0 0 0 0 0 0 0 0 0 0 0 0 0
Thirty-three patients (58%) received at least 80% of the planned dose of dabrafenib and 43 (75%) patients received at least 80% of the planned dose of trametinib. Nearly all patients had at least one adverse event (98%), and nearly half 49% had at least one grade 3/4 event. Table 5.1 displays that the majority of AEs experienced with dabrafenib and trametinib were grade 1–2.
5.3.2 Melanoma Patients Combination treatment with dabrafenib and trametinib was evaluated in various studies, with more data available in the melanoma population. Compared with patients who received single-agent dabrafenib, patients treated with combination dabrafenib plus trametinib experienced similar types of AEs . The most common AEs were pyrexia, chills, fatigue, headache, nausea, diarrhea, arthralgia, rash, and hypertension. As expected, established MEKi associated (trametinib) AEs were reported at a higher frequency with dabrafenib plus trametinib versus dabrafenib alone. These included peripheral edema (11–29% vs. 2%), decreased cardiac ejection fraction (4–9% vs. 3%), and acneiform dermatitis (6–16% vs. 3%). Conversely, known BRAFi-induced hyperproliferative skin lesions were reported less frequently with dabrafenib plus trametinib versus dabrafenib as a single agent (cutaneous squamous cell carcinoma (cuSCC)/keratoacanthoma (KA) [1–7% vs. 9–12%], papilloma [1–4% vs. 18–26%], and hyperkeratosis [4–9% vs. 33–41%]), as were pruritus (7–9% vs. 11%), palmar-plantar erythrodysesthesia (4–6% vs. 20–27%), and dry skin (8–9% vs. 13–14%) .
5.3.3 Pyrexia The incidence and grade of pyrexia in combination dabrafenib plus trametinib versus dabrafenib monotherapy was noticeably elevated (pyrexia, 52–71% vs. 25–33%;
5 BRAF in NSCLC
chills, 28–58% vs. 12–14%). Pyrexia was the most common AE leading to treatment alteration, including dose interruption (30–32%) and dose reduction (13–14%) as well as discontinuation (2–3%) . Pyrexia is episodic and was found to have a median time to onset of the first episode at 4.3 weeks. Relatively half of patients who experienced pyrexia had at least three episodes. Pyrexia was able to be managed in 97% of the patients who had a dose reduction or interruption during an acute pyrexia episode. The first episode lasts a median of 9 days and subsequent episodes lasting 4–5 days . Routine infectious workup is not recommended for patients with uncomplicated pyrexia without localizing symptoms since it is a known common toxicity of this drug regimen. Also, the dabrafenib and trametinib combination is not known to cause significant neutropenia nor febrile neutropenia, thus, it should not place patients at high risk for infection, as opposed to standard chemotherapy. Although pyrexia is commonly associated with BRAFi therapy, the level of pyrexia appears to be unique to combination dabrafenib plus trametinib. Symptoms that are likely to be associated with pyrexia include chills, night sweats, rash, dehydration, electrolyte abnormalities, and hypotension. Approximately 1/4 of patients experience associated symptoms without an elevated core body temperature. Clinical experience shows that pyrexia prophylaxis and management strategies require prompt interruption of both dabrafenib and trametinib at the first episode or associated symptom(s). Usually this results in rapid resolution of events, at which time both drugs can be safely restarted, often without dose reduction, about 24 h after complete resolution of the pyrexia . Though some treatment guidelines and prescribing information may suggest dose reduction/dose interruption, and in addition administering corticosteroids, acetaminophen, or nonsteroidal anti-inflammatory drugs, some of these strategies may not apply to real time experiences in the clinic. Per Daud and Tsai , clinical experience conveyed that dose reduction in complicated cases may not decrease the risk of pyrexia recurrence. Therefore, dose interruption is the preferred management plan. Though patients with prior pyrexia with complications, it may not be an effective prophylactic strategy. Taking into account current treatment strategies as well as clinical experience with these drugs, it is recommended that, for the initial management of pyrexia, therapy be withheld and then restarted at the same dose. In the case of pyrexia being a repetitive event, it has been determined that scheduled antipyretics (e.g., ibuprofen, acetaminophen) are effective, and recommend continuing them upon restarting therapy. If a patient’s body temperature does not return to baseline within 3 days after implementing these strategies, consider starting the patient on a limited burst of corticosteroids (e.g., prednisone 10 mg daily for 5 days) . Although it is optimal to re-introduce the BRAFi therapy at full dose, for these refractory cases, restarting at a lower dose and then attempting re-escalation to the full dose upon resolution of symptoms is helpful for pyrexia control. Please see Table 5.2. Permanent discontinuation of the drug is advised when a patient experiences fever events associated with refractory rigors, renal failure, or other serious AEs that occur despite the management strategies described above.
Table 5.2 Management of pyrexia, adapted from Daud and Tsai  Patient Education for Pyrexia  • Education on possible symptoms and timing during the course of treatment • Likely to occur during the first 30 days of treatment and median time of occurrence is 9 days – Following episodes are generally 4–5 days • Does NOT generally co-occur with sepsis Management per prescribing information • At initial sign of pyrexia (101.3–104 F, or 38.5–40 °C) – Withhold dabrafenib until fever resolves. Resume at the same dose • If fever is >104 or with rigors, hypotension, dehydration, or renal failure, withhold dabrafenib until fever resolves. May resume at lower dose or permanently discontinue • Recommend acetaminophen or NSAIDs for symptomatic management • Monitor serum creatinine and renal function during and after severe pyrexia • May consider secondary prophylaxis, if patient had a prior episode of high grade febrile reaction or fever with complications • Recommend corticosteroids (i.e., prednisone 10 mg daily) for at least 5 days for recurrent pyrexia if temperature does not return to baseline within 3 days of onset, or for pyrexia associated with complications, and no demonstration of infection Management per clinical experience • When initial sign of pyrexia, withhold dabrafenib and trametinib until the fever returns to baseline • Early intervention is crucial as there can be prompt resolution of events (usually within 24 h) • Dabrafenib and trametinib may be reinitiated safely 24 h after pyrexia resolves • Clinical experience supports holding treatment without a significant dose reduction as an optimal management plan – Dose reduction has not displayed risk reduction for recurrence of pyrexia • Recurrence can be managed best with corticosteroids and may avoid the need for dose reduction • Regular septic workup is not necessary for patient with uncomplicated pyrexia lacking localized infective symptoms • Recommend against antipyretics as a secondary prophylaxis measure
Recommended incremental dose adjustments for 150 mg → 100 mg → 75 mg. Recommended incremental dose adjustments 2 mg → 1.5 mg → 1 mg .
5.3.4 Cutaneous Skin Reactions Dermatologic AEs are considered a class effect of BRAFi and MEKi, although the type, extent, and etiology of the particular AE may vary for each distinct agent . General types of cutaneous toxicities commonly reported include rashes, skin irritations, acneiform dermatitis, hyperproliferative skin disorders, and photosensitivity. Remarkably, the combined regimen of MEKi and BRAFi using full doses of both agents appeared to generate fewer skin AEs and less toxicity compared with BRAFi
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monotherapy. Secondary skin malignancies with BRAFi treatment is due to an induced proliferation of cells carrying secondary mutations. BRAFi accelerate the growth of preclinical cancerous lesions as a paradoxical MAPK pathway is activated. When adding a MEKi, this paradoxical MAPK pathway activation is inhibited. Data from the COMBI-d double blind placebo controlled randomized phase III trial resulted in a reduced number of malignant and hyperproliferative skin lesions in combination therapy with dabrafenib/trametinib (2%) vs. dabrafenib monotherapy (9%) . It is important to perform a skin assessment to evaluate for secondary skin malignancies in patients receiving BRAFi therapy. In NSCLC, the recommended treatment for BRAF V600E positive disease is to be on the dual BRAFi plus MEKi therapy, therefore, the development of these secondary skin malignancies is uncommon. The recommendations per the drug’s package inserts are to refer to dermatology for a full skin assessment every 2 months. Having a dermatologist may be a good plan, however, a full skin assessment may also be done by the nurse or physician treating the patient, at the recommended 2-month interval. The lesions tend to appear in prior sun-exposed areas, such as the face, chest, and extremities, so are often visible, and also tend to be eruptive, which the patient is likely to notice. Patients should be educated on the rarity but possibility of these lesions and how to properly identify and notify the treating oncology team. The other skin AEs, such as skin rashes can have a debilitating effect on the quality of life for patients. In cases of patients with apparent skin toxicities, especially on exposed areas such as the face, stigmatization is a concern. Additionally, significant dermatologic AEs may lead to impairments in daily tasks for patients, specifically for those with hand and/or foot lesions. Therefore, proper proactive management of these cutaneous AEs is critical to avoid drug delays, interruptions, or discontinuations, and to limit their impact on quality of life . Guidelines for prophylaxis and management of cutaneous AEs have been recommended . Treatment is directed mainly at alleviating the symptoms, including the use of emollients, antihistamines, and analgesics; in rare cases, a short course of steroids may also be appropriate. For unbearable grade 2 or grade 3–4 cutaneous AEs, dabrafenib and trametinib alone or in combination should be withheld for ≤3 weeks. If the AE gradually improves, the drug(s) may be resumed at a lower dose; if the AE does not improve, the drug(s) should be permanently discontinued.
5.3.5 Hypertension Hypertension (HTN) is one of the most common serious AEs observed with trametinib. As seen in the METRIC trial, 12% of patients experienced grade 3–4 hypertension . In COMBI-d, frequency of any grade hypertension was reported in 14% of patients in the dabrafenib arm and 22% in the dabrafenib/trametinib arm . Please see Table 5.3 for suggested guidance on management of HTN per Welsh [9–11].
Table 5.3 Management of HTN with BRAFi and MEKi adapted from Daud and Tsai 
CTCAE definition (all in mm Hg) 
Prehypertension Systolic BP 120–39 Diastolic BP 80–89
• Continue both kinase inhibitors (KI) • Monitor BP every cycle
Stage 1 hypertension Systolic BP 140–159 Diastolic BP 90–99
Stage 2 hypertension Systolic BP ≥160 Diastolic BP ≥100
• Continue both KIs • Treat HTN according to the guidelines • If not improved to grade 1 or less despite antihypertensive treatment, then reduce dose of MEKi • Target BP to grade 1 or less
• Stop MEKi • Treat HTN according to guidelines • Target BP to grade 1 or less • Target BP to grade 1 or less • IF BP improves to grade 1 or less, restart MEKi and a lower dose • If BP does not improve or HTN recurs, lower dosing a second time, if recurs a third time, discontinue
Life threatening consequences Defined as malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis • Stop KI • Permanently discontinue MEKi • Treat HTN according to guidelines
5.3.6 LVEF Left ventricular dysfunction (LVEF)/QTc prolongation are additional cardiotoxicities that may occur with dabrafenib/trametinib. Earlier trials of trametinib revealed that 8% of patients experienced LVEF . LVEF being defined as an absolute decrease of 10% compared with baseline of that institution’s definition of lower limit of normal. Yet, few events were deemed to be directly related to trametinib and any decrease in LVEF was not symptomatic. Thirty-one percent of patients were reported to experience significant peripheral edema, in Flaherty et al.  though this was not reported in the COMBI-D trial [5, 6]. Different guidelines may have different management strategies. For instance, in Welsh and Corrie  there is a recommendation of a standard cardiac workup including an echocardiogram. However, if a patient has symptoms of heart failure or peripheral edema (Czupyrn and Cisneros ), CTCAE  suggests the full cardiac workup (consisting of
5 BRAF in NSCLC
Table 5.4 Suggested management of reduced left ventricular ejection fraction (LVEF), adapted from Daud and Tsai  GRADE LVEF
Grade 1 or 2
Asymptomatic, absolute decrease in LVEF =10-20% from baseline that is below LLN.
Refractory or poorly controlled heart failure due to drop in ejection fraction, intervention such as ventricular assist device, intravenous vasopressor support, or heart transplant indicated.
Recommendation Withhold Kinase Inhibitor for up Permanently to 4 weeks; Remeasure LVEF; Discontinue if improved to near normal value, resume at lower dose level; if not improved to normal after 2 dose reductions, permanently discontinue
cardiac enzymes, complete blood count, complete metabolic panel, brain natriuretic peptide, C-reactive protein, and chest radiograph) plus echocardiogram. Table 5.4 represents the guidelines per the Welsh article .
5.3.7 QTc Prolongation Exposure-dependent QTc is rarely associated with BRAFi, but does occur more in patients with another BRAFi named vemurafenib. Grading of QTC is seen in Table 5.5. Trametinib is not associated with increased risk of QTc prolongation as a single agent, but the risk remained at 3%, when combined with dabrafenib. It is recommended to use dabrafenib with caution in patients with untreatable electrolyte abnormalities, long QT syndrome or those who are taking other products known to prolong the QT interval. Per Welsh and Corrie  it is also recommended that ECG and electrolytes be measured in all patients prior to initiating treatment with BRAFi.
Table 5.5 Adapted from CTCAE grading scale Grade 1 (mild) QTc of 450–480 ms
Grade 2 (moderate) QTc 481–500 ms
Grade 3 (severe) QTc of 501 ms or greater on at least two separate electrocardiograms
Grade 4 (potentially life threatening) QTC of 501 ms or greater than 60 ms change from baseline and torsades de pointes, polymorphic ventricular tachycardia, or signs of symptoms of serious arrhythmia
Grading QTc Interval Prolongation: 
5.3.8 Ocular Toxicities Ocular complications are rare with BRAFi targeted agents, but are reported with MEKi. AEs occur in about 1% of patients and these physiologically develop either due to inflammatory response or breakdown of the blood–retina barrier . Only 1% of patients treated with dabrafenib experience uveitis [9, 13]. When uveitis arises, it tends to develop over weeks or months. Retinal changes are considered a class effect of MEKi. Most commonly reported are visual disturbances, including blurred vision, serous retinal detachment, retinal vein occlusion (RVO), and chorioretinopathy . The majority of ocular AEs are transient and will resolve but persistent symptoms may require dose interruption or dose reduction upon improvement. These are generally easily managed and may require topical steroids . Patients should be cautioned to immediately report any visual disturbances and referred to an ophthalmologist if any symptoms develop .
Significant advances have been made in the ability to identify oncogenic driver mutations in lung cancer. BRAF in NSCLC is considered an oncogenic driver, and the most common BRAF mutation, V600E (Val600Glu), is observed in 1–2% of lung adenocarcinomas. The combination of dabrafenib, a BRAFi, and trametinib, a MEKi, has substantial response rates and disease control rates in BRAF mutated metastatic NSCLC. The emergence of BRAF targeted therapies has transformed treatment for BRAF mutated patients by improving outcomes with generally manageable toxicities. As with any other targeted therapies, short- and long-term use of these drugs is associated with their own unique and somewhat predictable AEs. But these AEs differ from other cancer therapies and require vigilance to encourage patient safety. The most common AEs are cutaneous skin reactions, pyrexia, and HTN. The AEs associated with BRAF/MEKi are different than those from chemotherapy and immunotherapy and thus important for nurses to recognize and manage appropriately.
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References 1. Orton RCAJ, Sturm OE, Vyshemirsky V, Calder M, Gilbert DR, Kolch W. Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway. Biochem J. 2005;392:249–61. 2. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54. 3. Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, Shigematsu H, Yamamoto H, Sawai A, Janakiraman M, Taylor BS, Pao W, Toyooka S, Ladanyi M, Gazdar A, Rosen N, Solit DB. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 2008;68:9375–83. 4. Becker TM, Boyd SC, Mijatov B, Gowrishankar K, Snoyman S, Pupo GM, Scolyer RA, Mann GJ, Kefford RF, Zhang XD, Rizos H. Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene. 2013;33:1158–66. 5. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–51. 6. Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JBAG, Hansson J, Utikal J, Ferraresi V, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, Davies MA, Lane SR, Legos JJ, Mookerjee B, Grob JJ. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28:1631–9. 7. Planchard D, Besse B, Groen HJM, Souquet PJ, Quoix E, Baik CS, Barlesi F, Kim TM, Mazieres J, Novello S, Rigas JR, Upalawanna A, D’Amelio AM Jr, Zhang P, Mookerjee B, Johnson BE. Dabrafenib plus trametinib in patients with previously treated BRAFV600E- mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet. 2016;17:984–93. 8. Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, Giannone V, D’Amelio AM Jr, Zhang P, Mookerjee B, Johnson BE. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small cell lung cancer: an openlabel, multicentre phase 2 trial. Lancet Oncol. 2017;18:1307–16. 9. Daud A, Tsai K. Management of treatment-related adverse events with agents targeting the MAPK pathway in patients with metastatic melanoma. Oncologist. 2017;22:832–3. 10. Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol. 2015;7:122–36. 11. Common Terminology Criteria for Adverse Events (CTCAE). U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Version 4.03. 2010. 12. Flaherty K, Infante J, Daud A, Gonzalez R, Kefford R, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703. 13. Czupyrn M, Cisneros J. BRAF/MEK inhibitor therapy. Consensus statements from the faculty of the melanoma nursing initiative on managing adverse events and potential drug interactions. Clin J Oncol Nurs. 2017;21(4 Suppl):11–29. https://doi.org/10.1188/17.CJON.S4.11-29.
Mechanisms of Acquired Resistance to Targeted Therapy in NSCLC: Role of Repeat Biopsy and Nursing Considerations Emily Duffield
Currently there are multiple oncogenic driver mutations that have been identified in non-small cell lung cancer (NSCLC). As the field of molecular diagnostic testing advances, the number of identifiable oncogenic mutations continues to grow. While antineoplastic therapies have not yet been identified for all of the known oncogenic mutations that have been characterized in NSCLC, there are several which may be treated in the first-line setting with FDA approved targeted oral chemotherapies, including EGFR, ALK, ROS1, and BRAF V600E mutations. These driver mutations alter cell signaling pathways in the tyrosine kinase domain, allowing constitutive cell signaling. With these activating mutations in place, the oncogene is always turned on and promotes oncogenesis, including tumor growth, metastasis, and prevention of normal cellular apoptosis. Tyrosine kinase inhibitor (TKI) therapies targeting these specific driver mutations have proven to be very effective in the first-line setting, with treatment typically leading to a beneficial clinical and anti-cancer response. For this reason, patients with targetable mutations should receive a TKI therapy as their first-line treatment of choice. These patients will typically have a significant and durable response to therapy which with first-generation agents lasted on average for 9–12 months. Newer second- and third-generation agents have improved median PFS to as long as 19 or 25 months [1, 2]. However, due to the development of one or more resistance mechanisms, ultimately all patients will progress on targeted therapy. Resistance mechanisms arise as the tumor evolves over time in response to therapeutic pressure from the TKI and develops an alternate method of cell signaling, thus allowing the tumor to overcome the TKI therapy blockade. Ongoing E. Duffield (*) Smilow Cancer Hospital at Yale-New Haven Hospital, New Haven, CT, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 M. Davies, B. Eaby-Sandy (eds.), Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners, https://doi.org/10.1007/978-3-030-16550-5_6
clinical research continues to broaden the growing body of evidence documenting the range of resistance mechanisms that tumors can develop in response to targeted therapies.
Utility of Repeat Biopsy: Tissue Testing
Molecular profiling is used to identify those patients with actionable oncogenic driver mutations, and thus is an important tool that clinicians use to guide treatment decisions in the first-line setting. By obtaining a second biopsy at the time of patient relapse, providers can often identify the underlying molecular change that caused the tumor to become resistant to treatment. Knowledge of the underlying tumor biology can provide valuable information used to inform the selection of second- line therapy. This is particularly important for patients treated with a first- or second- generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as they will have a greater than 50% chance of developing the T790M resistance mutation . The role of repeat biopsy is less clear for other driver mutations as there are currently no FDA approved second-line therapies that have been specifically designed to target the resistance mutations that may be identified by repeat biopsy. However, the information gleaned from a repeat biopsy may still be used to guide second-line therapy selection, including potential for clinical trial enrollment, or, in rare cases, off-label use of drug known to target a particular mutation if all other treatment options have been considered and exhausted. Prior to performing a repeat biopsy, there are several risks and benefits that should be carefully weighed and considered. Most important is the potential benefit to the patient in terms of identification of resistance mechanisms and future treatment options. A major hurdle to overcome can be cost of the procedure, not only with respect to monetary value and potential financial toxicity, but also due to the potential for patient complications. Repeat biopsy may pose an undue financial burden to the patient because insurance may deem it “experimental,” and will not always cover the cost of the procedure. There may be some financial assistance available depending on whether the molecular testing is done within a hospital institution or sent out to a commercial lab. In particular, testing for the T790M resistance mutation in those patients who have progressed on first-line EFGR TKI therapy should be covered by insurance (as such testing is required in order to identify those patients who are eligible for second-line therapy with osimertinib), but broader molecular profiling to further characterize resistance mechanisms in those patients who either do not have EGFR T790M or who have other baseline mutations is often not covered by insurance. Patient comorbidities and the risk of potential complications from the procedure should be considered, as not all patients will be good candidates for undergoing a repeat biopsy. In this case the potential cost to the patient should be measured not only in dollars but in terms of potentially decreased quality of life. Certain patients may have underlying medical conditions that increase the risk of complications related to the repeat biopsy procedure, making them poor candidates, for example,
6 Mechanisms of Acquired Resistance to Targeted Therapy in NSCLC: Role of Repeat…
the risk of pneumothorax from a lung biopsy in a patient with a history of pneumonectomy, or the risk of holding anticoagulation in preparation for a procedure if they have had a recent myocardial infarction with stent placement or other clotting disorder. Lastly, certain patients may simply be reluctant to take the time off from work or other responsibilities to undergo yet another invasive procedure. When planning a repeat biopsy the selection of the target location for the procedure is particularly important, as a tissue sample collected from an actively growing lesion is far more likely to yield evidence of the resistance mechanism than a stable lesion. Thus, simply attempting a biopsy of the most accessible tumor area may not benefit the patient. Further, repeat testing of archived tissue collected prior to TKI therapy should not be performed as it will not demonstrate the mechanism of acquired resistance, which developed after the archival specimen was collected. Even when a tissue specimen is obtained from an appropriate lesion it may not be possible to determine the exact resistance mechanism responsible for drug failure. This ambiguity can arise due to tumor heterogeneity, as the subpopulation of resistant clones may not be sampled. In other instances, instead of “missing” the resistant clones, two different areas of the same tumor may be sampled and have a different molecular signature identified from each region of the tumor, again due to underlying tumor heterogeneity. Limitations of currently available molecular diagnostic assays may also yield a false negative result as the resistance mechanism may be unknown, or as yet uncharacterized.
Utility of Repeat Biopsy: Liquid Biopsy
Traditionally tumors have been tested for molecular profiling markers using a fresh tissue biopsy, and this method remains the gold standard due to high sensitivity, specificity, and well-established testing protocols present within all healthcare institutions. However, the new method of liquid biopsy has recently been validated and is now approved for use in a growing number of molecular diagnostic applications. Following a significant research and development investment in advancing these liquid biopsy techniques, there are now multiple commercially available platforms for liquid biopsy in the oncology arena. Some platforms have already obtained FDA approval and others continue to undergo further confirmatory testing and validation. The concept of liquid biopsy refers to molecular profiling which is accomplished by isolating tumor biomarkers from various body fluids, including blood, urine, amniotic fluid, and cerebrospinal fluid. At this time the majority of liquid biopsy tests use blood specimens, but urine specimens are being evaluated and provide an even less invasive sample collection method than blood. All cells, whether malignant or not, shed DNA into the bloodstream. This type of DNA is called cell free- DNA (cfDNA). The portion of the DNA in the blood that is shed by tumors is called circulating tumor DNA (ctDNA). The exact process by which ctDNA enters the bloodstream is not well characterized, but is thought to occur through several mechanisms, including being shed as free DNA due to the processes of apoptosis and
necrosis, as well as more active expulsion of extracellular vesicles that encapsulate nucleic acids and proteins . Most liquid biopsy tests evaluate and identify molecular markers by isolating the ctDNA that is shed by tumors into the blood. The ctDNA is typically a very small fraction of the overall circulating cell-free DNA, varying from 0.1% in early stage solid tumors to as much as 90% in hematologic malignancies . Because the amount of ctDNA can be exceedingly small, the methods used to identify the often very small fraction of ctDNA to evaluate tumor biomarkers must be highly sensitive and specific to enable them to tease out tumor- related genetic aberrations. The amount of ctDNA present in the blood varies based on tumor size, tumor stage, type of cancer, and degree of apoptosis/necrosis occurring in the tumor. It has also been shown to wax and wane as cancer patients respond to treatment and then progress. The unique ctDNA fragments are isolated from blood plasma and enriched prior to sequencing to determine the underlying molecular profile of the tumor. Both next-generation sequencing and real-time PCR techniques are used to identify actionable mutations in the ctDNA, with certain advantages and disadvantages noted for each relating to test sensitivity, turnaround time, need for bioinformatics, and cost . Concordance of molecular profiling accomplished through liquid biopsy and that obtained through tissue biopsy has been demonstrated in multiple studies, and is typically greater than 90% [5–10]. Lack of contemporaneous sampling and limitations of both tissue and liquid biopsy techniques are thought to explain why there is not 100% agreement between the two biopsy modalities. Another potential benefit of liquid biopsy is that it can provide a better understanding of overall tumor clonally across the spectrum of metastases throughout the body, as ctDNA is collected from any tumor shedding DNA material into the bloodstream. Tissue biopsy analysis is limited to only the population of the cells collected, and will not capture clones from every site of metastasis throughout the body in the same way that is possible with a liquid biopsy. Turnaround time for liquid biopsy results (measuring time of blood draw to time when results are provided to the clinician) ranges from three to 5 days for single gene tests to 2 weeks for broad molecular profiling of 70 genes or more. This time frame is similar to that of tissue based testing. Despite the advantages of liquid biopsy, it is important to note that there are some limitations to the technique. At the time of initial diagnosis, a tissue biopsy is still required to establish the histologic diagnosis and evaluate the tumor microenvironment for PD-L1 expression. However, if the tissue sample is small, or with scant malignant cells, proceeding with a liquid biopsy may allow for completion of full molecular profiling at the time of diagnosis. Liquid biopsy will also fail to identify genetic mutations if the tumor is not shedding DNA into the bloodstream or if the amount of ctDNA is below the limit of detection of the test. Although currently not commonly utilized, there are several potential future applications of liquid biopsy beyond its current use as a tool to understand a tumor’s molecular profile. Serial liquid biopsy could provide a viable method of sequential monitoring of tumor response to therapy, and could even prove to be more sensitive in identifying progression of disease than restaging with imaging alone, as is current practice. Further, it could be used as a minimally invasive
6 Mechanisms of Acquired Resistance to Targeted Therapy in NSCLC: Role of Repeat…
technique to facilitate early detection of cancer as well as promote early detection of disease recurrence.
Mechanisms of Acquired Resistance
Despite recent therapeutic advances, stage IV lung cancer remains a largely incurable, terminal diagnosis. Newer targeted therapies developed in the past few years have offered significant improvement in terms of clinical benefit to patients with increased progression free and in some cases overall survival, but complete responses remain quite rare. Ultimately, nearly all tumors will develop resistance to therapy, and patients will display signs of clinical progression of disease. Acquired resistance can occur either due to alteration of the binding mechanism at the target location or by changes to the downstream cell signaling cascade, often due to the development and upregulation of parallel cell signaling pathways . Resistance can develop at three distinct time points throughout the course of treatment. Some driver mutations may not actually confer a sensitizing effect to therapy, and thus are considered to have an intrinsic resistance to EGFR TKI targeted therapies. A second subset of patients may have an early partial response to therapy or mixed response, but then are seen to progress rapidly due to early adaptive resistance mechanisms . The third subset of patients may have a dramatic response to therapy lasting for many months or even years, but then begin to progress. Disease progression in these cases is thought to be due to underlying resistance mutations present in a small fraction of the initial tumor clones (representing underlying tumor heterogeneity), or as a result of novel mutations acquired as a result of selective pressure imparted by the first-line therapy . The classic definition of acquired resistance applies to this subset of patients who develop resistance to therapy following a prolonged period of clinical benefit. It is important to note that the events that drive acquired resistance exist along a continuum, with significant overlap in the biologic mechanisms that drive resistance, thus the intrinsic, adaptive, and acquired resistance mechanisms are by no means distinct or mutually exclusive. Interestingly it is felt that a population of resistant tumor clones can exist even within a tumor that is highly sensitive to first- line treatment. These resistance clones may only become visible following significant response to first-line therapy, when they are imaged and defined as residual disease, or they may evade detection until a patient with an initial complete response begins to show evidence of progressive disease . Further complicating the understanding of how resistance mechanisms develop is that genetic heterogeneity exists both within a single tumor and between metastatic lesions. Spatially distinct tumors can demonstrate acquired resistance at different rates based on underlying genetic differences as well as differences in the tumor microenvironment that may be present in different regions of the body. Human biology also impacts response to first-line cancer therapies, particularly in the case of the brain as a sanctuary site of residual disease. The protection of the blood-brain barrier often makes it difficult to achieve adequate levels of drug within the CSF. Thus, selection of therapeutic
agents that will not only control systemic disease but also have the ability to penetrate the CSF at clinically relevant levels is critical for providing best patient care. To date the EGFR inhibitor osimertinib and ALK inhibitors alectinib, brigatinib, ceritinib, and lorlatinib all appear to have enhanced CNS penetration and activity compared to first-generation TKIs [13–15]. Utilizing the tool of repeat biopsy, whether tissue or liquid modalities, provides healthcare professionals the opportunity to characterize and in many cases better understand the mechanisms of acquired resistance in a given individuals tumor.
6.4.1 EGFR Acquired Resistance Mutations Driver mutations in the EGFR domain are the most common type of mutation in non-small cell lung cancer that sensitize a tumor to targeted therapy. These activating mutations vary based on ethnicity and geographic region, but are found in 15–20% of Western/European patients, and up to 48% of Asian patients with lung adenocarcinoma . EGFR mutations can be further categorized based on the unique genetic changes that they harbor. The majority (90%) are either exon 19 deletions or exon 21 L858R point mutations. There are currently five targeted therapies approved for use patients with these common EGFR sensitizing mutations, including afatinib, dacomitinib, erlotinib, gefitinib, and the NCCN preferred agent osimertinib . The remaining 10% of EGFR mutations may or may not confer sensitivity to EGFR TKI therapies. Because they are less common, there is less research investigating how well these mutations respond to therapy. However, in January 2018 afatinib was approved by the FDA for use in treating L861Q, G719X, and S768I, three of the less common mutations that have been demonstrated to respond well to therapy with afatinib .
126.96.36.199 Primary Resistance Those mutations that do not respond to treatment with EGFR TKI therapy are deemed to have primary resistance mechanisms, which can arise as a result of a purely TKI therapy resistant mutation or a sensitizing mutation which is found in combination with additional genetic alterations that render TKI therapy ineffective . Exon 20 insertion mutations are the most common of the mutations that confer primary resistance to first-line EGFR TKI therapy, and may account for between 4% and 9% of all EGFR mutations [20–22]. Because of the significant clinical benefit that other types of EGFR mutations have experienced with EGFR TKI therapies, clinical trials are ongoing to try to identify an appropriate drug for this mutation subtype which may account for up to 9% of all EGFR mutations. Additional examples of primary resistance mechanisms are a de novo T790M mutation (an alteration resulting in single amino acid substitution from threonine to methionine at position 790 within the exon 20 kinase domain), or T790M mutation in combination with a sensitizing EGFR mutation . Interestingly, in about half of all de novo T790M mutant patients the T790M mutation is present as an underlying germline mutation that may confer genetic familial predisposition to the development of NSCLC in
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never smokers . Additional tumor mutations that have demonstrated primary resistance to EGFR TKI include L747S, D716Y (exon 19 deletion mutations), and T854A (exon 21 mutation) .
188.8.131.52 Acquired Resistance Tumors develop acquired resistance after treatment with targeted therapy. One clinical definition that is commonly accepted for acquired resistance is progression of systemic disease following a partial or complete response to EGFR TKI therapy that lasted for at least 6 months or longer. Thus these acquired resistance mechanisms are felt to arise due to the selective pressure exerted on the tumor by first-line TKI cell signaling blockade. Secondary resistance is seen following first-line therapy, and now that second-line therapies have become established, tertiary resistance mechanisms are now beginning to be documented and investigated. 184.108.40.206 Secondary Resistance Tumors that initially respond well to first-line EGFR TKI therapy but later progress are said to have developed a secondary resistance mechanism. T790M has been the most common type of secondary resistance mutation seen in patients with baseline EGFR activating mutations treated with first- and second-generation EGFR TKIs. T90M has been shown to account for approximately 50% of acquired secondary resistance cases following treatment with first- or second-generation EGFR TKIs . However, the observed profile of resistance mutations is rapidly changing following FDA approval of osimertinib for use in the first-line setting. Following first- line osimertinib therapy, T790M mediated resistance is rarely identified due to blockade of the T790M pathway by osimertinib. The decrease in resistance due to T790M is being replaced by an increased proportion of MET and HER2 amplifications, as well as mutations in EGFR C797S, PIK3CA, and RAS . The T790M mutation is considered a “gatekeeper” mutation because the conformational change caused by the alteration of the amino acid threonine to the bulkier methionine residue (as outlined above) results in either a conformational change of the adenosine triphosphate (ATP) binding pocket or in a heightened affinity of the receptor site for ATP, thereby preventing binding of the TKI at its target location and rendering it ineffective . Osimertinib is a third-generation EGFR TKI that overcomes this resistance through tight covalent bonding at the ATP site. However, tertiary resistance has been documented when the C797S point mutation occurs at the covalent binding site for osimertinib . Additional secondary resistance mutations besides T790M that have been documented include D761Y, L747S, and T854A. Just as they reduce sensitivity to EGFR TKI in the setting of primary resistance, when they develop following EFGR TKI therapy they also confer secondary resistance. However, the exact mechanism by which this resistance is conferred remains unknown . Secondary resistance also develops through development of “second site” mutations, which alter downstream cell signaling. There are three main pathways mediated by the EGFR kinase domain, namely the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/ mitogen-activated protein kinase (MAPK) pathway; the
phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway, and the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway . These pathways are regulated during normal cell growth, but constitutive signaling through these pathways can promote oncogenesis characterized by rapid cell growth, proliferation, metastasis, and inhibition of apoptosis . Upregulation of downstream signaling as a result of secondary mutations allows tumors to overcome the blockade presented by first-line therapies, and can happen at multiple downstream sites, including the development of a secondary BRAF, PIK3CA, or NRAS mutation or increased expression of NRAS or KRAS . Amplification and overexpression of certain genes can also lead to upregulation of downstream cell signaling, as is the case with MET amplification, which accounts for 5–20% of acquired resistance cases . MET is a transmembrane protein that when activated can trigger a broad spectrum of downstream cell signaling through the tyrosine kinase domain. Amplification of MET gene expression activates ERBB3 and in turn activates the downstream PI3K/AKT and MAPK pathways [19, 28]. Overexpression of HER2 can also lead to increased downstream signaling, and accounts for up to 12% of acquired resistance cases . HER2 does not have a dedicated ligand binding domain, but instead forms dimers with other HER family members (primarily HER3) leading to activation of downstream PI3K/AKT and MEK/MAPK pathways. Phenotypic or histologic transformation is another escape mechanism that has been documented in up to 14% of acquired resistance cases . In this case of acquired resistance the lung adenocarcinoma undergoes transformation to small cell lung cancer (SCLC). The exact mechanism by which this pronounced epithelial-to- mesenchymal transition happens remains unclear; however, loss of function in TP53 and Rb1 is frequently identified in concordance with the original EGFR mutation, suggesting that the transformed SCLC clones are truly a derivative of the original adenocarcinoma cells rather than a de novo variant [29, 31]. With movement of osimertinib into the first-line setting it is possible that a greater proportion of histologic transformation will be observed.
220.127.116.11 Tertiary Resistance Just as secondary resistance develops as a result of treatment with first-line EGFR targeted therapies, additional acquired resistance mechanisms have been seen following treatment with second-line EGFR directed therapies targeting the T790M mutation. Osimertinib is currently the only FDA approved for treatment of patients who have progressed on first-line EGFR TKI and develop the T790M resistance mutation; however, several others have been investigated. Patients treated with second-line osimertinib have demonstrated a variety of tertiary resistance mechanisms, some of which appear to be unique, while others are more similar to those resistance mechanisms seen after first-line therapy. The most common appears to be development of the C797S mutation, which confers resistance to osimertinib; however, L844V and L718Q have been documented as well . Amplification of MET and HER2 has also been identified as both secondary and tertiary resistance mechanisms, sometimes alone or in combination with the C797S mutation [25, 33]. In
6 Mechanisms of Acquired Resistance to Targeted Therapy in NSCLC: Role of Repeat…
other cases of resistance the exact mechanism is not able to be identified, demonstrating that additional research is needed to better understand the escape mechanisms as well as to define additional future treatment strategies.
6.4.2 ALK Acquired Resistance Mutations A gene fusion between echinoderm microtubule associated protein like-4 (EML4) and anaplastic lymphoma kinase (ALK) results in increased tyrosine kinase activity that promotes cellular proliferation, survival, and supports oncogenic transformation. ALK rearrangement has been demonstrated in up to 5% of NSCLC adenocarcinoma cases. Similar to the challenges seen with EGFR targeted therapies, acquired resistance mechanisms have been documented following treatment with ALK- directed therapies as well, with the types of resistance falling into the same three categories as is seen with EGFR resistance, namely ALK-specific resistance mutations, changes to downstream cell signaling that negates the therapeutic inhibition of ALK by ALK targeted drugs, or other as yet unknown mechanisms . Currently there are five ALK inhibitors with FDA approval, the first generation (crizotinib), second generation (ceritinib and alectinib), the next generation (brigatinib), and the third generation (lorlatinib). Initially ceritinib and alectinib were approved for use after progression on crizotinib, but both have now been approved for use in the first-line setting. At this time brigatinib remains FDA approved for second-line therapy only, but it is recommended as a first-line agent by the NCCN guidelines. Lorlatinib is approved for use in the second-line setting (after alectinib or ceritinib) or third-line setting (after crizotinib and one additional ALK inhibitor). Unfortunately, no matter how the drugs are sequenced, resistance mechanisms will develop at some point during therapy, and patients will relapse. Some of the mutations that have been demonstrated seem to be unique to certain drugs, while other resistance mutations such as G1202R can confer resistance to all ALK inhibitors . Following treatment with crizotinib multiple resistance mechanisms have been observed, the first was L1196M, a gatekeeper mutation that changes the conformation of the ATP binding pocket and interferes with TKI binding [36, 37]. ALK acquired resistance as a result of L1196M is quite similar to the T790M mutation that arises after first-generation EGFR TKI therapy. The G1269A mutation has also been shown to alter TKI binding ability. The exact mechanisms by which additional mutations act remain unclear, but multiple additional mutations have been identified and subsequently reported, including C1156Y G1269A, 1151T-ins, L1152R, F1174L, I1171T, S1206Y, E1210K, G1202, D1203N, V1180L, and G1202R [34, 38–44]. In addition to these point mutations in the ALK domain, second site mutations such as EGFR, KRAS, amplification of MET or KIT, or activation of IGF-1R among others can cause downstream signaling changes and bypass pathways which account for approximately one third of the resistance mechanisms . Further complicating the treatment paradigm following development of resistance is that many tumors will have more than one resistance mechanism contributing to drug
failure. Despite advances in molecular profiling, approximately one third of refractory cases will not have an identifiable mechanism of resistance. Second-generation ALK TKIs were designed as more highly potent ALK inhibitors, and can overcome some of the resistance mutations that develop after treatment with crizotinib. For example, ceritinib has been shown to have activity against crizotinib refractory patients harboring the L1196M, G1269A, and S1206Y mutations  and alectinib has shown activity against L1196M, G1269A, and C1156Y. To summarize, the most commonly identified ALK mutations arising after TKI exposure include: L1196M for crizotinib, G1202R and compound ALK mutations after ceritinib, and G1202R after alectinib [45–47]. G1220R has been shown to promote resistance to both first- and second-line ALK TKIs . Brigatinib has been shown to have potent activity against multiple mutant forms of ALK in crizotinib resistant patients, including L1196M . In vitro data suggested high potency against as many as 17 different resistant mutations that were identified in patients following first-line ALK TKI therapy . Although F1174L and G1202R resistance mutations have been detected after lengthy treatment with brigatinib, suggesting that they may arise as a mechanism of acquired resistance, successful anti-tumor responses have also been observed in patients when both of these mutations were present at baseline . This finding suggests that brigatinib does in fact have clinical activity against both of these mutations. In addition to overcoming some of the resistance mechanisms that develop following treatment with crizotinib, it is important to note that the second- and next- generation ALK inhibitors have better blood-brain barrier penetration and have higher efficacy against CNS metastases compared to crizotinib . Now that alectinib is approved for use in the first-line setting patients are seeing prolonged PFS on first-line therapy, and delayed onset of resistance mechanisms . Secondary ALK mutations seem to be responsible for a greater proportion of relapse following treatment with second- and third-generation ALK TKIs. As more patients are treated with ALK TKI, the body of evidence is growing and seems to suggest a unique resistance mechanism profile for each drug. For example, I1171 mutations have been identified in cases of alectinib resistance but are rare in ceritinib resistance cases. Alternatively, F1174 mutations appear to cause resistance to ceritinib but not alectinib [36, 42]. Lorlatinib is the most recently approved ALK TKI, and as a third-generation agent it is currently approved for use in either the second- or third-line setting for ALK resistance. Like the second-generation ALK TKIs it has excellent brain penetration, which is important given the propensity of ALK-rearranged NSCLC to metastasize to the brain. Clinical trials have demonstrated both intracranial and systemic responses to lorlatinib in patients . Importantly, lorlatinib has been shown to have excellent activity against the highly TKI resistant G1202R mutation [51, 52]. Because lorlatinib has more recently been approved, less is understood about the spectrum of resistance mechanisms that may arise in response to treatment. However limited data exist to suggest that compound or “double” ALK mutations as well as off-target mutations in alternate cell signaling pathways such as PI3K, RAS, and EGFR can confer resistance [53, 54].
6 Mechanisms of Acquired Resistance to Targeted Therapy in NSCLC: Role of Repeat…
For all NSCLC patients with actionable driver mutations, there remains a need for further research to determine how best to address the resistance mechanisms that arise following treatment with targeted therapies. Much research is being conducted using tumor-derived cell lines as well as xenograft mouse models to better understand the molecular changes driving resistance mechanisms.
Targeted therapies in lung cancer have provided significant clinical benefit for the subset of NSCLC patients found to have actionable driver mutations. Appropriate use of molecular profiling at baseline and then periodically throughout treatment will allow clinicians to most effectively identify the changing mutation profile and select the ideal therapeutic regimen for the patient throughout the continuum of their cancer treatment journey. The cost and benefit of repeat biopsy must be carefully weighed at this time as broad spectrum molecular profiling is often not covered by insurance, which limits the capability of many patients to obtain such testing at this time. However as the field of oncology proceeds further down the path towards personalized medicine, it is likely that routine use of molecular profiling information will become not only the established standard of care, but will provide invaluable insight into clinical decision making and guide treatment selection.
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The Impact and Toxicity of Checkpoint Inhibitors in Management of Lung Cancer Stephanie Crawford Andrews and Marianne Davies
Advances in molecular biology, cancer immunology, and the development of agents that effectively manipulate the immune system have led to and will continue to revolutionize the practice of medical oncology. Significant improvements in survival and reductions in morbidity are being achieved with such agents used before, instead of, after, or in combination with more traditional cytotoxic chemotherapy. Checkpoint inhibitors targeting cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the programmed cell death protein-1/programmed cell death protein-L1 (PD-1/PD-L1) pathway have demonstrated their ability to stabilize, reduce, and sometimes produce complete remissions in widely different cancers including malignant melanoma, Merkel cell carcinoma, Hodgkin’s disease, urothelial carcinoma, head and neck cancer, hepatocellular carcinoma, gastric and gastroesophageal junction adenocarcinoma, microsatellite instability-high or mismatch repair deficient cancers, breast cancer, cervical cancer, primary mediastinal B-cell lymphoma, renal cell carcinoma, and most significantly lung cancer, the most common cause of cancer death in this country.
7.1.1 Immune Checkpoint Inhibitor Agents Since the 2011 Food and Drug Administration (FDA) approval of ipilimumab for melanoma there has been an explosion in investigation of other checkpoint S. C. Andrews (*) H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA e-mail: [email protected] M. Davies Yale Comprehensive Cancer Center, Yale University School of Nursing, New Haven, CT, USA © Springer Nature Switzerland AG 2019 M. Davies, B. Eaby-Sandy (eds.), Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners, https://doi.org/10.1007/978-3-030-16550-5_7
S. C. Andrews and M. Davies
inhibitors in many tumor types. These have paved the way for immunotherapy in advanced and metastatic lung cancer. The fusillade of checkpoint inhibitors blocking the programmed cell death protein-1 (PD-1)/programmed cell death protein- ligand 1(PD-L1) pathway has resulted in improved objective response rates, progression free survival, and overall survival by up-regulation of cytotoxic T lymphocyte activity and cell proliferation. This chapter will focus on the current achievements, toxicity, and management of the four FDA approved anti-PD-1/ PD-L1 agents in advanced lung cancer [1–3]. Table 7.1 describes the usual dose, duration of infusion, and interval between treatments for nivolumab, pembrolizumab, atezolizumab, and durvalumab. These infusions are well tolerated with few low-grade reactions managed by extending the treatment duration; severe infusion reactions are rare and no premedication is necessary .
Mechanism of Action
The cancer immunity cycle is initiated by tumor associated antigens released into circulation that are taken up by antigen presenting cells. Antigen presenting cells, also called dendritic cells, then deliver the antigen to the T-cell via the major histocompatibility complex. This along with B7 joining to CD28 primes and activates the T-cell. The T-cell then travels from the nodal tissue into the bloodstream and infiltrates into the tumor microenvironment. Here the cytotoxic T-cell identifies and destroys the human cancer cells, self-propagating the system again with release of additional antigens . The body must maintain homeostasis and prevent collateral damage by the T-cell else autoimmunity would ensue. The body protects itself from unconstrained immune response with a number of inhibitory factors which dampen the immune response. One such pathway is the PD-1/PD-L1 pathway. PD-1 is found on the T-cell and up-regulates to modulate the immune response. Its ligand PD-L1 is found on antigen presenting cells, macrophages, and human cancer cells. Coupling of PD-1/PD-L1 extinguishes the immune response rendering the T-cell unarmed and unable to continue the goal of cancer cell elimination. The blockade of the PD-1/PD-L1 pathway leads to apoptosis . Monoclonal antibodies developed to block this pathway in lung cancer include pembrolizumab, nivolumab, atezolizumab, and durvalumab each approved by the Food and Drug Administration (FDA) .
ECOG performance status 0 or 1 patients and select performance status 2 patients with unresectable stage IIIB or IV squamous or nonsquamous lung cancer who do not have mutational drivers for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or pertinent oncogenic receptor tyrosine kinase (ROS1) may be considered for treatment based on their prior chemotherapy and level of tumor expression of PD-L1 (if known) [5, 6].
Q 2 weeks
Q 3 weeks
10 mg/ kg
Q 2 weeks Q 4 weeks
Freq Q 3 weeks
240 mg 480 mg
Dose 200 mg
Considerations for PD-L1 testing
60 min first infusion; 30 min for subsequent
Infusion minutes 30 min
Table 7.1 Approved immunotherapy agents in lung cancer Indications 1. In combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK mutations 2. In combination with carboplatin and either paclitaxel or nab-paclitaxel, as first-line treatment of metastatic squamous NSCLC 3. Single agent in first-line treatment of patients with NSCLC expressing PD-L1 >1% with no EGFR or ALK mutations, and in stage III where patient not candidates for surgical resection or definitive chemoradiation or metastatic 4. Single agent in second-line treatment in NSCLC whose tumors express > or equal to 1% PD-L1 (TPS), with disease progression on platinum-based chemotherapy regimen. Patients with EGFR or ALK should have received prior targeted therapy 5. Single agent in patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least one other line of therapy 1. Single agent for metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK aberrations should have disease progression on FDA-approved therapy for those mutations prior to nivolumab therapy 2. Metastatic small cell lung cancer with progression after platinum-based chemoth erapy and at least one other line of therapy 1. First line in combination with carboplatin, paclitaxel, and bevacizumab for patients with nonsquamous NSCLC with no EGFR or ALK mutations 2. Single agent for metastatic NSCLC who have progressed on or after platinumbased chemotherapy. Patients with EGFR or ALK aberrations should have disease progression on FDA-approved therapy for those mutations prior to therapy 3. First-line in combination with carboplatin and etoposide for patients with extensive stage small cell lung cancer Unresectable stage III non-small cell lung cancer whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy 2. Metastatic small cell lung cancer with progression after platinum-based chemoth erapy and at least one other line of therapy
7 The Impact and Toxicity of Checkpoint Inhibitors in Management of Lung Cancer 67
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Organ dysfunction, as described by hematologic, hepatic, and renal parameters, has been a significant limitation of many cytotoxic agents. These considerations are less compelling in choosing checkpoint inhibitors. However, given that checkpoint inhibitors activate the immune system and may accentuate or promote autoimmunity, care to identify and considering the relevance of preexistent autoimmune disorders are necessary as these patients were excluded from clinical trials. Antiphospholipid syndrome, psoriasis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, polymyalgia rheumatic, scleroderma, Sjogren’s syndrome, systemic lupus erythematosus, vasculitis, and other autoimmune conditions may be exacerbated . Cardiac, hepatic, lung, and kidney transplant patients are excluded from the clinical trials and in all but the most desperate clinical situations . In contrast to cytotoxic therapy, checkpoint inhibitors have been shown to be effective in controlling brain metastasis; asymptomatic metastasis did not exclude patients from several trials. CheckMate 017 and 057, phase 3 studies of nivolumab in patients with nonsquamous and squamous NSCLC included 6% and 12%, respectively [9, 10]. Multiple trials have demonstrated a relationship between tumor response and the extent of PD-L1 expression as determined on pretreatment tumor samples. Higher expression tumors respond more often, with longer lasting benefits irrespective of the PD-1/PD-L1 inhibitor used. Unfortunately, only a minority of patients are high expressers; all levels appear to benefit and in most trials there were a few responders without measurable PD-L1 expression . To date multiple assays are used to quantitate PD-L1 expression; at this point ongoing trials suggest that these assays are comparable [12, 13]. However, an accepted common standard is not yet in place making comparisons difficult . Despite this, PD-L1 testing at diagnosis is endorsed by American Society of Oncologists (ASCO), National Comprehensive Cancer Network (NCCN), and Society for Immunotherapy of Cancer (SITC) [15–17].
Results of Clinical Trials
7.4.1 Metastatic Disease: First-Line Therapy Phase I–II early trials in previously untreated patients demonstrated significant responses in cancers expressing PD-L1 with each of these agents, atezolizumab , durvalumab , nivolumab , and pembrolizumab . After these successes phase III trials were begun.
18.104.22.168 Pembrolizumab Monotherapy In high expression (≥50%) PD-L1 selected patients, the KEYNOTE 024 trial with pembrolizumab induced objective responses in 44.8% of patients compared to 27.8% with a platinum doublet; median progression free survival was 10.3 months compared to 6 months. Hazard ratio for survival was 0.6 (p = 0.005) . High PD-L1 expression (≥50%) was found in only 30% of otherwise KEYNOTE 024
7 The Impact and Toxicity of Checkpoint Inhibitors in Management of Lung Cancer
candidates. Phase III trials of nivolumab (CheckMate 026) and durvalumab (MYSTIC), each of which had lower PD-L1 expression requirements than the KEYNOTE 024 trial, did not achieve superior patient benefit compared to chemotherapy [22, 23]. Based on the results of these trials the FDA approved and American Society of Clinical Oncologists (ASCO) and National Comprehensive Cancer Network (NCCN) practice guidelines recommend pembrolizumab as a single agent as initial treatment for patients with a high level of PDL-1 expression (≥50%) [24, 25]. Follow-up analysis of KEYNOTE 024 high expression (>50% TPS) demonstrated an overall survival benefit of 30.0 months of pembrolizumab compared to 14.2 months with chemotherapy (Hazard ratio 0.63) . The duration of response surpassed the chemotherapy arm.
22.214.171.124 Pembrolizumab Plus Chemotherapy Patients with a tumor proportion score of 50% or greater make up a minority of those with lung cancer. Several studies have been designed to evaluate the contribution of combined immune checkpoint inhibitor (ICPI) and chemotherapy to overall survival. Based on data from KEYNOTE-021, pembrolizumab in combination with a platinum doublet chemotherapy regimen was granted accelerated approval . KEYNOTE-189 was a confirmatory phase 3 study of patients with metastatic nonsquamous NSCLC without EGFR or ALK mutations. Patients were randomized to carboplatin or cisplatin, pemetrexed ± pembrolizumab. The overall survival in the pembrolizumab-chemotherapy arm was 69.2% versus 49.4% in the chemotherapy arm (HR, 0.49; p 3.5 g of protein/24 h, or nephrotic syndrome) affects a smaller percentage of patients, approximately 2% . The exact cause of proteinuria is unknown, and factors associated with and the severity of proteinuria are not completely characterized . Although reports from renal biopsies of patients on VEGF-targeted therapies are rare, bevacizumab has been cited as the most common causative agent . Histologic findings include thrombotic microangiography (TMA), collapsing glomerulopathy, and isolated incidences of cryoglobulinemia and immune complex glomerulonephritis [48–53]. The unproven hypothesis of proteinuria is that TMA leads to glomerular capillary endothelial injury, which is responsible for proteinuria . Presently, there are no evidence-based guidelines for treating proteinuria . Periodic monitoring, as in urine testing (urine dipstick, urine collection for urine- protein-clearance) is recommended . If protein excretion exceeds 2 g/24 h, hold treatment (bevacizumab); if the patient develops nephrotic syndrome permanently, discontinue bevacizumab . ACE inhibitors are recommended for treatment of bevacizumab-induced proteinuria, and would also treat hypertension which commonly accompanies proteinuria [40, 54].
8.6.4 Thromboembolism Both arterial and venous thromboembolism have been associated with bevacizumab [55, 56]. The underlying cause of thromboembolism associated with bevacizumab remains unclear . The primary hypothesis is that disturbance of tumor-associated
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endothelial cells can switch the naturally anticoagulant surface of the endothelium to a prothrombotic surface, thereby facilitating the activation of systemic coagulation . Prompt diagnosis and initiation of anticoagulation is crucial for patients who develop venous thromboembolism (VTE) . Presently, there is not enough information either for or against preventive anticoagulation . It is reasonable to continue bevacizumab treatment for those patients who are responding to treatment, provided they are on concurrent anticoagulation .
8.6.5 GI Perforation (GIP) Although all VEGF targeted therapies can cause GIP and fistula formation, it has been associated with bevacizumab . As with other toxicities, the exact cause of GIP is unknown . Hypotheses include intestinal wall disruption or ulceration in areas of tumor necrosis, disturbance of platelet-endothelial cell homeostasis which then causes submucosal inflammation and ulcer formation, impaired healing of either pathologic or surgical bowel injury, and mesenteric ischemia from thrombosis and/or vasoconstriction [57, 59, 60]. GIP has been primarily associated with metastatic colorectal carcinoma and epithelial ovarian cancer, although GIP can occur with other malignancies . GIP can lead to peritonitis, fistula formation, and intraabdominal abscess [40, 61]. The management of GIP is minimization of risk. Patients who are scheduled for elective surgery should discontinue bevacizumab six-to-eight (6–8) weeks, or at the very least 28 days prior to surgery . Any patient on bevacizumab, who presents with new onset abdominal pain, needs immediate evaluation including history, physical examination, abdominal imaging studies, and lab work (infection, anemia) . The diagnosis of GIP renders immediate and permanent discontinuation of bevacizumab .
8.6.6 Hemorrhage All VEGF-targeted agents have been associated with increased risk of hemorrhage . The mechanisms of bevacizumab-related thromboembolism are the same for hemorrhage . Interruption of endothelial cell function, by targeting VEGFRs, may increase susceptibility to bleeding . Two meta-analyses evaluated the incidence and risk of bevacizumab-related hemorrhage [63, 64]. The first meta-analysis reviewed 20 randomized clinical trials (RCTs) (bevacizumab plus chemotherapy versus chemotherapy) and included 12,617 patients . The findings from this study revealed that the highest incidence of high-grade hemorrhage was in patients with NSCLC (11.5%), and bevacizumab significantly increased the risk of high-grade hemorrhage in patients with NSCLC (relative risk 2.84) and renal cell carcinoma (RR 7.0) . The second meta-analysis evaluated nine RCTs with 3745 patients on either bevacizumab plus chemotherapy or chemotherapy alone . In this analysis, 89
8 The Role of Anti-Angiogenic Agents (VEGF)
severe hemorrhagic events (2.43%) were reported in the nine (9) clinical trials, 72 (3.6%) in the bevacizumab arms, and 17 (1.4%) in the chemotherapy only arms . The conclusion from both meta-analyses is that the addition of bevacizumab to chemotherapy significantly increases the risk of developing grade ≥3 hemorrhagic events compared to control arms . Although the occurrence was infrequent, bevacizumab therapy has been associated with a higher risk of bleeding, in two distinct patterns . The first pattern, minor mucocutaneous hemorrhage that did not require any change in bevacizumab treatment; the second pattern was major hemoptysis . In the toxicity profile from the phase II clinical trial, six patients developed severe hemoptysis, four episodes were fatal . Of the six patients, four had squamous cell histology, and two had adenocarcinoma . Bleeding arose from centrally located tumors close to major blood vessels, and cavitation or necrosis had occurred in most cases . In evaluating potential risk factors, squamous histologic subtype, due to its anatomic location near central vessels, and bevacizumab treatment were the only factors associated with hemoptysis . Due to these findings, subsequent clinical trials excluded patients with squamous histology . Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous histology and 4% of patients with non-squamous histology (Genentech package insert). This data is the main reason bevacizumab is not part of the treatment plan for patients with squamous histology. Evaluation of the patient is critical, including checking hemoglobin, hematocrit, and platelets. Patient education is crucial with explanation of signs/symptoms of bleeding including nosebleeds, gingival bleeding, hematemesis, and hematuria. The patient needs to be instructed to come to the emergency room immediately if they experience bleeding on bevacizumab. Treatment with bevacizumab is permanently discontinued, and the patient transfused with the necessary blood product . For any hemoptysis, patients should immediately notify their oncology provider or go directly to the emergency department. They must be reminded that there is risk of fatal pulmonary hemorrhage with bevacizumab. However, if scant hemoptysis occurs, especially directly after a respiratory procedure, such as bronchoscopy, it may be reasonable to monitor for it to cease, and then continue treatment with bevacizumab.
Ramucirumab like bevacizumab is a recombinant monoclonal antibody. Possessing a high affinity for VEGFR2, ramucirumab binds to it and blocks the ligands VEGF-A, VEGF-C, and VEGF-D, thereby preventing the activation of VEGFR2 . VEGFR2 inhibition results in reduced tumor vascularity and growth by inhibiting ligand induced proliferation of endothelial cells . Based upon the results of the REVEL trial, the Food and Drug Administration (FDA) approved ramucirumab  on 12 December 2014, for use in combination with docetaxel to treat patients with metastatic non-small cell lung cancer (NSCLC)
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whose cancer continues to grow during or after treatment with platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor mutations should have disease progression after being treated with FDA-approved drugs for these indications prior to receiving ramucirumab . The REVEL trial, a multicenter, double-blind, randomized phase 3 trial, randomized 1253 patients with squamous or non-squamous NSCLC to receive docetaxel 75 mg/m2 plus ramucirumab 10 mg/kg, versus docetaxel 75 mg/m2 plus placebo on a 21-day cycle [69, 70]. The OS and PFS favored patients who received docetaxel plus ramucirumab versus only docetaxel showing an OS of 10.5 versus 9.1 months [69, 70]. The REVEL trial was unique in that it included patients with squamous cell histologies, which had previously been excluded from trials with VEGFR inhibitors. The positive response and proven safety in patients with squamous cell NSCLC is encouraging given the lack of targeted therapy options for treatment [69, 70].
Overall, the adverse effects of ramucirumab are very similar to bevacizumab. Table 8.1 compares the rates of common toxicities for each. Patients treated with ramucirumab experienced more bleeding events of any grade, epistaxis being the Table 8.1 Most common adverse effects of bevacizumab and ramucirumab [68, 71, 72] Adverse effect Hypertension
Bevacizumaba 3–36% depending on dose
Decreased red blood cells requiring transfusion Headache Hyponatremia Epistaxis Neutropenia
Anemia Skin rash Hemorrhage Arterial thrombosis Gastrointestinal perforation Reversible posterior leukoencephalopathy
22–49% 17–19% 17–55% 12% Grade ≥3: 8–27% Grade 4: 27% 24% Grade ≥ 3: 4% Exfoliative dermatitis 23% 40% Grades 3 and 4: 6% 6% ≤3% 30 mg/24 h) Serum creatinine in men >1.5 mg/dL, women >1.4 mg/dL Calculated or estimated glomerular filtration rate 55 years, women >65 years) Cigarette smoking Dyslipidemia as measured by: Total cholesterol >190 mg/dL or Low-density lipoprotein cholesterol >130 mg/dL or High-density lipoprotein cholesterol (men 100 mg/dL Family history of premature CV disease (first-degree male relative age 35 in (in persons of east Asian ancestry: male waist circumference >35 in and for women >31 in) CV cardiovascular Adapted, with permission, from Mancia et al. 
• Conduct and document blood pressure as well as a formal assessment of cardiovascular risk factors prior to treatment initiation (Table 8.3); • Recognize that hypertension is common among many cancer patients and should be treated before initiation of therapy; • Monitor BP frequently during the first treatment cycle and then throughout treatment; • Aim for a goal of 140/90 as the maximum BP .
8.10.2 Proteinuria Similar to bevacizumab, patients should be evaluated with a urinalysis routinely to monitor for proteinuria . With bevacizumab, there are no dose reductions; however, it is recommended that ramucirumab be reduced to 8 mg/kg for proteinuria ≥2 g/24 h. If proteinuria of more than 2 g/24 h recurs, withhold treatment and
8 The Role of Anti-Angiogenic Agents (VEGF)
further reduce to 6 mg/kg. Discontinue ramucirumab permanently for urine protein of more than 3 g/24 h [68, 75].
8.10.3 Epistaxis and Hemoptysis For grade 3 or 4 bleeding from any site (Table 8.2), bevacizumab and ramucirumab should be discontinued permanently [68, 71]. Lung cancer patients can exhibit hemoptysis and/or a major bleed from the lung wall or parenchyma or from a major vessel which can result in rapid and large volume blood loss. Therefore, it is important to routinely ask the patient about any hemoptysis including frequency, color, amount, worsening or improving symptoms . Any patient experiencing any hemoptysis should likely be discontinued from ramucirumab. For management of epistaxis: The patient should sit upright, lean forward and apply direct pressure to the soft tissues of the nose for at least ten minutes while breathing through the mouth. Electrical cauterization, application of silver nitrate, or topical vasoconstrictors may be utilized in the emergency room for bleeding that will not stop with pressure applied. Nasal packing may be applied by emergency room clinicians as well. Instruct the patient with packing, particularly posterior packing, to watch for signs of infection and respiratory distress [77, 78]
8.11 Conclusion Bevacizumab was one of the initial targeted therapies approved for treatment in combination with chemotherapy for metastatic NSCLC. Ramucirumab also showed promise in improving overall survival and progression-free survival in NSCLC patients when combined with docetaxel in the second-line setting. While their use has declined in the last few years, due to the treatment success of targeted therapies and immunotherapies, they remain reasonable treatment options for patients who meet the eligibility criteria. The advanced practice provider as well as the bedside and outpatient nurse needs to be aware of the toxicities and knowledgeable of their management in order to keep the patient safe and so that beneficial treatment may continue.
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rial, double-blind study of cediranib in patients with advanced solid tumors. J Clin Oncol. 2009;27(36):6152–9. https://doi.org/10.1200/JCO.2009.22.2273. 38. Neill, T.A. Reversible posterior leukoencephalopathy syndrome. 2018. http://www.uptodate. com. Accessed 25 Jan 2018. 39. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, Pessin MS, Lamy C, Mas J-L, Caplan LR. A reversible leukoencephalopathy syndrome. N Engl J Med. 1996;334(8):494– 500. https://doi.org/10.1056/NEJM199602223340803. 40. Choueiri TK, Sonpavde G. Toxicity of molecularly targeted antiangiogenic agents: non- cardiovascular effects. 2017. http://www.uptodate.com. Accessed 15 Sept 2017. 41. Sclafani F, Giuseppe G, Mezynski J, Collins C, Crown J. Reversible posterior leukoencephalopathy syndrome in breast cancer. J Clin Oncol. 2012;30(26):e257–9. https://doi.org/10.1200/ JCO.2011.38.8942. 42. Strandgaard S, Paulson OB. Cerebral autoregulation. Stroke. 1984;15(3):413–6. https://doi. org/10.1161/01.STR.15.3.413. 43. Bastos B, Ibrahim M, Hoffman J, Kernan W, Pinto D. Reversible posterior leukoencephalopathy syndrome secondary to bevacizumab. J Hematol Oncol Pharm. 2011;1(2):1–8. 44. Marinella MA, Markert RJ. Reversible posterior leucoencephalopathy syndrome associated with anticancer drugs. Intern Med J. 2009;39(12):826–34. https://doi. org/10.1111/j.1445-5994.2008.01829x. 45. Vaughn C, Zhang L, Schiff D. Reversible posterior leukoencephalopathy syndrome in cancer. Curr Oncol Rep. 2008;10(1):86–91. 46. Shord SS, Bresler LR, Tierney LA, Cuellar S, Geroge A. Understanding and managing the possible adverse effects associated with bevacizumab. Am J Health Syst Pharm. 2009;66(11):999– 1013. https://doi.org/10.2146/ajhp080455. 47. Wu S, Kim C, Baer L, Zhu X. Bevacizumab increased risk for severe proteinuria in cancer patients. J Am Soc Nephrol. 2010;21(8):1381–9. https://doi.org/10.1681/ASN.2010020167. 48. Izzedine H, Massard C, Spano JP, Goldwasser F, Khayat D, Soria JC. VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management. Eur J Cancer. 2010;46(2):439–48. https://doi.org/10.1016/J.EJCA.2009.11.001. 49. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Quaggin SE. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129–36. https://doi.org/10.1056/NEJMoa0707330. 50. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol. 2004;22(11):2184–91. https://doi.org/10.1200/JCO.2004.11.022. 51. Maynard SE, Min JY, Merchan J, Lim K-H, Li J, Mondal S, Libermann TA, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649– 58. https://doi.org/10.1172/JCI17189. 52. Bollee G, Patey N, Cazajous G, Robert C, Goujon J-M, Fakhouri F, Bruneval P, Noel L-H, Knebelmann B. Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant. 2009;24(2):682–5. https://doi.org/10.1093/ndt/gfn657. 53. George BA, Zhou XJ, Toto R. Nephrotic syndrome after bevacizumab: case report and literature review. Am J Kidney Dis. 2007;49(2):e23–9. https://doi.org/10.1053/j.ajkd.2006.11.024. 54. Dincer M, Altundag K. Angiotensin-converting enzyme inhibitors fbevacuzmab-induced hypertension. Ann Pharmacother. 2006;40(12):2278–9. https://doi.org/10.1345/aph.1H244. 55. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, Ruff P, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506. https://doi.org/10.1200/ JCO.2012.42.8201. 56. Zangari M, Fink LM, Elice F, Zhan F, Adcock DM, Tricot GJ. Thrombotic events in patients with cancer receiving antiangiogene agents. J Clin Oncol. 2009;27(29):4865–73. https://doi. org/10.1200/JCO.2009.22.3875.
8 The Role of Anti-Angiogenic Agents (VEGF)
57. Mir O, Mouthon L, Alexandre J, Mallion J-M, Deray G, Guillevin L, Goldwasser F. Bevacizumab-induced cardiovascular events: a consequence of cholesterol emboli syndrome? J Natl Cancer Inst. 2007;99(1):85–6. https://doi.org/10.1093/jnci/djk011. 58. Choueiri TK, Sonpavde G. Toxicity of molecularly targeted antiangiogenic agents: cardiovascular effects. 2017. http://www.uptodate.com. Accessed 15 Sept 2017. 59. Han ES, Monk BJ. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol. 2007;105(1):3–6. https://doi.org/10.1016/j. ygyno.2007.01.038. 60. Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer. 2007;7(6):475–85. https://doi.org/10.1038/nrc2152. 61. Ganapathi AM, Westmoreland T, Tyler D, Mantyh CR. Bevacizumab-associated fistula formation in postoperative colorectal cancer patients. J Am Coll Surg. 2012;214(4):582–8. https:// doi.org/10.1016/j.jamcollsurg.2011.12.030. 62. Cortes J, Caralt M, Delaloge S, Cortes-Funes H, Pierga JY, Pritchard KI, Bollag DT, Miles DW. Safety of bevacizumab in metastatic breast cancer patients undergoing surgery. Eur J Cancer. 2012;48(4):475–81. https://doi.org/10.1016/j.ejca.2011.11.021. 63. Hapani S, Sher A, Chu D, Wu S. Increased risk of serious hemorrhage with beva cizumab in cancer patients: a meta-analysis. Oncology. 2010;79:27–38. https://doi. org/10.1159/000314980. 64. Lai X-X, Xu R-A, Li Y-P, Yang H. Risk of adverse events with bevacizumab addition to therapy in advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials. Onco Targets Ther. 2016;9:2421–8. 65. Gridelli C, Maione P, Rossi A, De Marinis F. The role of bevacizumab in the treatment of non-small cell lung cancer: current indications and future developments. Oncologist. 2007;12:1183–93. 66. Spratlin J, Cohen R, Eadens M, Gore L, Camidge D, Diab S, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1Monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28(5):780–7. 67. Fuchs C, Tomasek J, Yong C, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-esophageal junction adenocarcinoma (REGARD): an international, randomized multicenter, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9. 68. Cyramza (ramucirumab) [prescribing information]. Indianopolis, IN: Eli Lilly and Company. http://pi.lilly.com/us/cyramza-pi.pdf. 69. Garon E, Ciuleanu T, Arrieta O, Prabhash K, Syrigos K, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomized phase 3 trial. Lancet. 2014;384(9944):665–73. https://doi. org/10.1016/S0140-6736(14)60845-X. 70. Reck M, Paz-Ares L, Bidoli P, Cappuzzo F, Dakhil S, Moro-Sibilot D, Borghaei H, Johnson M, Jotte R, Pennell NA, Shepherd FA, Tsao A, Thomas M, Carter GC, Chan-Diehl F, Alexandris E, et al. Outcomes in patients with aggressive or refractory disease from REVEL: a randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer. Lung Cancer. 2017;112:181–7. https://doi.org/10.1016/j. lungcan.2017.07.038. 71. Avastin (bevacizumab) [prescribing information]. Genentech. https://www.avastin-hcp.com. 72. Wang ZP, Zhang HF, Zhang F, Hu BL, Wei HT, Guo YY. Bevacizumab did not reduce the risk of anemia associated with chemotherapy: an up-to-date meta-anlaysis. Eur J Clin Pharmacol. 2015;71(5):517–24. https://doi.org/10.1007/s00228-015-1818-y. 73. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. June 2010. National Institutes of Health, National Cancer Institute. http://evs.nci. nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 74. Maitland M, Bakris G, Black H, Chen H, Durand J, Elliott W, Ivy S, Leier C, Lindenfeld J, Liu G, Remick S, Steingart R, Tang W. Initial assessment, surveillance, and management of blood
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pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. JNCI: J Natl Cancer Inst. 2010;102(9):596–604. 75. Grenon N. Managing toxicities associated with antiangiogenic biologic agents in combination with chemotherapy for metastatic colorectal cancer. Clin J Oncol Nurs. 2013;17(4):425–33. 76. Thompson K. Hemoptysis. Cancer Therapy Advisor. 2017. http://www.cancertherapyadvisor. com/hospital-medicine/hemoptysis/article/602521/. Accessed 10 Mar 2018. 77. Damron B, Brant J, Belansky H, Friend P, Samsonow S, Schaal A. Putting evidence into practice. Clin J Oncol Nurs. 2009;13(5):573–83. 78. Rushing J. Managing epistaxis. Nurs Crit Care. 2011;6(2):48.
Nursing Considerations for Patients Treated with Targeted Therapies Kelly E. Goodwin and Marianne Davies
reparing Patients for Treatment on Targeted P Therapies: Nursing Considerations
Lung cancer remains the leading cause of cancer deaths in the USA. It is estimated that 228,150 new cases of lung cancer will be diagnosed in 2019, representing 13% of all new cancer cases. Lung cancer rates vary significantly by sex, age, race/ethnicity, socioeconomic status, and geography. While overall survival rates are improving and great advances have been made in tobacco control as well as well as screening and early detection advances, lung cancer remains a very common cancer. Understanding driver mutations and acquired resistance and their treatments are very important. Despite all of these advanced, it is estimated that there will be more than 142,670 deaths in 2019 from lung cancer, accounting for 24% of all cancer-related deaths in the USA . The treatment of non-small cell lung cancer (NSCLC) has changed dramatically over the past 10 years due to advances in the understanding of biologic underpinnings of the disease. There has been an explosion of new drugs approved for the treatment of NSCLC, marking an exciting and hopeful time in lung cancer research and care. The vast majority of these new drugs are oral therapies targeting genetic mutations or rearrangements like EGFR, ALK, ROS1, and BRAF . Caring for patients who are treated with a mutation targeted therapy can be challenging and requires a collaborative multidisciplinary team, often including consultants at large academic medical centers. Oncology nurses and advanced practice nurses (APNs) K. E. Goodwin Thoracic Cancers Team, Massachusetts General Hospital Cancer Center, Boston, MA, USA e-mail: [email protected] M. Davies (*) Yale Comprehensive Cancer Center, Yale University School of Nursing, New Haven, CT, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 M. Davies, B. Eaby-Sandy (eds.), Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners, https://doi.org/10.1007/978-3-030-16550-5_9
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may contribute to improved outcomes and quality of life in this increasingly complex population through securing access to treatment, providing patient education, improving medication adherence, optimizing symptom management, and managing dose modifications or interruptions [3, 4].
9.1.1 Access to Therapy The number of oral oncology therapies introduced to the market has increased significantly in the past decade and it is estimated that they make up 25–30% of all oncology drugs currently in development . While oral anticancer therapies may be more convenient and better tolerated than traditional intravenous medications they can be associated with significant challenges including difficulties with access to medications and high costs. Targeted therapies are typically more expensive than intravenous chemotherapy and are usually billed to the patient’s prescription drug insurance plan as opposed to their general medical coverage. In an attempt to contain costs many insurance companies require completion of a time-consuming prior authorization (PA) process for the approval of these high cost specialty medications, resulting in delays in initiating therapy. Because of the high cost of these agents, the special handling and storage requirements, the risk of drug–drug interactions, and the need for increased monitoring and compliance, the majority of these medications are only available through mail order specialty pharmacies which are designed to provide supplemental clinical services. Some insurance companies require that the drug is supplied by their own managed specialty pharmacy. While studies have shown that the use of specialty pharmacies is associated with higher rates of adherence and lower rates of abandonment than traditional retail pharmacies, other studies have shown that the use of specialty pharmacies increased nurse and staff burden and delays in medication receipt [6, 7]. The PA process can take hours to weeks with a median of 8 days between when the prescription is written and when it is received by the patient . There are multiple steps in obtaining prior authorization including an initial application which documents medical need, biomarker-driven decision making and prior therapies, specialty pharmacy referral, verification of benefits, and determination of out of pocket expenses. Co-pays typically average between 10 and 20% of the drug cost. The average cost can be greater than $100,000 per year [9–11]. Co-pays can present a substantial financial hardship even for patients who are well-insured and can make treatment almost unattainable for under or uninsured patients. Nurses can help patients with the complex process of applying for financial assistance through patient assistance and co-pay programs offered by drug manufactures, charitable foundations, or other sources. Some health care organizations have established patient co-pay assist programs as well. Applications for assistance can further delay initiation of therapy as the manufacturer or agency typically requires income verification. Ongoing access may change over the course of therapy if patients reach financial caps on coverage plan or if insurance benefits change. Unfortunately, patients on Medicare in most states are not eligible to take advantage of patient
9 Nursing Considerations for Patients Treated with Targeted Therapies
assistance or co-pay programs that have been set up by pharmaceutical companies [12, 13]. In response to the rising costs incurred by patients for oral anticancer therapies, several states have passed oral parity laws that limit costs incurred (i.e., co-pays, coinsurance, benefit limits) for oral therapies and are on par with co-pays for infusion therapies typically covered under a pharmacy benefit . These laws apply only to state-regulated insurance plans. The prior authorization process can be quite burdensome even for high resource oncology practices and cause profound anxiety for newly diagnosed patients or those progressing on or intolerant of their current therapy. Nurses can help manage the expectations of patients and alleviate their anxiety by being well informed about the process and timing of drug distribution and empowering patients and caregivers to manage drug refill ordering. The consequences of delaying cancer therapy can be severe. Unfortunately, if a prior authorization is denied, the appeal process can contribute to further delays in therapy. Denials can be the result of incomplete applications but may also be due to recent changes in clinical practice which are not yet reflected in updated national guidelines, FDA indications, or insurance company uptake. Until the Fall of 2017 first- and second-generation EGFR TKIs like gefitinib, erlotinib, and afatinib were the standard of care for first-line treatment in patients with newly diagnosed metastatic EGFR mutant NSCLC. The results of the FLAURA trial presented at the September 2017 European Society for Medical Oncology (ESMO) Congress and published in the New England Journal of Medicine in November 2017 led thoracic oncologists to adopt osimertinib as the standard of care for these patients instead, as this randomized phase 3 study demonstrated a near doubling of progression-free survival in TKI-naïve patients treated with osimertinib vs erlotinib or gefitinib . Within days of the public presentation, Astra-Zeneca, the maker of osimertinib, applied for an update to the NCCN guidelines asking that the drug be included as a category 1 recommendation in the first-line setting. The NCCN guidelines published a flash update within 2 weeks supporting the change in recommendation. Astra-Zeneca applied to the FDA for a change in indication in December 2017 and was granted approval on April 18, 2018 . This example demonstrates that the process of FDA approval of new drugs typically takes several months and subsequent uptake by payers can take considerably more time during which time the drug is denied. Nurses and Advanced Practice Nurses (APNs) can help to gain access to this important drug through writing letters of medical necessity during an appeal process citing the published data, updated NCCN guidelines along with the patient’s clinical information. While there are significant impediments to accessing commercially available targeted therapies for NSCLC, a new set of challenges arise when patients have exhausted these drugs due to progression of disease or intolerance. Nurses can play an important role in helping patients gain access to novel agents through clinical trials by helping to refer patients to academic medical centers, serving as a liaison between the local and consulting teams, reviewing trial eligibility, ensuring proper wash-out periods from last therapy, and assisting with logistics of study participation including communicating with the trial sponsor or a social worker for assistance with lodging or transportation.
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9.1.2 Education Caring for patients taking oral targeted therapies is challenging because of the changing paradigm in monitoring oncology patients from traditional office visits during intravenous treatment to more periodic observation with oral administration. As a result, patients have increased responsibility in self-management. Initiation of systemic therapy is associated with distress for many patients . This stress can have a negative impact on patients’ ability to comprehend and remember educational content and is associated with poor health outcomes. Educating patients on how to live with cancer, manage and integrate cancer therapy into their lives is a crucial role of the oncology nurse. Nurse-led teaching can help reduce stress and improve patients’ level of knowledge and comprehension about treatment . Patients need detailed instruction on safe handling and administration of medications, potential drug and food interactions, monitoring and reporting side effects, use of supportive care agents, frequency of follow-up assessments and their responsibility in setting up delivery of refills in order to promote safety, optimal dosing, and adherence. Each oral anticancer agent may have unique administration guidelines. Food can have significant impacts on the bioavailability and tolerance of many targeted therapies for the treatment of lung cancer. First-generation EGFR inhibitors, for example, must be taken on an empty stomach at least 1 h before or 2 h after eating and patients should be cautioned to avoid grapefruit juice and Seville oranges (found in marmalade) as they can raise the level of the targeted therapy in the bloodstream and lead to more prolonged, significant side effects. Some targeted therapies must be taken with food or water to improve bioavailability and minimize esophagitis. It is important that nurses and APNs familiarize themselves with the unique administration instructions so patients can be advised appropriately. It is important that nurses tailor both written and spoken education to the patients’ level of health literacy and language [18, 19]. Nurses should engage caregivers in education and utilize interpretation services for patients in whom English is a second language. The “teach-back” method which encourages patients to actively participate in the education by asking questions can help nurses to assess patient learning and comprehension . In addition to providing such practical information, nurses may also help with setting expectations setting including normalizing dose interruptions or dose reductions for the management of toxicities, the continuation of drug past progression if still deriving clinical benefit and the timing of repeat solid or liquid biopsies to assess for acquired resistance mutations at the time of progression. The Multinational Association of Supportive Care in Cancer (MASCC) Education Study Group designed the useful MASCC Oral Agent Teaching Tool (MOATT) with the input of oncology nurse experts, nurse coordinators, and a pharmacist to help improve patient, caregiver, and health professional education surrounding these potentially life extending but toxic therapies. The tool recognizes that age, culture, concurrent illness, and family and social supports may affect education needs. Patient education is a dynamic, ongoing process and may include the use of validated tools as well as reminder cues, handouts and asking for feedback to
9 Nursing Considerations for Patients Treated with Targeted Therapies
improve information retention and application. The MOATT is available in twelve languages and recommends that education sessions be structured to (1) assess a patient’s understanding of their disease, treatment plan, current medications, and ability to obtain and take an oral cancer therapy, (2) provide general information on storage, handling, disposal, and remembering to take oral cancer therapies as well as how to report side effects, (3) review drug specific instructions including dose, schedule, side effects and potential interactions, and (4) evaluate the patient’s understanding of the information presented through questioning [20–22].
Treatment Initiation and Monitoring
9.2.1 Nursing Assessment Nurses and APNs will contribute to the assessment of patients prior to the start of therapy and throughout the trajectory of disease and treatment. Patients need a full review of systems and physical examination to assess baseline symptoms and physical functioning. Patients should be assessed for factors that may influence adherence to therapy. It is particularly important to assess if patients have the ability to swallow oral cancer therapy drugs. Patients who require feeding tube for administration of medications may or may not be candidates for oral therapeutics, if the agent is not able to be crushed. Medications, including over-the-counter, herbal, and supplements, should be reviewed and reconciled. Patients must be instructed to discuss the addition of any new drugs prior to initiation, to minimize the risk of drug– drug interactions that might lead to potentially fatal toxicities. A complete blood count (CBC), comprehensive metabolic panel (CMP), and electrocardiogram (ECG) should be obtained prior to the start and then regularly throughout therapy. Diagnostic imaging scans will be done to provide a baseline status of the extent of the lung cancer. The scans will be obtained periodically to assess the effect of treatment on the cancer and to assess for potential toxicities. Nurses should participate in evaluating patients for anticipated toxicities throughout the course of therapy. While oral therapy may be more convenient than traditional intravenous chemotherapy, patients should be taught that convenience does not equal freedom from toxicities. Proactive monitoring, treatment, and education will help to optimize the therapeutic index of the drugs. In addition to constitutional complaints like fatigue and appetite changes, tyrosine kinase inhibitors (TKIs), for example, may cause significant mucositis, rash, paronychia, diarrhea, hepatotoxicity, and pneumonitis . Common and unique side effects of targeted therapies and management are outlined in Tables 9.1 and 9.2. Such side effects can be uncomfortable and cause anxiety for ill-informed patients as they may mimic the symptoms of progressive cancer or another oncologic emergency, particularly if a patient has a history of CNS involvement or prior blood clots. Preparing patients for potential side effects and arming them with supportive care medications and lifestyle modifications can help empower patients living with
K. E. Goodwin and M. Davies
Table 9.1 Common toxicity management Toxicity Dermatologic: Skin rash, pruritic
Oral agent EGFRIs
Dermatologic: Paronychia Dermatologic: Trichomegaly Mucositis
EGFRIs and ALKIs
Interstitial lung disease/pneumonitis
Crizotinib, ceritinib, alectinib, brigatinib Crizotinib
Cardiotoxicity: QT prolongation Cardiotoxicity: Myopathy Hepatotoxicity Visual changes Edema Hyperglycemia Myalgias Pyrexia/fever Neurocognitive changes
Nursing considerations Encourage moisturizers; avoid soaps containing alcohol, perfumes; minimize sun exposure; sunscreen; see MASKCC guidelines below Avoid tight shoes; diluted vinegar soaks; topical steroids; podiatrist consult Trim lashes; ophthalmology consult Baking soda and NS rinses; topical analgesics; diet modifications Monitor bowel pattern; loperamide, diphenoxylate/atropine; hydration and electrolyte repletion; possible dose reduction Chest CTA; oxygen support; may need steroids; expect discontinuation of drug; pulmonary consultation Monitor ECG; echocardiogram; expect dose reduction
Osimertinib EGFRIs, ALKIs ALKIs, BRAFI Crizotinib; alectinib Ceritinib; BRAFI ALKIs—alectinib, brigatinib BRAFIs Lorlatinib
Monitor LFTs Recommend no driving at night; ophthalmology evaluation Monitor weight and swelling; may need diuretic Monitor blood glucose regularly; may need anti-hyperglycemic Monitor CPK Temp >104, hold and dose reduces May need dose adjustment; neurology consult
Table 9.2 Summary of MASCC rash management recommendations  Topical
Recommended Alclometasone 0.05% cream or Fluocinonide 0.05% cream BID and Clindamycin 1% cream Doxycycline 100 mg BID or Minocycline 100 mg QD Isotretinoin low dose 20–30 mg/day
Not recommended Vitamin K cream
9 Nursing Considerations for Patients Treated with Targeted Therapies
incurable lung cancer to see their life-threatening illness as a manageable, chronic condition. It is also important to remind patients at the onset of treatment that when treating incurable cancer, quality of life is an important consideration in treatment decision-making. Nurses should explain that dose interruptions or dose reductions may be recommended when patients are experiencing signficant treatment-related side effects due to toxicities and that these side effect may wax and wane over time. Patients should be encouraged to call the health care team with questions or concerns at any time. Variation in monitoring exists between prescribers and nurses can help to develop practice guidelines that optimize adherence and safety while allowing for patient flexibility . While targeted therapies can provide significant and long-lasting clinical and radiographic benefits for patients with metastatic NSCLC, these patients will unfortunately develop progressive disease at some point. At the time of progression patients may experience physical symptoms related to their disease as well as anxiety regarding the next steps of treatment. Oncology nurses can help alleviate patient fears by being knowledgeable about testing required at the time of progression and how such tests can direct the selection of the next appropriate therapy. For some patients with only modest progression who are still deriving clinical benefit from the targeted agent, continuing the same TKI post-progression is feasible and may delay salvage therapy [26, 27]. If patients will require treatment changes, nurses can help to explain the need for tumor DNA resequencing to identify mechanisms of acquired resistance. Nurses may help in the collection and shipment of blood, a “liquid biopsy,” for the analysis of circulating tumor DNA or help prepare patients for repeat tissue biopsies. Patients will need to be educated about diet, fluid, and medication intake prior to the procedure (including how long anticoagulation must be held prior to and following the procedure) or travel restrictions if there were any biopsy-related complications (i.e., pneumothorax). Patients should be informed that the presence of a new actionable mutation may result in a recommendation for another targeted therapy or promising clinical trial while the absence of another actionable mutation may make traditional chemotherapy the most appropriate option. While some medical centers may have results available from rapid molecular testing within days of the procedure it is more likely that patients may need to wait several weeks to receive such results. This period of waiting and uncertainty can be a stressful time for patients. Oncology nurses may need to provide more significant emotional reassurance and aggressive symptom management during this time.
9.2.2 Telephone Triage Patients treated with oral targeted therapies for lung cancer receive their care on an outpatient basis, requiring them to self-administer therapy, manage the symptoms of their illness and the side effects of their treatment at home. Patients receiving traditional intravenous chemotherapy may call the oncology office for symptom management guidance, prescription refills, test results, administrative issues, and
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reassurance. While patients receiving oral targeted therapies may have additional questions about how to adjust dosing if a dose was missed or vomited, working with a specialty pharmacy and patient assistance program or reimbursement issues. Appropriate and timely telephone triage can improve health outcomes by enhancing the nurse–patient relationship, improving continuity of care, and minimizing inappropriate appointments and hospitalizations . Well-prepared oncology nurses providing remote care through telephone triage can be the best advocates for patients trying to live with and integrate cancer into their daily lives. Nurse education and the development and implementation of triage protocols are essential in managing this increasingly complex patient population. Utilization of an evidence-based, multidisciplinary telephone triage process that incorportates the assessment of symptom severity, self-management strategies and offer of same-day office visits, has demonstrated a decreased use of emergency department services by oncology patients by up to 60% . Guidelines should outline the information the nurse must consistently obtain for a given symptom scenario, prioritize reporting of patient symptoms to the medical team, convey a response to the patient/caregiver, document the telephone encounter, and follow up plan. Some institutional guidelines may include standing orders for the management of non-emergent interventions. Because telephone triage of complex patients can be time consuming, with a mean time of 12 min to manage individual calls, sustainable protocols should be readable, informative, use appropriate terms, and fit into the clinic work flow . Developing and implementing telephone triage protocols can be difficult. Barriers to using them include limited access to or awareness of protocols, complexity of patients with multiple symptoms, inconsistencies with physician practices, inadequate time, lack of electronic resources, and outdated evidence underlying protocols . The Oncology Nursing Society (ONS) has published a number of useful resources to guide nurses performing telephone triage that outline the history of telephone triage, discuss the legal concerns associated with telehealth, offer tips to improve telephone communication, review telephone triage practice models, and provide a systematic approach to performing a telephone nursing assessment. Telephone Triage for Oncology Nurses, second Edition provides symptom management guidelines for more than 40 common complaints among oncology patients, from anxiety, depression, and alternations in sexuality to oncologic emergencies like febrile neutropenia or deep vein thrombosis and common drug toxicities like fatigue, nausea/vomiting, bowel changes, and rash . Symptom management guidelines for respiratory complaints, gastrointestinal upset, and skin toxicities are particularly relevant for nurses providing guidance to patients receiving oral targeted therapies for lung cancer. In order to properly triage patients, nurses must understand the class effects of these oral oncolytic therapies so that they can ask questions which help differentiate whether a patient’s symptom is related to their underlying disease, a concomitant illness, or a significant toxicity of their treatment. For example, respiratory complaints like worsening cough, wheezing, or dyspnea may be related to lung cancer, infection, or druginduced pneumonitis.
9 Nursing Considerations for Patients Treated with Targeted Therapies
Unfortunately, there is a frustrating lack of resources for nurses and other oncology clinicians providing telephone triage to patients receiving oral targeted therapies. The ONS Oral Adherence Toolkit contains some basic information on specialty pharmacy and reimbursement resources, a list of helpful websites, assessment/interviewing techniques, barriers to adherence, summaries of common health behavior changes therapies, and sample treatment calendars. Only 16 drugs are listed in the oral therapy agent information table providing manufacturer information, indications, drug interactions, and administration relative to food . Only two of these drugs are indicated for the treatment of lung cancer. A briefer table lists some common class effects of TKIs versus angiogenesis inhibitors versus fluoropyrimidines, selective estrogen receptor modulators, and aromatase inhibitors. The Essentials of Oral Oncolytics Guide (EOOG) may be a useful adjunct to the ONS Toolkit and manufacturer’s full package insert. The EOOG includes generic and brand names of many common oral therapies, drug indications, dosing/administration instructions, recommended dose adjustments, common side effects, warnings and suggested pretreatment testing and on-treatment monitoring, and was designed with the input of oncology clinicians from 17 northeastern US practices in response to the lack of a condensed resource . It is not specific to lung cancer therapy. Nurses can help to create informative, evidence-based, disease-specific resources to be used for telephone triage of complex thoracic oncology patients receiving oral targeted therapies. Tools will need to be updated regularly as the landscape of lung cancer treatment continues to evolve.
9.2.3 Adherence Medication adherence is synonymous with compliance, though seen as a less judgmental term by patients and providers, and is defined as taking a medication in accordance with the prescribed interval and dosing [34, 35]. While direct control over life-extending therapy may be empowering for some patients it can certainly be overwhelming for others . According to a series of interviews with lung cancer patients taking erlotinib, surviving with lung cancer is organized into three stages: (1) deciding to take the medication based on the doctor’s recommendation, (2) preparing to the take the medication through pretesting, education, and drug acquisition, and finally (3) treating lung cancer as a chronic condition through standardization over a prolonged treatment period with the support of family and providers and through ongoing monitoring and payment . While adherence to chronic oral medications, in particular oral anticancer therapies, can improve patient outcomes and health care costs , surprisingly rates of adherence vary significantly from 29 to 93% [39, 40]. Patients may intentionally or inadvertently miss or skip doses, take doses at the wrong time or with prohibited medications or foods which affect bioavailability, or there may be delays in processing or shipping refills. Demographic, system, disease, and treatment-related factors may impact medication adherence. Poor adherence may result in discontinuation of a therapy as cancer progression may be related to inadequate dosing instead of true lack of efficacy. Understanding
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barriers to adherence may help nurses develop interventions to optimize dosing, safety, and response to therapy [41, 42]. Low literacy, limited access to healthcare facilities or pharmacies, insurance status (uninsured or underinsured), high out-of-pocket costs, unstable living conditions (homelessness), unemployment, busy professional or social lifestyle, multiple comorbidities with complex medication regimens, stress/anger/anxiety/forgetfulness, impaired cognition, lack of family or social supports (unmarried/unpartnered), younger age, older age, and female sex have all been associated with decreased adherence to oral medications in patients with cancer. Poor disease and prognostic understanding, severe side effects, and lack of disease-related symptoms may also contribute to poor adherence, perhaps because patients do not perceive a benefit with ongoing treatment [18, 43–46]. Effective symptom management, improved quality of life, and satisfaction with clinical services (a strong patient–provider relationship, good provider communication, continuity of care, positive reinforcement from healthcare provider, appropriate education materials) were among the strongest indicators of better adherence among patients with CML, metastatic renal cell, breast, and NSCLC [47, 48]. Desire for survival and having a routine further promote adherence . Previous use of IV chemotherapy and higher baseline total health care costs were associated with improved adherence to erlotinib in a study exploring determinants of adherence among lung cancer patients while enrollment in a low-income subsidy program (Medicare and Medicaid) and higher out-of-pocket costs for erlotinib were associated with increased nonadherence . Presumably prior IV chemotherapy may impart a better understanding of disease and the benefit of therapy with longer time from diagnosis while higher baseline health costs may indicate closer involvement and follow-up with the oncology team. Dual eligibility for low-income subsidy benefits (both Medicare and Medicaid) improved adherence of erlotinib therapy. Medication adherence may be assessed with questionnaires, patient interviews, treatment diaries, electronic medication monitors (pill caps), performing pill counts, measurements of drug or metabolite in blood/urine, and tracking refills through pharmacy utilization or insurance claims . Pretreatment assessment of patients with medication adherence scales may help predict patients at high risk for nonadherence prior to the start of therapy, providing an opportunity for nurses to implement supportive services . Interventions to enhance adherence generally include improved counseling/education, development of written materials using appropriate terminology, institution of reminders/prompts, patient recorded administration documents such as drug calendars, better symptom management, and improved communication with the oncology team via routine telephone calls and office visits [37, 48]. Nurse-led educational classes promote adherence in patients with lung cancer . Motivational interviewing, accompanied by cognitive behavioral therapy, delivered by APNs not only led to improved adherence but also improved symptom profile for patients initiating oral anticancer therapies . A focus group of lung cancer patients receiving erlotinib therapy suggested that support groups and group interventions matched for gender, age, and length of time in therapy may improve adherence and survivorship . Unfortunately, a systematic review of these
9 Nursing Considerations for Patients Treated with Targeted Therapies
interventions has showed moderate to low study quality and partly inconsistent results . Technology, such as e-health smartphone applications, provides additional tools that can promote adherence through reminders and dosing documentation [52, 53]. Just as targeted therapy for advanced lung cancer is tailored to mutation and patient characteristics, nurses and other oncology providers should consider personalized approaches to patient education and interventions to support adherence. More research is needed on strategies to promote adherence to oral cancer therapies.
9.2.4 Multidisciplinary Approach As our understanding of genetic drivers in metastatic NSCLC evolves and more therapeutic options become available, patients are living longer and challenging traditional concepts of cancer survivorship. A collaborative multidisciplinary approach to the management of disease-related symptoms and the side effects of targeted therapy can improve quality of life for these complex patients [54–56]. Inevitably disease progression will occur. Depending on the degree and pace of progression and the patient’s symptom burden or performance status, localized therapy may be offered that can help maximize the length of time on targeted treatment and prevent premature switching to other systemic therapies . As previously discussed, nurse navigators, case managers, and social workers can assist with drug acquisition, insurance roadblocks, and applications for financial assistance for patients treated with targeted therapies for advanced lung cancer. Additionally, they can help arrange transportation and lodging for patients who are travelling from a distance for standard care or clinical trial participation. Palliative care providers can provide critical support managing distressing symptoms like pain, nausea, bowel changes, and anxiety and may help patients to explore end of life preferences and decision-making. Multiple studies have demonstrated improvement in quality of life, mental health outcomes, caregiver satisfaction, and survival in patients with lung cancer receiving palliative care services . Additional psychosocial support can be offered through psycho-oncology clinicians and cognitive behavioral therapists who can help patients manage baseline psychiatric issues which may interfere with medication adherence as well as the understandable anxiety, anger, and depression which can be present throughout the trajectory of a cancer diagnosis. Many patients with targetable mutations receiving oral therapies are younger—still of child-bearing potential—or have young children at home. Patients should be counseled on the potential teratogenic effects of these medications and appropriate contraception methods. Fertility experts can assist with family planning while parenting groups and child psychologists can help young patients talk to their children about their diagnosis and treatment. Interventional pulmonologists, interventional radiologists, cardiologists, and thoracic surgeons are essential in the management of malignant pleural effusions, pericardial effusions, and other cardiopulmonary complications of lung cancer and targeted therapy. They may obtain pleural fluid for evaluation of progressive disease
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and acquired resistance through therapeutic and diagnostic thoracentesis or placement of an indwelling pleural catheter. Nurses can provide teaching and home services for the management of catheters, allowing patients to manage respiratory symptoms through intermittent drainage in the comfort of their homes with minimal physician intervention. Medical specialists including cardiologists, dermatologists, gastroenterologists, and endocrinologists can help manage TKI related toxicities and comorbid diseases. Cardiologists may help manage hypertension, bradycardia, or arrhythmias related to targeted therapies as well as any comorbid conditions. Lymphedema specialists within many departments of physical therapy can assist with the management of distressing peripheral edema. Dermatologists are essential in the management of significant rashes and diffuse granulomatous reactions as well as paronychia related to TKI therapy. They may introduce additional topical agents, oral antibiotics, or steroids. Gastroenterologists are helpful in diagnosing and treating pill-induced esophagitis which can be a complication of oral oncolytic therapy. Endocrinologists may initiate testosterone replacement to treat male hypogonadism associated with crizotinib, a condition which can cause fatigue, difficulty concentrating, decreased sex drive, erectile dysfunction, infertility, decrease in body hair, decrease in muscle mass, gynecomastia, and osteoporosis. They may also assist in the management of drug-related hyperglycemia. Despite the best efforts of a team of dedicated and knowledgeable physicians, nurses, and other allied health professionals to improve symptom management and quality of life metastatic lung cancer harboring a driver mutation will ultimately progress. Progression historically resulted in a change of cancer-directed therapy but for patients treated with TKIs that paradigm is changing with a better understanding of mechanisms of drug resistance and the heterogeneity of tumor growth . Pathologists are not only instrumental members of a multidisciplinary team at original diagnosis through tissue testing and genetic analysis but also at times of progression as they may identify secondary mutations contributing to drug resistance or transformation to other histological subtypes (i.e., transformation to small cell lung). Progressive disease can be organized into three categories: systemic progression, oligoprogression (limited to five or fewer sites), and CNS-sanctuary progression . Degree of progression can influence therapeutic options. For patients with clear radiographic or clinical systemic progression and sufficient fitness for treatment, another TKI or chemotherapy may be indicated. For patients with oligoprogression or CNS-only progression, incorporation of local therapies with the cooperation and coordination of a multidisciplinary team involving radiation oncologists, neuro-oncologists, surgeons, or interventionalists can offer highly personalized and effective treatment that maximizes TKI therapy and delays switching to salvage therapy . Surgery, external beam radiation, stereotactic radiosurgery, or radiofrequency ablation to sites of oligoprogression can result in local disease control and delay further progression [61–63]. A significant percentage of patients who respond to initial targeted therapy will develop CNS progression as the first or only site of progression [64, 65]. Brain metastases, leptomeningeal disease, and intramedullary spinal cord metastasis can cause devastating symptoms such as pain,
9 Nursing Considerations for Patients Treated with Targeted Therapies
focal weakness, and neurocognitive deficits . While newer generation drugs have demonstrated higher CNS penetration many patients may benefit from local therapies including resection, stereotactic radiosurgery, or whole brain radiation therapy with ongoing targeted therapy are highly effective. Delivery of personalized, effective therapy to patients with metastatic lung cancer with an identified driver mutation can be challenging and rewarding. A multidisciplinary team approach can improve quality of life and survival and should include regular consultation with experts at a large academic medical center with access to promising novel therapies only available through clinical trials. Although they are not infusing intravenous chemotherapy, nurses can make significant impacts in the management of these special patients through access to therapy, education, telephone triage, interventions to improve adherence and persistence, and care coordination/navigation.
Nurses and APRNS are instrumental members of the multidisciplinary team caring for patients with lung cancer. They provide patient education (pretreatment/ongoing), frequent communication, routine monitoring, early recognition, assessment and management of AEs. They provide ongoing supportive care to support medication adherence and promote self-management. These activities provide patients the opportunity to safely continue on therapy in setting of clinical benefit.
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