Improving Clinical Trial Awareness in NSCLC: Pilot Testing A Novel Healthcare IT Platform for Incorporating Education at the Point of Care

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1 Improving Clinical Trial Awareness in NSCLC: Pilot Testing A Novel Healthcare IT Platform for Incorporating Education at the Point of Care Target Audience This activity has been designed to meet the educational needs of Medical Oncologists involved in the care of patients with non-small cell lung cancer (NSCLC). Educational Objectives After completing this activity, the participant should be better able to: Apply appropriate biomarker testing when treating advanced NSCLC patients based on current evidence Develop a treatment plan for NSCLC patients that incorporates biomarker and molecular testing results Educate patients on targeted therapy agents currently in clinical trials Select appropriate patients for clinical trials of targeted therapies for treatment of NSCLC Define the process of immune surveillance Describe the role of immune checkpoint inhibitors such as the PD-1 (programmed cell death-1) antibodies in NSCLC Educate patients on immunotherapy agents being investigated Select appropriate patients for clinical trials of immunotherapies for treatment of NSCLC Identify three immune-related adverse events (iraes) experienced by NSCLC patients receiving immunotherapy Describe management strategies for common iraes experienced by patients with NSCLC receiving immunotherapy Chair Corey Langer, MD Abramson Cancer Center, University of Pennsylvania Faculty Heather Wakelee, MD Stanford Cancer Institute Naiyer A. Rizvi, MD Memorial Sloan Kettering/Weill Cornell Medical College Julie Renee Brahmer, MD Sidney Kimmel Comprehensive Cancer Center Matthew M. Burke, MBA, RN, MSN, APRN-BC Smilow Cancer Hospital at Yale-New Haven Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and On Q Health, Inc. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation The Postgraduate Institute for Medicine designates this enduring material for a maximum of 3.75 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Release date: March 23, 2015 Expiration date: March 23, 2016 Estimated time to complete activity: 3.75 hours Disclosure of Conflicts of Interest Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. Corey Langer, MD, reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Grant/Research Support, Bristol Myers Squibb, Pfizer, Eli Lilly and Company, Genentech Inc., OSI (Astelas), Merck & Co., GlaxoSmithKline, Nektar Therapeutics; Scientific Advisor, Bristol- Myers Squibb, ImClone Systems, Sanofi US, Pfizer, Inc., Eli Lilly and Company, Amgen, AstraZeneca, Novartis, Genentech, Inc., Bayer, Onyx Pharmaceuticals, Inc., Abraxis, Abbott Laboratories, Morphotek, Inc., Biodesix, Inc., Clarient, Inc., Caris Dx, Vertex Pharmaceuticals, Synta Pharmaceuticals, Celgene Corporation, Boehringer-Ingelheim; Speakers Bureaus, Eli Lilly and Company, Genentech, Inc., OSI, Imclone-BMS (all curtailed as of 12/10); Data and Safety Monitoring Committee, Eli Lilly and Company, Amgen, Synta Pharmaceuticals, Agennix. Heather Wakelee, MD, reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Consulting fees, Peregrine Parmaceuticals, Inc.; Contracted Research, Genentech, Inc., Roche Pharmaceuticals, Celgene Corporation, Eli Lilly and Company, Pfizer, Inc., Novartis, Clovis Oncology, AstraZeneca, Exelixis, Inc., Regeneron Pharmaceuticals, Inc., Xcovery, Bristol-Myers Squibb. Naiyer A. Rizvi, MD, reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Consulting fees, Merck & Co., Bristol-Myers Squibb, AstraZeneca, MedImmune, LLC, Genentech, Inc. Julie Renee Brahmer, MD, reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Consulting fees, Merck & Co., Bristol-Myers Squibb, Eli Lilly and Company, Celgene Corporation; Contracted Research, Bristol-Myers Squibb, MedImmune, AstraZeneca, Merck & Co. Matthew M. Burke, MBA, RN, MSN, APRN-BC, reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Consulting fees, Pfizer, Inc.; Speakers Bureaus, Bristol-Myers Squibb, Genentech, Inc., ION Solutions. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: 1A

2 Improving Clinical Trial Awareness in NSCLC: Pilot Testing A Novel Healthcare IT Platform for Incorporating Education at the Point of Care The following PIM planners and managers, Laura Excell, ND, NP, MS, MA, LPC, NCC, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CCMEP, and Jan Schultz, MSN, RN, CCMEP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. The following On Q Health, Inc. planners and managers reported the following: Timothy J. DiChiara, PhD, Consulting Fees, Gilead Sciences; Karen Hammelef, DNP, RN, Speakers Bureau, Novartis Pharmaceuticals Corporation. Method of Participation and Request for Credit There are no fees for participating and receiving CME credit for this activity. During the period March 23, 2015 through March 23, 2016 participants must read the learning objectives and faculty disclosures and study the educational activity. If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation on On the navigation menu, click on Find Post-test/Evaluation by Course and search by course ID Upon registering and successfully completing the post-test with a score of 75% or better and the activity evaluation, your certificate will be made available immediately. Media e-monograph Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities. Jointly provided by Postgraduate Institute for Medicine and On Q Health, Inc. This activity is supported by an independent educational grant from Bristol-Myers Squibb Company. 1B

3 Genetics and Biomarkers in Non-Small Cell Lung Cancer Genetics and Biomarkers in Non-Small Cell Lung Cancer Corey Langer, MD Lung cancer is the leading cause of cancer death among both men and women in the United States. In 2015, an estimated 221,200 new cases of lung and bronchial cancer will be diagnosed and 158,040 deaths are estimated to occur. Only 16.8% of lung cancer patients are alive 5 or more years after diagnosis, despite current treatment approaches. 1 However, considerable progress has been made in the last 10 years in the identification of molecular pathways that determine the behavior of cancer cells. This recent research has led to the realization that lung cancer is a biologically diverse group of malignancies driven by a variety of molecular pathways. The identification of actionable genetic mutations for these pathways and genetic tests for these mutations has provided researchers the opportunity to develop targeted therapies with the goal of improving outcomes while reducing adverse effects. 2 The incidence of mutations in NSCLC Between 2009 and 2012, fourteen centers enrolled 1,007 patients in the Lung Cancer Mutation Consortium to test for 10 oncogenic drivers. 3 Of the patients with non-small cell lung cancer (NSCLC) that had testable samples, 64% were found to have an oncogenic driver, and approximately one third of these proved actionable. There are many genetic mutations identified in NSCLC, yet only a subset is useful clinically or prognostically. Lazarus and Ost define useful genetic markers as those that can be identified accurately using genetic testing, are common in the population of interest, and point to an oncogenic pathway for which an effective targeted therapy exists. 2 Multiple molecular markers have been found to have clinical value in advanced NSCLC. For example, epidermal growth factor (EGFR) mutations are observed in 10% to 15% of the Western population, anaplastic lymphoma kinase (ALK) rearrangements in 4% to 8%, and human epidermal growth factor receptor 2 (HER2) and mesenchymalepidermal transition (MET) amplifications, BRAF mutations, and rearranged during transfection (RET) and ROS1 gene rearrangements in roughly 1% to 2% each. 4 On the other hand, KRAS mutations, one of the most common molecular changes in NSCLC, is currently of little clinical utility beyond its prognostic value. 5 Biopsy and testing guidelines Molecular testing guidelines for lung cancer from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology, recommend testing for EGFR mutations and ALK fusions in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors. Furthermore, they recommend that clinicians prioritize EGFR and ALK testing over other molecular predictive tests, particularly if tissue samples are limited. With their therapeutic and prognostic importance supported by practice guidelines, it is critically important that proper biopsy technique accommodate these crucial tests. Specimens for histologic and molecular analysis are preferably obtained via surgery or core biopsy to provide sufficient tissue samples; however, up to 70% of patients may not be eligible for this approach. 6 Minimally invasive techniques can be used to obtain specimens in patients with unresectable NSCLC, although diagnosis and testing may be more difficult due to insufficient tissue. On the other hand, tissue is not always required for diagnosis. A recent multicenter study of cytologic specimens obtained during endobronchial ultrasound (EBUS) reported that EGFR analysis was possible in 90% of specimens for which it was requested. 7 Anaplastic lymphoma kinase fusion genes can also be identified in cytologic specimens obtained through EBUS. 8 Various other methods are used to test samples for mutations, including polymerase chain reaction (PCR) systems that can identify multiple biomarkers simultaneously but do not detect gene rearrangements, fluorescence in situ hybridization (FISH) that is useful for detecting ALK gene rearrangements, and immunohistochemistry. Next-generation sequencing (NGS) can detect panels of mutations and gene rearrangements, and has been recommended by the National Comprehensive Cancer Network (NCCN). However, genetic testing is costly and should only be performed in populations in which the mutations are most likely to be prevalent. Testing for sensitizing EGFR mutations and ALK gene rearrangements is recommended in the NCCN guidelines for patients with adenocarcinomas or for those with squamous cell carcinomas who are never smokers, have small biopsy specimens, or have mixed histology. 9 Next-generation sequencing testing can also identify other driver mutations that are seen in NSCLC, including HER2, BRAF mutations, ROS1 and RET gene rearrangements, and MET amplification, which have off-label targeted therapies available. EGFR mutations The prevalence of EGFR mutations in adenocarcinomas is 15% in Caucasian patients and up to 50% in Asian patients, with higher EGFR mutation frequency in nonsmokers, women, and nonmucinous adenocarcinomas. The most commonly found EGFR mutations are deletions in exon 19 in 45% of patients and mutations in exon 21 in 40%. 9 These mutations are referred to as sensitizing EGFR mutations, as they result in activation of the tyrosine kinase domain and are thus sensitive to small molecule tyrosine kinase inhibitors such as erlotinib, gefitinib, and afatinib. Mutation screening analysis using multiplex PCR can detect EGFR; NGS can also be used. 4 Epidermal growth factor mutations primarily occur in adenocarcinomas; however, testing is recommended for patients with squamous cell carcinoma who have never smoked or in those whose biopsy specimens are small or of mixed histology. The targeted therapy agents currently FDA approved for use in patients with EGFR mutations are detailed in Table 1. Numerous additional agents are currently being evaluated in clinical trials. 1

4 Genetics and Biomarkers in Non-Small Cell Lung Cancer Table 1. NCCN (2015) recommendations for targeted therapy of known genetic alterations in NSCLC Genetic alteration EGFR mutations ALK rearrangements HER2 mutations BRAF mutations MET amplification ROS1 rearrangements RET rearrangements Available targeted agents erlotinib, gefitinib, afatinib crizotinib, ceritinib trastuzumab, afatinib vemurafenib, dabrafenib crizotinib crizotinib cabozantinib EML4-ALK translocation EML4-ALK gene rearrangements are estimated to occur in 2% to 7% of patients with NSCLC in the United States. They are almost exclusively found in nonsquamous cell carcinomas. Patients with EML4-ALK mutations have clinical characteristics similar to those with EGFR mutations (for example, they are often never smokers). Unique characteristics of this population are that, compared with patients with EGFR mutations, patients with EML4-ALK mutations are relatively more likely to be men and are often younger than 55 years of age. 10 The FISH assay is used to detect this genetic translocation, although NGS can also be used. 4 EML4-ALKpositive cancers are highly sensitive to small-molecule ALK kinase inhibitors such as crizotinib. 11 Targeted therapies currently approved for use in NSCLC with EML4-ALK gene rearrangement are described in Table 1 and include crizotinib and ceritinib; several others are currently being evaluated in clinical trials. HER2 Human epidermal growth factor receptor 2 (HER2) is a cell surface receptor. It has attracted renewed interest in NSCLC because it is a known oncogene in breast cancer that can be inhibited with appropriate therapy. Human epidermal growth factor receptor 2 protein overexpression is found in 6% to 35% of patients with NSCLC, while gene amplification occurs in 10% to 13% of patients. 12 HER2 mutations are present in 1% to 2% of lung adenocarcinomas and are more common in women, Asians, and never smokers. 13 These mutations exhibit different sensitivity to the EGFR tyrosine kinase inhibitors and may have a possible prognostic role. Recently, HER2 amplification has been suggested as a possible mechanism of acquired resistance in EGFR-mutated tumors initially responsive to EGFR tyrosine kinase inhibitors. 14 The role of HER2 amplification in NSCLC is currently under investigation and clinical trials with targeted agents such as afatinib are ongoing. BRAF mutations BRAF is a member of the RAF kinase family. Mutations in BRAF have been identified in a number of cancers, including melanoma, colorectal cancer, and thyroid cancer. It is found in 1% to 3% of patients with NSCLC 15 and occurs more frequently in smokers. 16 In a phase 2 trial of 78 patients with BRAF V600E-mutated NSCLC, the BRAF kinase inhibitor dabrafenib demonstrated a 32% response rate and a median duration of response of 11.8 months in the second-line setting. 17 Clinical trials of other BRAF-targeted agents are ongoing. ROS1 ROS1 is a receptor tyrosine kinase with a prevalence of 1.7% in a study of 1,073 NSCLC tumors. 18 Chromosomal rearrangements leading to fusion of ROS1 with a number of partners stimulates pathways that drive cellular transformation, among other actions. 19 ROS1 has been identified in lung cancer, gastric cancer, cholangiocarcinomas, and glioblastomas. Crizotinib has demonstrated high activity in a subset of 50 patients with ROS1-positive NSCLC, with an overall response rate of 72% and a median duration of response of 17.6 months. 20 Clinical trials of other ROS1- targeted agents such as LDK378 and AP26113 are ongoing. RET gene rearrangements Rearranged during transfection (RET) is an oncogene first identified in papillary thyroid cancer, with both activating mutations and gene rearrangements observed. In a study of 996 patients with NSCLC, the RET fusion gene was detected in 1.4% of NSCLCs and in 1.7% of lung adenocarcinomas. 21 Most patients in this study were found to have more poorly differentiated tumors (64%) and had a tendency to be younger (72% less than 60 years of age) never smokers (82%) with smaller tumors (<3 cm) and N2 disease (54%). Trials in patients with NSCLC evaluating multitargeted kinase inhibitors that target RET, such as cabozatinib, vandetanib, sunitinib, sorafenib, lenvatinib, and ponatinib, are ongoing. MET amplifications Mutations of the receptor tyrosine kinase mesenchymalepidermal transition (MET) are rare in lung cancer, but MET expression is seen in one third of lung cancers of both adenocarcinoma and squamous histology. 22 Targeted therapies, including tivantinib and onartuzumab, have not been successful to date in MET protein-expressing lung cancer; however, clinical trials with crizotinib and other agents are ongoing. KRAS mutations Approximately 25% of adenocarcinomas in a North American population have KRAS mutations, making it the most common mutation found in NSCLC after p53. 5 KRAS mutations occur most frequently in non-asians, in patients with mucinous adenocarcinoma, and in smokers. 23 Its use as a predictive marker has been supported in the literature, as patients with KRAS mutations demonstrate shorter survival than those with wild-type KRAS. 24 The role of KRAS as a useful or clinical biomarker in NSCLC is promising on several fronts. First, KRAS status has the potential for predicting which patients will benefit from EGFR TKI therapy; however, unlike colorectal cancer, the association between the absence 2

5 Genetics and Biomarkers in Non-Small Cell Lung Cancer of KRAS mutation and benefit from anti-egfr monoclonal antibodies has not been demonstrated in NSCLC. 5 In addition, primary resistance to TKI therapy may be associated with KRAS mutation, so KRAS gene sequencing could be useful for the selection of patients as candidates for TKI therapy. 25 Targeted therapy is not currently available for patients with KRAS mutations, although several agents, including selumetinib, are currently undergoing clinical evaluation. In summary, understanding the variety of actionable biomarkers in NSCLC and the use of genetic testing to personalize therapy is rapidly evolving. Current practice guidelines support the routine testing and subsequent targeted therapy for EGFR and ALK mutations. Trials are ongoing to advance our understanding of other mutations and to subsequently develop targeted agents for these subset populations of NSCLC with the overriding goal to improve survival for this highly prevalent and highly morbid cancer. References 01. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Lung and Bronchus Cancer. statfacts/html/lungb.html. Accessed January 22, Lazarus DR, Ost DE. How and when to use genetic markers for non-small cell lung cancer. Curr Opin Pulm Med 2013;19(4): Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311(19): Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013;8(7): Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter? J Clin Oncol 2013;31(8): Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83(5): Billah S, Stewart J, Staerkel G, Chen S, Gong Y, Guo M. EGFR and KRAS mutations in lung carcinoma: molecular testing by using cytology specimens. Cancer Cytopathol ;119(2): Cameron SE, Andrade RS, Pambuccian SE. Endobronchial ultrasound-guided transbronchial needle aspiration cytology: a state of the art review. Cytopathology 2010;21(1): National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer, v nscl.pdf. Accessed January 22, Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27(26): Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013;31(8): Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 2013;31(16): Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 2005;65(5): Ricciardi GR, Russo A, Franchina T, et al. NSCLC and HER2: between lights and shadows. J Thorac Oncol 2014;9(12): Chen D, Zhang LQ, Huang JF, et al. BRAF mutations in patients with non-small cell lung cancer: a systematic review and metaanalysis. PLoS One. 2014;9(6):e Planchard D, Mazieres D, Riely GJ, et al. Interim results of phase II study BRF of dabrafenib in BRAF V600E mutation positive non-small cell lung cancer (NSCLC) patients ASCO Annual Meeting Abstracts. J Clin Oncol 2013;31(15 suppl):abstr Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC): A multicenter, open-label, phase II trial (BRF113928). ESMO 2014 Congress Abstracts. Ann Oncol 2014;25(5):abstr LBA38_PR. 18. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30(8): Acquaviva J, Wong R, Charest A. The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Biochim Biophys Acta 2009;1795(1): Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014;371(21): Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol 2012;30(35): Zer A, Leighl N. Promising targets and current clinical trials in metastatic non-squamous NSCLC. Front Oncol 2014;4: Slebos RJ, Hruban RH, Dalesio O, Mooi WJ, Offerhaus GJ, Rodenhuis S. Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J Natl Cancer Inst 1991;83(14): Tsao MS, Aviel-Ronen S, Ding K, et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in nonsmall cell lung cancer. J Clin Oncol 2007;25(33): Miller VA, Riely GJ, Zakowski MF, et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol 2008;26(9):

6 Emerging Targeted Therapies in Non-Small Cell Lung Cancer Treatment Emerging Targeted Therapies in Non-Small Cell Lung Cancer Treatment Heather Wakelee, MD A decade ago, the oncology community first learned of the importance of testing for molecular changes in non-small cell lung cancer (NSCLC). Striking responses to the first epidermal growth factor receptor (EGFR)-targeted agents in a minority of patients led to the discovery of EGFR gene mutations in those tumors. 1,2 It is now known that EGFR-activating mutations can be found in tumors from approximately 50% of Asian and 15% of Western patients with NSCLC, 3,4 and testing for these mutations prior to the initiation of therapy is now the standard of care. Overcoming EGFR resistance Multiple trials with EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib have demonstrated superior response rates and progression-free survival (PFS) in the first-line setting compared to standard platinum doublet chemotherapy in patients with NSCLC harboring EGFRactivating mutations. 4-7 Unfortunately, resistance to these drugs develops, frequently in less than a year from initiation of therapy. Although a variety of resistance mechanisms have been identified, the most common is the EGFR T790M point mutation in exon 20, accounting for 50% to 60% of cases. 8-9 The first successful strategy to overcome this resistance was the combination of cetuximab, a monoclonal antibody against EGFR, and the second-generation EGFR TKI afatinib. 10 Neither drug alone or in combination with other drugs has much activity in this setting (up to 8% for afatinib alone), 11 but in a phase Ib study, patients with acquired EGFR inhibitor resistance had a 29% response rate with the combination (32% with and 25% without the presence of T790M). 10 However, side effects, including rash, diarrhea, and mucositis, were significant. Activity in this setting has also been seen using two compounds with high affinity for T790M mutations but little for wild-type EGFR. These agents, rociletinib (CO-1686) and AZD9291, have shown response rates of approximately 60% for patients with T790M resistance mutations, and some activity in those with other mechanisms of resistance A common adverse event of CO-1686 is hyperglycemia, but this is manageable with traditional agents used for glycemic control. AZD9291 has been associated with rash and diarrhea, but substantially less than with the firstand second-generation EGFR TKIs. Novel EGFR-targeting agents: necitumumab Novel agents targeting wild-type EGFR also are in development. For example, the anti-egfr antibody necitumumab was recently studied in combination with firstline chemotherapy in patients with squamous cell histology and no EGFR-activating mutations. This large randomized phase III trial showed a small but statistically significant survival benefit with the addition of necitumumab to first-line chemotherapy (11.5 vs. 9.9 months) Targeting ALK-positive NSCLC Soon after the identification of EGFR gene mutations, investigators in Japan discovered a fusion protein involving echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK), leading to constitutive kinase activity of ALK. 15 The frequency of ALK gene rearrangements in unselected patients with NSCLC has since been found to range from 3% to 6%. 16 The first ALK-targeted agent, crizotinib, was approved in 2011 for patients with ALK-positive NSCLC. 17 Phase III trials have demonstrated the superiority of crizotinib over chemotherapy as either a firstline or second-line agent. 18,19 Progress in overcoming ALK resistance is being made. Unlike with EGFR, there does not appear to be one dominant resistance pathway; multiple secondary resistance mutations have been identified. Fortunately, several potent secondand third-generation ALK inhibitors are in development and one, ceritinib (formerly LDK378), was approved in Others, including AP26113 and alectinib, have been granted breakthrough therapy designation by the FDA and are currently in multiple late-stage trials. Ceritinib has demonstrated a response rate of 66% in patients naive to crizotinib and 55% in patients previously treated with crizotinib, and the PFS was significantly longer in those without prior exposure to crizotinib. 21 Ongoing trials are comparing ceritinib to chemotherapy in ALK-rearranged NSCLC in the first-line setting (NCT ) or after prior exposure to a platinum doublet and crizotinib (NCT ). AP26113 has demonstrated activity in a phase I/II trial: in 72 patients with ALK-positive NSCLC, the response rate was 72% and median PFS was 56 weeks. 22 Similar results were found in patients previously treated with crizotinib and in patients with untreated or progressing brain metastases. Common toxicities included fatigue, nausea, and diarrhea, but serious adverse events were relatively infrequent. The potent ALK inhibitor alectinib has demonstrated striking first-line activity in a Japanese population, with over 90% of patients achieving an objective response. 23 In a global trial of alectinib in patients previously treated with crizotinib, over 50% of patients had a response, including those with central nervous system metastases. 24 Similar to the other ALK inhibitors, common toxicities included fatigue, transaminitis, rash, and peripheral edema. Novel agents targeting other mutations: ROS-1, HER2, BRAF The ALK inhibitors also have activity against the less common ROS-1 gene rearrangements. 25 Crizotinib has demonstrated a response rate of 71% and a PFS of 19.2 months in this subset of patients. 26 Another 1% to 2% of NSCLC tumors harbor mutations in exon 20 of human epidermal growth factor receptor 2 (HER2); emerging therapies for this subset include afatinib and the anti- HER2 antibody trastuzumab. 27 Approximately 1% to 3% of NSCLC patients have BRAF-activiting mutations, of which approximately 50% are the V600E mutation more commonly described in melanoma. 28 Dabrafenib, with known activity in

7 Emerging Targeted Therapies in Non-Small Cell Lung Cancer Treatment BRAF melanoma, demonstrated a response rate of greater than 50% in BRAF (V600E)-mutant NSCLC. 29 Following this positive data in melanoma, an ongoing trial (NCT ) is examining dabrafenib with trametinib in patients with BRAF NSCLC. Additional altered genes of interest in NSCLC include FGFR1 amplification, MEK1 mutations, rearranged during transfection (RET) translocations, and mesenchymal-epidermal transition (MET) amplification, with multiple ongoing trials in these patient groups. Other novel classes of targeted agents A variety of drugs with novel mechanisms of action continue to be explored in the treatment of NSCLC. The CDK4/6 inhibitor abemaciclib (LY ) is currently in phase III testing for patients previously treated for stage IV NSCLC with KRAS mutations (NCT ). A previous phase I/ II trial of abemaciclib demonstrated a 51% disease control rate. 30 Custirsen (OGX-011), a clusterin inhibitor, is being investigated in combination with docetaxel in the secondline phase III ENSPIRIT trial. In an earlier phase II trial, the overall response was 31% and the 1- and 2-year survival rates were 54% and 30%, respectively. 31 The most common serious adverse events associated with custirsen were febrile neutropenia, fever, pleural effusion, and dyspnea. Cancer stem cell inhibitors are another novel class of agents being investigated in early-phase trials. One example is BBI608, which had phase I results reported at the American Society of Clinical Oncology (ASCO) Annual Meeting in Of 20 evaluable patients, 11 (55%) had stable disease with a median time to progression of 16 weeks. Ongoing phase I studies open to lung cancer patients and patients with other solid tumors include a single-agent trial (NCT ) and another combining BBI608 with paclitaxel (NCT ). Discovery of EGFR-activating mutations paved the way for the molecular era of NSCLC therapy. First-line testing for EGFR and ALK are now the standard of care, and the availability of assays and targeted drugs are leading to routine testing for multiple additional gene mutations including ROS-1, HER2, and BRAF. Other agents such as clusterin, cancer stem cell inhibitors, and CDK4/6 inhibitors, also hold promise for the future treatment of this common and deadly malignancy. References 01. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21): Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304(5676): Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361(10): Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361(10): Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362(25): 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(3): Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31(27): Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352(8): Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2(3):e Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFRmutant lung cancer with and without T790M mutations. Cancer Discov 2014;4(9): Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 2013;31(27): Janne PA, Ramalingam SS, Yang JC, et al. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor resistant non-small cell lung cancer (NSCLC) ASCO Annual Meeting Abstracts. J Clin Oncol 32(15 suppl);abstr LV, Soria JC, Gadgeel SM, et al. First-in-human evaluation of CO- 1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M) ASCO Annual Meeting Abstracts. J Clin Oncol 2014;32(15 suppl):abstr Thatcher N, Hirsch FR, Szczesna A, et al. A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY ) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-nsclc) ASCO Annual Meeting Abstracts. J Clin Oncol 2014;32(15 suppl):abstr Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448(7153): Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008;14(13): Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363(18): Mok T, Kim DW, Wu YL, et al. First-line crizotinib versus pemetrexed cisplatin or pemetrexed carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014) ASCO Annual Meeting Abstracts. J Clin Oncol 2014;32(15 suppl):abstr

8 Emerging Targeted Therapies in Non-Small Cell Lung Cancer Treatment 19. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368(25): Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370(13): Kim DW, Mehra R, Tan DS, et al. Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): results of the ASCEND-1 trial ASCO Annual Meeting Abstracts. J Clin Oncol 2014;32(15 suppl):abstr Gettinger SN, Bazhenova L, Salgia R, et al. ALK inhibitor AP26113 in patients with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC): updated efficacy and safety data. Ann Oncol 2014;25(suppl 4):iv426-iv Nakagawa K, Kiura K, Nishio M, et al. A phase I/II study with a highly selective ALK inhibitor CH in ALK-positive nonsmall cell lung cancer (NSCLC) patients: updated safety and efficacy results from AF-001JP ASCO Meeting Abstracts. J Clin Oncol 2013;31(15 suppl):abstr Gadgeel S, Ou S-H, Chiappori AA, et al. A phase 1 dose escalation study of a new ALK inhibitor, CH /RO , in ALK+ non-small cell lung cancer (NSCLC) patients who have failed crizotinib. J Thorac Oncol 2013;8(Suppl 2):abstr O Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30(8): Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014;371(21): Mazieres J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 2013;31(16): Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011;29(15): Planchard D, Mazieres D, Riely GJ, et al. Interim results of phase II study BRF of dabrafenib in BRAF V600E mutation positive non-small cell lung cancer (NSCLC) patients ASCO Annual Meeting Abstracts. J Clin Oncol 2013;31(15 suppl):abstr Goldman JW, Gandhi L, Patnaik A, et al. Clinical activity of LY , a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with non-small cell lung cancer ASCO Annual Meeting Abstracts. J Clin Oncol 2014;32(15 suppl):abstr Laskin JJ, Nicholas G, Lee C, et al. Phase I/II trial of custirsen (OGX-011), an inhibitor of clusterin, in combination with a gemcitabine and platinum regimen in patients with previously untreated advanced non-small cell lung cancer. J Thorac Oncol 2012;7(3): Jonker DJ, Stephenson J, Edenfield WJ, et al. A phase I extension study of BBI608, a first-in-class cancer stem cell (CSC) inhibitor, in patients with advanced solid tumors ASCO Annual Meeting Abstracts. J Clin Oncol 2014;32(15 suppl):abstr

9 Overview of Immuno-Oncology Naiyer A. Rizvi, MD Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide, accounting for more than 1.6 million cases and 1.3 million deaths annually. 1 For patients with advanced stage non-small cell lung cancer (NSCLC), the most common form of lung cancer in the United States, cytotoxic chemotherapy improves outcomes, 2,3 but durable disease control is disappointingly rare; fewer than 5% of patients are alive 5 years later and median survival is approximately 10 months. 4,5 Histology-specific chemotherapy, 6 maintenance chemotherapy, 7-11 the addition of bevacizumab, 12 and the identification of targetable driver oncogenes have all improved outcomes, but there remains an urgent need for better treatment strategies for the majority of patients with advanced NSCLCs. T-cell checkpoint inhibitors, particularly those targeting the programmed cell death 1 receptor (PD1) and its ligand (PDL1), have recently demonstrated promising activity in NSCLCs and represent a new paradigm for the treatment of patients with lung cancers. Cancer immunoediting is a dynamic interaction between the host immune system and cancer cells. The three phases of immunoediting are elimination, equilibrium, and escape. During elimination (or immunosurveillance), the immune system is capable of recognizing and destroying tumors through responses elicited by its innate and adaptive arms. The immune response: innate and adaptive The innate immune system consists of cells and proteins that are always present and ready to mobilize and attack tumors. It includes natural killer (NK) cells, dendritic cells, macrophages, neutrophils, basophils, eosinophils, and mast cells. The adaptive immune system is able to recognize a broad array of foreign cells and an immune response can be mounted, releasing interferon gamma, perforin, and granzyme, as well as inflammatory cytokines that cause apoptosis in target cells. The adaptive immune system is slower in response and is antigen specific. It is called into action against tumors that are able to evade or overcome innate immune defenses. Components of the adaptive immune system are normally silent; however, when activated, these components adapt to the presence of tumors by activating, proliferating, and creating potent mechanisms for neutralizing or eliminating the tumors. There are two types of adaptive immune responses: humoral and cell mediated. Humoral immunity is mediated by antibodies produced by B lymphocytes, which, when activated, can mature into effector cells that attack tumor cells. Mature B cells are called plasma cells; plasma cells secrete antibodies, which are glycoprotein molecules that bind antigens with high affinity and help to eliminate those antigens. Cell-mediated immunity is mediated by T lymphocytes. Unlike B cells, which recognize many types of circulating antigens, the vast majority of T cells are only able to recognize peptide fragments that are displayed by major histocompatibility (MHC) molecules on the surfaces of antigen-presenting cells (APCs). This process is initiated 7 Overview of Immuno-Oncology by immature dendritic cells that are capable of capturing tumor antigens and can present tumor antigens with MHC molecules to naive T cells. When activated, these naive T cells can mature into effector cells that attack tumor cells. These effector T cells either assist leukocytes in killing ingested tumor cells or directly kill tumor cells. Antigen-presenting cells with MHC I molecules and the antigens they present are mainly recognized by CD8+ cytotoxic T cells (and not by CD4+ cells) and lead to direct tumor cell killing. Antigenpresenting cells with MHC II molecules are restricted to specialized types of cells such as dendritic cells, macrophages, and B cells. Major histocompatibility II molecules and the antigens they display are mainly recognized by CD4+ helper T cells (not by CD8+ cells) and assist in tumor cell killing. For T-cell activation, not only is interaction between the antigen- MHC complex between APCs and T cells required, but a second signal between CD80/86 on dendritic cells and CD28 on T cells also is required. Inhibitory feedback loops Tumor cells may not be completely eliminated, rather they enter an equilibrium phase in which the adaptive immune system constrains growth of clinically undetectable tumor cells. This functional dormancy can be broken in the escape phase where a dominant immunosuppressive tumor environment exists and tumor growth can no longer be controlled. Multiple immune system barriers originate in the body s own mechanisms for immune regulation and can be engaged by tumor cells to their advantage. In order to avoid a harmful effect on the body s own healthy tissue, the immune system contains inhibitory feedback loops that serve as selfchecks in the cancer-immunity cycle. These immunological brakes are essential for avoiding autoimmune events and come in two primary forms distinguished by their site of origin: central tolerance and peripheral tolerance. Central tolerance, originating in secondary lymphoid tissues (primarily the lymph nodes and spleen), operates through the transformation of naive cells into cells with highly enriched suppressor activity. Specific suppressor immune cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), are formed, recruited to (or potentially induced in) the tumor, and suppress T-cell activation. Peripheral tolerance, distinguished by its origination at the site of the tumor, is largely a function of checkpoint ligands and receptors that function as self-regulating mechanisms of T cell activation. Induction of checkpoint ligand expression at the site of the tumor appears to be mediated by a feedback mechanism specifically designed to reduce tissue damage at the site of an immune response. In this case, chronic T-cell activation results in sustained expression of cytokines and cytotoxic proteins, induced expression of inhibitory ligands (e.g., PD-L1, PD-L2, CD80, CD86) and checkpoint receptors (e.g., PD-1, LAG3, TIM3, CTLA4, ICOS), followed by binding of checkpoint ligands and receptors that results in the progressive loss of key cytokine (IFN-g, TNF-a, and IL-2) expression. Peripheral tolerance is thought to be part of the normal life cycle of activated T cells as they become spent

10 Overview of Immuno-Oncology and proper activation signals (checkpoints) are required to reinduce the cell-mediated immune response. Cancer cells have the ability to co-opt these regulatory mechanisms, thus creating barriers to T-cell activation and cell-mediated elimination of tumor cells. Ultimately, it is this capacity to mute the body s immune response that enables cancer cells to escape immune surveillance and grow unrestricted into clinically apparent tumors. Immune checkpoint targeting agents Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is the first immune checkpoint to be clinically targeted for the treatment of cancer with an antibody. Since CTLA-4 is expressed on both T effector cells and Tregs, anti-ctla-4 therapy likely operates through two mechanisms of blocking immune checkpoints. First, inhibition of CTLA-4 signaling on T cells acts directly on those cells, allowing them to enter an active proliferative effector phase. In the absence of the CTLA-4 blockade, this proliferation is limited by the fact that CTLA-4 out-competes and even physically excludes ligands from binding to its stimulatory rival CD28. When active, effector T cells are expected to infiltrate the tumor and exert direct cytotoxic effects on tumor cells through various cytokines. Second, inhibition of CTLA-4 signaling on Tregs inhibits their ability to suppress the activity of effector T cells. The precise mechanism of this effect on Tregs is still debated, perhaps mediated by depletion of the Treg population itself or by inhibition, without affecting the number of Tregs. Whichever mechanism is involved, blocking the CTLA-4 checkpoint enables a CD28-mediated antitumor immune response and limits the Treg suppressor response. Programmed cell death-1 (PD-1) is an inhibitory signaling receptor expressed on the surface of T cells that negatively regulates T-cell activation. 19 When PD-1 engages with its cognate ligands (PDL1, also known as B7-H1, or PD-L2, also known as B7-DC), it signals intracellularly in T cells to inhibit effector T-cell function via induction of effector T-cell apoptosis, suppression of effector T-cell proliferation, or cytokine production Both PD-L1 and PD-L2 ligands of PD-1 are expressed not only by APCs but also by tumor cells and cells in the tumor microenvironment. An overexpression of PD-1 ligands by tumor cells and cells in its microenvironment leading to ineffective tumor infiltrating effector T-cells is postulated to be one important mechanism by which tumor cells prevent immune-mediated destruction. 19,24 Indeed, overexpression of the PD-L1 within solid tumors has been associated with poor prognosis and diminished tumor infiltrating effector T-cells, including non-small cell lung cancer (NSCLC). 28,29 Immune checkpoint inhibitors such as PD-1 antibodies block the interaction of PD-1 with its ligands, PD-L1 and PD-L2, resulting in activation of T cell-mediated immune responses against tumor cells. This T-cell response can be exhausted during cancer progression; its restoration with immune checkpoint inhibitor antibodies can lead to dramatic and durable antitumor responses. 30,31 The PD-1 receptor and its ligand PD-L1 differ from the CTLA-4 pathway in that the PD-1/PD-L1 complex likely plays a larger role in peripheral tolerance (suppression of T cell activation at the site of the tumor or infection), whereas CTLA-4 is more broadly involved in T-cell (see Figure 1) activation. 32 In addition, PD-L1 expression can be induced not only in T cells and other immune cells, but also in various tissues, including tumors. Together, these two attributes tie PD-1/PD-L1 more directly to the tumor and serve as potential explanations for the heightened therapeutic efficacy and seemingly superior side-effect profile demonstrated to date with PD-1/PD-L1-targeted agents versus their anti-ctla4 counterparts. In keeping with this biologic role, PD-1/PD-L1 knockout mice do not develop spontaneous autoimmune responses, instead demonstrating unchecked responses to infections. The activity of immune checkpoint inhibitors has been well established in melanoma and the unexpected activity observed with anti-pd-1 antibodies has reinvigorated immunotherapy research in NSCLC Figure 1. Examples of checkpoint inhibition. (A) When patrolling natural killer (NK) cells encounter tumor cells, their activating receptor (AR) is stimulated by tumor-associated antigen (TAA). However, simultaneous interaction of inhibitory killer immunoglobulin receptors (KIRs) with tumor ligands, predominantly human leukocyte antigen (HLA-C), deactivates the NK cell. NK cell activity can be restored by the addition of monoclonal antibodies that bind to inhibitory KIRs. (B) CD8+ cytotoxic T cells become activated to kill tumors cells when their antigen-specific T-cell receptors (TCRs) bind major histocompatibility complex (MHC) class I on the tumor cell surface. However, tolerance occurs when the T-cell programmed-death receptor-1 (PD-1) interacts with its ligand, PD-L1, which is aber rantly expressed by the lung tumor cell. Infusion of monoclonal antibody to bind these proteins, as either a-pd-l1 (e.g., MPDL3280A, MEDI4736) or a-pd-1 (e.g., nivolumab, MK-3475) abrogates this interaction, thus promoting effector T-cell mediated rejection of tumor. (C) Dendritic cells are antigen-presenting cells (APCs) that load tumor peptides onto MHC class II protein and then present them to TCRs on CD4+ helper T-cells. A critical second signal is the binding of CD28 with B7-1/2 on the APC. After activation, the interaction of PD-1 with PD-L1 normally pro vides negative feedback by inducing helper T-cell anergy. This off signal can be blocked by a-pd-l1 or a-pd-1 antibody, thereby maintaining T-cell activity against cancer cells. Illustration reprinted from Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control 2014;21(1):80-89, with permission. Copyright 2014 Moffitt Cancer Center. 8

11 Overview of Immuno-Oncology References 01. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN Int J Cancer 2010;127(12): Spiro SG, Rudd RM, Souhami RL, et al; Big Lung Trial participants. Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 2004;59(10): NSCLC Meta-analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced nonsmall-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26(28): Postmus PE, Brambilla E, Chansky K, et al.; International Association for the Study of Lung Cancer International Staging Committee. The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol 2007;2(8): Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest 2009;136(1): Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advancedstage non-small-cell lung cancer. J Clin Oncol 2008;26(21): Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009;374(9699): Belani CP, Brodowicz T, Ciuleanu TE, et al. Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E- MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol 2012;13(3): Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. The Lancet Oncol 2012;13(3): Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2009;27(4): Perol M, Chouaid C, Perol D, et al. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced nonsmall-cell lung cancer. J Clin Oncol 2012;30(28): Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New Engl J Med 2006;355(24): Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New Engl J Med 2004;350(21): Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cacer: correlation with clinical response to gefitinib therapy. Science 2004;304(5676): Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101(36): Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI s Lung Cancer Mutation Consortium (LCMC) ASCO Annual Meeting. J Clin Oncol 2011;29(15 suppl):abstr CRA Pao W, Hutchinson KE. Chipping away at the lung cancer genome. Nat Med 2012;18(3): Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. New Engl J Med 2013;368(25): Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192(7): Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8(8): Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 2008;111(7): Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: releasing the restraints on anti-tumor immunity for patients with melanoma. Cancer J 2012;18(2): Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigenspecific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009;114(8): Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7- H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012;24(2): Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 2004;101(49): Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD- L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009;15(3): Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 2007;104(9): Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 2004;10(15): Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. 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12 Overview of Immuno-Oncology 34. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-deathreceptor-1 treatment with pembrolizumab in ipilimumabrefractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014;384(9948): Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-pd-1 antibody in cancer. N Engl J Med 2012;366(26):

13 Emerging Immunotherapies in NSCLC Julie Renee Brahmer, MD Sidney Kimmel Comprehensive Cancer Center Until recently, multiple immunotherapy trials have failed to yield significant improvements in survival for patients with non-small cell lung cancer (NSCLC). However, oncologists enthusiasm was rekindled in 2012 when the first hints of activity of immune checkpoint inhibitors were reported. 1 Since then, multiple types of inhibitors have resulted in consistent long-term disease control in NSCLC. 2 This monograph reviews the safety and efficacy of these agents in lung cancer. Background Cancer uses multiple mechanisms to evade the immune system. 3 One such mechanism is coopting checkpoint pathways in order to shut down the immune system or to shield the cancer cells from the immune system. 4 Checkpoint pathways are typically used by the immune system to control responses to infection or inflammation (i.e., to keep the immune system in check ). One such pathway is the programmed death-1 (PD-1) pathway. 5 The receptor of this pathway is typically expressed on T cells the lymphocytes primarily responsible for killing cancer cells. The receptor then binds to one of its ligands, either PD-L1 or PD-L2, both of which are expressed in tissues in response to inflammation and on tumor cells. Antibodies have been developed that bind to either the ligand or the receptor in this pathway, blocking the binding so the tumor is not able to shield itself from the immune system. The T cells remain active and are able to kill tumor cells. PD-1 blockade PD-1 receptor inhibitors in clinical development include nivolumab (formerly BMS [MDX-1106]), a fully human IgG4 antibody, and pembrolizumab (formerly MK [lambrolizumab]), a humanized IgG4 antibody. Both antibodies have demonstrated consistent and durable responses in lung cancer with minimal side effects and are currently in phase 3 trials in patients with stage 4 NSCLC. 1,6-8 The single-arm studies of nivolumab have demonstrated promising efficacy and a tolerable safety profile. A phase 2 trial of nivolumab in heavily pretreated patients with squamous cell lung cancer demonstrated a response rate of 15% (17 of 117 patients). 9 The median duration of response has not been reached and 76% of responses were ongoing at 11 months of follow-up. These data are consistent with previously reported data from the multi-arm expansion cohorts from the phase 1 trial of nivolumab. 10 In that trial, a 17% response rate was reported across all doses and histologies tested, and a 25% response rate was reported in patients treated with a dose of 3 mg/kg. This study reported a median duration of response of 17.1 months, a median overall survival of 9.9 months, and 1-, 2- and 3-year survival rates of 42%, 24%, and 18%, respectively. 10 This is the first time survival at 3 years has been reported in immunotherapy for lung cancer. The most common adverse events were fatigue, rash, and diarrhea. The grade 3-5 toxicity rate was 14%, with 2 patients dying due to complications from pneumonitis. In 11 Emerging Immunotherapies in NSCLC general, however, nivolumab is well tolerated and most of the side effects are low grade. Based on these encouraging data, multiple phase 3 studies were launched, including several comparing second-line nivolumab to docetaxel in squamous (NCT ) and non-squamous (NCT ) tumors, and another comparing first-line nivolumab to platinum doublets in a subset of patients with PD-L1-positive tumors (NCT ). Pembrolizumab also has demonstrated significant activity in patients with advanced lung cancer. In a group of 262 patients with treatment-naive or previously treated advanced NSCLC, pembrolizumab treatment resulted in a 26% and 20% overall response rate, respectively. 8 In the pooled population, the median progression-free survival (PFS) was 13 weeks and the 6-month overall survival was 64%. PD-L1 expression on tumor cells was measured and was associated with an increased response rate of 23% compared to 9% in patients whose tumor sample did not test positive for PD-L1 expression. In general, this antibody was also well tolerated, with a grade 3-5 toxicity rate of 9%, mostly commonly pneumonitis. PD-L1 antibodies Several manufacturers are developing antibodies to target PD-L1. Theoretically, blocking the ligand rather than the receptor might lead to fewer side effects because the PD-L2 binding to PD-1 is not blocked. MPDL3280a is a humanengineered IgG1 antibody that blocks PD-L1. In a phase I study, an overall response rate of 24% and a 24-week PFS rate of 48% were observed in patients with squamous and nonsquamous histologies. 11 These responses were long lasting and often continued even after the antibody was stopped after one year of treatment. The incidence of all grade 3 and grade 4 adverse events, regardless of attribution, was 34%, including pericardial effusion (6%), dehydration (4%), dyspnea (4%), and fatigue (4%). Interestingly, the investigators associated PD-L1 expression on the infiltrating T cells with response and not with expression on the tumor cells. Clearly, using PD-L1 expression on either tumor infiltrating cells or tumor cells themselves as a biomarker of response is not standardized across the antibodies being studied; caution must be taken when using this as a decision to treat or not treat a patient outside of a clinical trial. Indeed, responses have been seen in patients whose tumors did not express PD-L1. MEDI4675 is another human engineered IgG1 antibody that blocks PD-L1. In a phase I study, this antibody demonstrated activity in heavily pretreated patients with advanced NSCLC. 12 Objective response plus stable disease was observed in 18 of 114 patients (16%). While some responses were reported at the first assessment (6 weeks), others appeared following initial progression. Adverse events occurred in 20% of patients (all grade 1 or 2), the most frequent of which were dyspnea (16%), fatigue (15%), and nausea (15%). Interestingly, with this agent and others, a trend of higher response rates is seen in former and current smokers compared to patients who never smoked. This is consistent with all of the PD-1 and PD-L1 antibodies studied thus far in lung cancer.

14 Emerging Immunotherapies in NSCLC Conclusions and future directions PD-1 and PD-L1 antibodies are being combined with multiple other agents, including chemotherapy, tyrosine kinase inhibitors, and other checkpoint pathway blockers such as ipilimumab, a cytotoxic T cell (CTLA-4) inhibitor. The future holds great promise for checkpoint inhibitors, with the first FDA approval in lung cancer expected in However, further knowledge is needed about the mechanisms that each tumor uses to thwart the immune system and personalize immunotherapy for each patient. Immunotherapy has the potential to change the treatment landscape and improve survival in patients with lung cancer. References 01. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-pd-1 antibody in cancer. N Engl J Med 2012;366(26): Brahmer JR. Immune checkpoint blockade: the hope for immunotherapy as a treatment of lung cancer? Semin Oncol 2014;41(1): Chen DS, Mellman I. Oncology meets immunology: the cancerimmunity cycle. Immunity 2013;25;39(1): Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12(4): Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 2007;19(7): Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-pd-l1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26): Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC) ASCO Annual Meeting Abstracts. J Clin Oncol 2014;32(15 suppl):abstr Garon EB, Gandhi L, Rizvi N, et al. Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non small cell lung carcinoma (NSCLC). ESMO 2014 Congress Abstracts. Annals of Oncol 2014;25(suppl 5):abstr LBA Ramalingam SS, Mazières S, Planchard D, et al. Phase II study of nivolumab (anti-pd-1, BMS , ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer. Presented at the 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, Abstract LB Gettinger SN, Horn L, Gandhi L, et al. Long-term survival, clinical activity, and safety of Nivolumab (Anti-PD-1; BMS , ONO- 4538) in patients (pts) with advanced non-small cell lung cancer (NSCLC). Int J Radiat Oncol 2014;90(5 suppl):s Spigel DR, Gettinger SN, Horn L, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2013;31(suppl; abstr 8008). 12. Antonia SJ, Ou S, Khleif S, et al. Clinical activity and safety of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer. ESMO 2014 Congress Abstracts. Annals of Oncol 2014;25(suppl 4):abstr 1325P. 12

15 Management of Immune-Mediated Adverse Events in the Treatment of Advanced Non-Small Cell Lung Cancer Management of Immune-Mediated Adverse Events in the Treatment of Advanced Non-Small Cell Lung Cancer Matthew M. Burke, MBA, MSN, APRN-BC While not yet FDA approved for the treatment of non-small cell lung cancer (NSCLC), novel immunotherapy agents are being used in clinical trials and expanded-access protocols. These agents including nivolumab (BMS , a fully human monoclonal antibody against programmed cell death protein 1 [PD-1]); MPDL3280A (an antibody that inhibits programed death ligand-1 [PD-L1]); pembrolizumab (MK- 3475, a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD- L2); and ipilimumab, (a human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) have been shown to induce durable tumor regression and prolonged disease stabilization. 1 As a class, these agents are exceedingly well tolerated, but the immune-based etiology of certain unique side effects may be new to some clinicians. Immune-related adverse events (IRAEs) have the potential to affect any organ system; therefore, an autoimmune cause should always be considered when trying to determine the etiology of an adverse event. The most common IRAEs reported in a variety of trials are fatigue, infusion reactions, diarrhea, arthralgias, rash, nausea, pruritus, and headaches. 2 This monograph describes several clinically significant IRAEs that have been seen in patients with advanced NSCLC throughout the clinical development of these drugs. The focus is primarily on anti-pd-1/pd-l1 antibodies due to the lack of published single-agent anti- CLTA-4 studies in NCSLC. In all these trials, patients with a history of autoimmune disease or those requiring high doses of systemic steroids were typically excluded. When relevant, lessons learned from our extensive clinical experience combining these agents are noted. Immune-related pneumonitis While fairly uncommon (occurring in approximately 3% of patients), pneumonitis is a serious IRAE that can be seen in patients receiving treatment with immune checkpoint inhibitors such as nivolumab, pembrolizumab, and MPDL3280A. 2 Indeed, early in the clinical development of these drugs, deaths were reported as a result of immunerelated pneumonitis. 2 This IRAE has been seen in multiple tumor types with both anti-pd-1 and anti-pd-l1 antibodies, but may be of particular interest in the treatment of advanced NSCLC for multiple reasons. First, in the setting of chronic lung inflammation and immunologic changes that can lead to the development of NSCLC, increasing the immune response by inhibiting PD-1 can result in an exaggerated response against normal lung tissue. Examples of chronic lung inflammation include chronic pneumonia, emphysema, pulmonary edema, acute respiratory distress syndrome, tuberculosis, or pneumoconiosis. Second, many patients administered these newer agents are likely to have been heavily pretreated with other agents that also can cause pneumonitis, such as erolontib, gefitinib, gemcitabine, docetacel, and premetrexed. In addition, patients with 13 NSCLC may have multiple pre-existing pulmonary conditions in addition to tumor burden, including pleural effusions, chronic obstructive pulmonary disease, thromboembolism, pulmonary infections, and cardiovascular disease. 3 Finally, in patients with advanced lung cancer, the differential diagnosis of pneumonitis cough, dyspnea, tachypnea, and hypoxia with patchy inflammatory or ground-glass changes on computed tomography scan is lengthy and may require specialty consultation with interventional pulmonology for bronchoscopic evaluation and biopsy. In the setting of worsening clinical symptoms and a lack of other causes, immune-related pneumonitis should be considered and treated in patients receiving anti-pd1/l1 antibodies. A variety of treatment algorithms have derived from clinical protocols. Many of these algorithms are not evidenced-based, given the fairly small number of cases and limited population. The treatment of immune-related pneumonitis is based on its severity, keeping in mind that overlapping treatment may be necessary in some patients. For patients with asymptomatic grade 1 pneumonitis in whom the diagnosis of pneumonitis is made by clinical or diagnostic observation only, close clinical monitoring should be considered. 4 In patients with symptomatic grade 2 pneumonitis that limits instrumental activities of daily living, the causative therapy should be withheld and the patient treated with moderate doses of steroids (1-2 mg/kg per day of prednisone or equivalent) tapered slowly over at least 28 days until improvement or resolution of symptoms occurs. 4 For patients with severe symptoms or those requiring oxygen or interventions such as a ventilator, the immune therapy should be permanently suspended and treatment with high-dose intravenous steroids should be administered. 4 In cases of steroid-refractory or steroid-resistant pneumonitis, other immunosuppressive agents such as infliximab or mycophenolate may be considered as an adjunct to steroids. As clinical experience with these agents increases, several difficult dilemmas may arise. In patients who develop pneumonitis, continuation of therapy should be based on severity of symptoms. A patient with grade 2 pneumonitis who is treated successfully with moderate doses of steroids and tapered down successfully may show an excellent radiologic response to therapy. Some patients are able to continue therapy while remaining on a small steroid dose ( 10 mg of prednisone or equivalent per day). 4 Combining treatments, such as anti-pd1/pd-l1 antibodies plus an anti- CTLA-4 antibody or concomitant radiation therapy, may increase the risk of pneumonitis and thus patients should be monitored carefully. Immune-related dermatitis Reported as a common IRAE in almost all clinical trials of anti-pd-1, anti-pdl-1, and anti-ctla-4 antibodies, rash or dermatitis can be a challenging side effect for clinicians to manage. 2 Different from the rashes commonly seen with the use of EGFR inhibitors, the exact mechanism of immunerelated dermatitis remains unknown. Several small case series have described it as lichenoid dermatitis with marked T-cell infiltrates and few PD-1-positive cells. 5 While usually

16 Management of Immune-Mediated Adverse Events in the Treatment of Advanced Non-Small Cell Lung Cancer mild, responsive to topical corticosteroid treatment, and not dose-limiting, complications have been reported, including Steven-Johnson syndrome, toxic epidermal necrolysis, and other serious full-thickness rashes. 6 The rash can have a variable or patchy distribution, may be pruritic or not, may be seen early in treatment or long after, and can occur in the oral mucosa and palmar/plantar surfaces. 7 In the absence of systemic symptoms (fever, severe eosinophilia, nausea, and electrolyte abnormalities), mild rashes are usually treated symptomatically with topical nonsteroidal creams, followed by topical corticosteroids plus urea cream. 8 Serious, unresponsive cases may require systemic steroids and ultraviolet light therapy. Immune-related colitis While reported in only 1% to 2% of patients treated with single-agent anti-pd-1, immune-related colitis is an important clinical issue to consider when treating patients with this class of therapy. 2 It is of particular interest when anti-pd-1 is administered concurrently with anti-ctla-4; grade 3-4 cases have been reported in up to 9% of these patients. 9 The clinical presentation of immune-related colitis can be variable, ranging from mild symptoms such as abdominal discomfort and nausea to a much more severe scenario involving lifethreatening diarrhea and bowel perforation. Early intervention by withholding treatment, ruling out infectious causes (such as Clostridium difficile), radiologic evaluation, and close observation are important for patients who present with signs or symptoms of colitis. When colitis was first seen with anti-clta-4, extensive colonoscopic evaluations were performed and were helpful to understand the inflammatory mechanism of the colitis. Currently, computed tomography scan of the abdomen and pelvis with contrast is commonly used to determine the extent of colonic inflammation. Similar to pneumonitis, comprehensive, evidence-based guidelines are lacking for the management of more severe colitis. Some clinicians have extrapolated from the general colitis literature and recommend the elimination of dietary secretagogues (such as caffeine- or lactose-containing foods), but no peerreviewed data exist supporting these recommendations in this setting. Steroids (prednisone or equivalent mg/ kg per day) should be considered in patients with persistent grade 2 diarrhea lasting more than 5 days. If symptoms worsen, steroids should be increased to 1 to 2 mg/kg per day of prednisone or equivalent. 4 Inpatient management with fluid/electrolyte repletion and intravenous steroids may be required for more serious cases. Steroid taper should only be initiated after symptoms improve to grade 1 or less; in patients on high-dose steroids, the taper should last at least 1 month. Rapid tapering can result in recurrence of colitis, and patients should be monitored closely. Steroid-refractory colitis has been reported in a small number of patients receiving anti-ctla-4; in those cases infliximab has been used. 10 Budesonide is not recommended for the prevention of diarrhea/colitis. 11 Other immune-related events Other immune-related events observed with the use of anti-pd1, PD-L1, and anti-clta-4 antibodies include infusion reactions, fatigue, endocrinopathies, nephritis, hepatitis, arthralgias, nausea, and headaches. It is important to note that most of the infusion reactions were seen at higher doses than those that are being used in current trials. In addition, these reactions tended to be mild and responded well to antihistamines and histamine-2 blockers. Patients should be monitored closely during infusion and may occasionally require premedication, although steroids should not be used. Endocrinopathies, which may manifest much more profoundly than just fatigue, should always be considered in patients with NSCLC treated with these agents. 12 The challenge with this group of side effects is that they can take many forms, including hypothyroidism, hyperthyroidism (including thyroiditis and thyroid storm), hypophysitis, hypoadrenalism, hypogonadism, or a combination of these. Symptoms of endocrinopathies can be vague and include weight loss, worsening fatigue, sore throat, voice changes, tachycardia, or altered mental status. In these cases, endocrine laboratory tests such as thyroid-stimulating hormone, free thyroxine (T4), and cortisol should be ordered. Special consideration should be given to patients who develop IRAES that require prolonged steroids or other immunosuppressive agents, as cases of serious opportunistic infections have been reported. 13 National Comprehensive Cancer Center Network guidelines recommend considering pneumocystis prophylaxis with trimenthorprim-sulfamethoxale, atovaquone, or pentamadine for patients treated with prednisone 20 mg or equivalent daily for at least 4 weeks. 14 The role of antiviral and antifungal medications in this population is still being studied. The key to managing immune-related events from this therapeutic class is communication with your patient. The entire team should be briefed on the potential side effects and patients should be encouraged to report side effects early. In most cases, IRAEs can be managed with supportive care, delaying treatment, or oral/topical steroids. This new class of drug may occasionally result in more severe toxicity and thus require input from experts in pulmonology, dermatology, gastroenterology, or endocrinology. These more serious events may require high-dose steroids and discontinuation of treatment. Particular attention should be given to patients receiving multiple immune therapy agents together or those receiving one of these agents in close succession to another line of therapy. 14

17 Management of Immune-Mediated Adverse Events in the Treatment of Advanced Non-Small Cell Lung Cancer References 01. Forde PM, Kelly RJ, Brahmer JR. New strategies in lung cancer: translating immunotherapy into clinical practice. Clin Cancer Res 2014;20(5): Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-pd-1 antibody in cancer. N Engl J Med 2012;366(26): Lilenbaum RC, Cashy J, Hensing TA, Young S, Cella D. Prevalence of poor performance status in lung cancer patients: implications for research. J Thorac Oncol 2008;3(2): OPDIVO (nivolumab) injection: Highlights of prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; Accessed January 22, Joseph RW, Cappel M, Goedjen B, et al. Lichenoid Dermatitis in Three Patients with Metastatic Melanoma Treated with Anti-PD-1 Therapy. Cancer Immunol Res 2014;3(1): Gutzmer R, Wollenberg A, Ugurel S, Homey B, Ganser A, Kapp A. Cutaneous side effects of new antitumor drugs: clinical features and management. Dtsch Arztebl Int 2012;109(8): Choi JN. Dermatologic adverse events to chemotherapeutic agents, Part 2: BRAF inhibitors, MEK inhibitors, and ipilimumab. Semin Cutan Med Surg 2014;33(1): Lacouture ME, Wolchok JD, Yosipovitch G, Kahler KC, Busam KJ, Hauschild A. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol 2014;71(1): Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369(2): Pages C, Gornet JM, Monsel G, et al. Ipilimumab-induced acute severe colitis treated by infliximab. Melanoma Res 2013;23(3): Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15(17): Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 2013;98(4): Kyi C, Hellmann MD, Wolchok JD, Chapman PB, Postow MA. Opportunistic infections in patients treated with immunotherapy for cancer. J Immunother Cancer 2014;2: National Comprehensive Cancer Network, Prevention and Treatment of Cancer-Related Infections, Version Accessed January 22,