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Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Oncology Grand Rounds Non-Small Cell Lung Cancer Nurse and Physician Investigators Discuss New Agents, Novel Therapies and Actual Cases from Practice Thursday, April 28, 2016 6:00 PM – 8:00 PM Faculty Sarah B Goldberg, MD, MPH John V Heymach, MD, PhD Amanda E Magnoli, MSN, RN, ANP-BC, AOCNP Wendi J Stone, MSN, RN, NP-C Moderator Neil Love, MD Oncology Grand Rounds Series Recently Approved Agents November 21, 2012 – April 26, 2016 Immunotherapy • Nivolumab • Pembrolizumab • Ipilimumab • Blinatumomab Ovarian Cancer • Olaparib • Bevacizumab Gastrointestinal Cancers • Liposomal irinotecan (MM-398) • TAS-102 • Ramucirumab Lymphomas and CLL • Belinostat • Idelalisib • Ibrutinib Non-Small Cell Lung Cancer Melanoma • Osimertinib • Afatinib • Ceritinib • Necitumumab • Nivolumab • Ramucirumab • Talimogene laherparepvec • Cobimetinib/vemurafenib • Nivolumab • Pembrolizumab • Crizotinib • Alectinib Breast Cancer • Palbociclib • T-DM1 • Pertuzumab www.fda.gov; www.centerwatch.org Bladder Cancer • Obinutuzumab • Ofatumumab • Venetoclax • Pembrolizumab • Dabrafenib • Trametinib • Ipilimumab Recently Approved Agents November 21, 2012 – April 26, 2016 Non-Small Cell Lung Cancer • Osimertinib • Afatinib • Ceritinib • Necitumumab • Nivolumab • Ramucirumab • Pembrolizumab • Crizotinib • Alectinib www.fda.gov; www.centerwatch.org Oncology Grand Rounds: Themes • New agents and treatment strategies: Benefits and risks • Counseling patients about side effects – Practical implementation • End-of-life care • Psychosocial issues in patient care • Supporting the supporters • Job satisfaction and burnout in oncology professionals • The oncology professional just entering practice • The bond that heals Courtesy of Christiana Care Health System Overview of Lung Cancer • Estimated number of new cases and deaths in 2016: – New cases = 224,390 – Deaths = 158,080 • Stage at diagnosis (percent of patients who present with): – Stage I disease = 13% – Stage II disease = 7% – Stage III disease = 25% – Stage IV disease = 55% • 53% men, 47% women • Five-year survival estimates (2005-2011) = 18% Cancer Facts and Figures 2016; cruk.org/cancerstats 2016: Evolving Identification of Molecular Subsets in Lung Adenocarcinoma Large cell No mutations detected 38% Squamous KRAS 24% Small cell Adenocarcinoma AKT1 NRAS ALK 8% MEK1 HER2 MET AMP PIK3CA DOUBLE BRAF MUTANTS Kris MG et al. JAMA 2014;311(19):1998-2006. EGFR 17% Module 1: Management of EGFR Mutation-Positive NSCLC Discussion Topics • Overview of lung cancer: Histologic subtypes and genomic assays, tumor mutations and gene rearrangements; algorithms for tissue testing • Types of EGFR mutations and clinical implications (exon 19 deletion, exon 21 L858R mutation, exon 20 insertion) • Options for first-line treatment • Side effects of EGFR tyrosine kinase inhibitors • Relevance of T790M mutations and considerations for rebiopsy • Next-generation tyrosine kinase inhibitors: osimertinib, rociletinib 64-Year-Old Man with EGFR T790M MutationPositive Metastatic NSCLC (Ms Magnoli) • October 2012: A retired funeral home director and nonsmoker developed dyspnea and was found to have metastatic adenocarcinoma • Carboplatin/paclitaxel/bevacizumab • Testing revealed EGFR tumor mutation – Switched to erlotinib with 17-month response – T790M tumor mutation detected on disease progression • December 2015: Osimertinib initiated after several other treatments were received • Clinical improvement observed with osimertinib 64-Year-Old Man with EGFR T790M MutationPositive Metastatic NSCLC (Ms Magnoli) 11/20/2015 1/14/ 2016 Osimertinib initiated on 12/2015 Common EGFR Mutations at First Diagnosis Exon Exon 18 T790M G719X Other Exon 20 INS Exon 21 L858R 40% Exon 19 50% http://www.egfr-mutation.com/how-to-test/mutation-testing-methods.html Tissue Testing in NSCLC • Squamous vs nonsquamous • Smokers vs nonsmokers • Women vs men • Asians vs other • Adequate tissue? • Multiplex vs individual assays (EGFR, ALK) • ROS1 • ASCO, CAP, NCCN recommendations Case discussion points (Ms Magnoli) • What were some of the key patient education points that you addressed when the patient was started on erlotinib? • What are the most common toxicity/tolerability issues with erlotinib? • How did the patient tolerate treatment with erlotinib? First-Line Treatment Options in EGFR MutationPositive NSCLC • Erlotinib – 150 mg/d (PO) until disease progression (PD) or unacceptable toxicity1-3 • Afatinib – 40 mg/d (PO) until PD or unacceptable toxicity4-5 • Gefitinib • 250 mg/d (PO) until PD or unacceptable toxicity6 1Zhou C et al. Lancet Oncol 2011;12(8):735-42; 2Rosell R et al. Lancet Oncol 2012;13(3):23946; 3Seto T et al. Lancet Oncol 2014;15(11):1236-44; 4Sequist LV et al. J Clin Oncol 2013;31(27):3327-34; 5Wu YL et al. Lancet Oncol 2014;15(2):213-22; 6Ichiihara E et al. J Thorac Oncol 2015;10(3):486-91. IPASS Trial: Progression-Free Survival (PFS) Results Gefitinib (n = 66) Carboplatin/paclitaxel (n = 74) HR (95% CI) = 0.55 (0.35 to 0.87) Probability of PFS Probability of PFS HR (95% CI) = 0.38 (0.26 to 0.56) Time since random assigment (months) EGFR Exon 19 deletion Fukuoka M et al. J Clin Oncol 2011;29(21):2866-74. Gefitinib (n = 64) Carboplatin/paclitaxel (n = 47) Time since random assigment (months) EGFR L858R mutation LUX-Lung 3 and 6: Combined Overall Survival Analysis by Mutation Category L858R Del19 Afatinib Chemo n = 236 n = 119 Median, mo 31.7 20.7 HR 0.59 p-value p = 0.0001 0.8 0.6 0.4 0.2 0 Chemo n = 93 22.1 26.9 HR p-value 1.0 Estimated OS probability Estimated OS probability 1.0 Median, mo Afatinib n = 183 1.25 p = 0.1600 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Yang CH et al. Lancet Oncol 2015;16:141-51. 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Phase IIb LUX-Lung 7 Trial: First-Line Afatinib versus Gefitinib in Advanced EGFR-Mutant NSCLC Afatinib (n = 160) Gefitinib (n = 159) Median PFS 18-mo PFS 24-mo PFS 11.0 mo 27% 18% 10.9 mo 15% 8% 0.73 Median TTF 13.7 mo 11.5 mo NR 70% 56% NR ORR HR TTF = time to treatment failure; ORR = objective response rate; NR = not reported • Overall survival data: not mature at 27.3-mo follow-up • Serious adverse events occurred more frequently with afatinib Park K et al. Proc ESMO 2015;Abstract LBA2 PR. Skin Rash with Tyrosine Kinase Inhibitors • Most frequent dermatologic side effect reported is acneiform eruption. • Affects mainly face, upper chest and/or back. • Also known as acne, acneiform skin reaction/rash, follicular rash and maculopapular skin rash. Ricciardi S et al. Clin Lung Cancer 2009;10(1):28-35. Prophylaxis of Dermatologic Toxicities with EGFR Inhibitors Within first 6 weeks of EGFR TKI administration • Employ proactive approach • Thick, alcohol-free emollient cream • Sunscreen ≥SPF15, preferably with zinc oxide or titanium dioxide • Good hygiene Lynch TJ et al. Oncologist 2007;12:610-21. Management of Dermatologic Toxicities with EGFR Inhibitors • Hydrocortisone 1% or 2.5% cream • Clindamycin 1% gel • Pimecrolimus 1% cream • Doxycycline 100 mg BID • Minocycline 100 mg BID • Methylprednisolone dose pack • Dose reduction, interruption or discontinuation Lynch TJ et al. Oncologist 2007;12:610-21. T790M: Incidence in NSCLC • Tissue biopsy is the gold standard and the basis upon which FDA approvals for “T790M-specific” EGFR TKIs were made • Baseline rate of EGFR T790M (EGFR TKI-naïve): – All lung cancers: 0.5% – EGFR-mutant NSCLC: 2% • Acquired resistance to EGFR TKIs (incidence of a second-site EGFR T790M mutation): 62% Yu HA et al. Ann Oncol 2014;25(2):423-8. Yu HA Clin Cancer Res 2013;19(8):2240-7. Case discussion points (Ms Magnoli) • What were some of the key patient education points that you addressed when the patient was started on osimertinib? • What are the most common toxicity/tolerability issues with osimertinib? • How did the patient tolerate treatment with osimertinib? New Agent Profile: Osimertinib • Mechanism of action: – An orally available, irreversible, third-generation, mutantselective epidermal growth factor receptor (EGFR) inhibitor that selectively and covalently binds to and inhibits the activity of the mutant forms of EGFR, including the T790M EGFR-mutant form • Indication: – For the treatment of patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy • Recommended dose: – 80 mg orally once daily, with or without food www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=747632 Osimertinib package insert, April 2016 AURA: Osimertinib (AZD9291) in EGFR TKIResistant NSCLC: Response in Individual Patients Best percentage change from baseline in target-lesion size Evaluable patients with T790M+ NSCLC, expansion cohorts only (N = 127) ORR: 61% Most Common ≥Grade 3 AEs: • Diarrhea • Fatigue • Interstitial lung disease-like events Janne PA et al. N Engl J Med 2015;372(18):1689-99. Case discussion points (Ms Magnoli) • What is your general experience with rociletinib and the hyperglycemia associated with it? How common is the hyperglycemia? How is it managed clinically? Rociletinib (CO-1686) in EGFR Mutation-Positive NSCLC Change from baseline (%) Centrally confirmed T790M+ disease in patients within therapeutic dose range (N = 40) 900 mg BID FB/500 mg HBr 625 mg BID HBr 750 mg BID HBr * Ongoing 1000 mg BID HBr ORR to date: 58% Most Common ≥Grade 3 AEs: • Hyperglycemia and impaired glucose tolerance • QT prolongation Sequist LV et al. Proc ASCO 2014;Abstract 8010. FDA Denies Accelerated Approval for Rociletinib “April 12, 2016: The oral agent rociletinib, an experimental treatment for a subset of lung cancer patients, has not been recommended for accelerated approval from the US Food and Drug Administration (FDA). Instead, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 in favor of waiting for the results of an ongoing Phase III randomized clinical trial to be submitted before a regulatory decision is made.” http://www.medscape.com/viewarticle/861848 Case discussion points (Ms Magnoli) • How do you think this patient’s experience as a funeral home director has affected his perspective on being diagnosed with cancer? Module 2: ALK, ROS1 and Other Genetic Mutations in NSCLC Discussion Topics • ALK and ROS1 tumor rearrangements: Indications for testing • Efficacy of crizotinib in patients with ALK and ROS1 rearrangements; unique toxicities associated with crizotinib — vision abnormalities, hypogonadism • Next-generation ALK inhibitors: ceritinib, alectinib and others in development; optimal sequencing of available ALK inhibitors; tolerability issues and dosing • Other tumor mutations: BRAF, RET, HER2 54-Year-Old Man with ALK-Positive Metastatic NSCLC (Ms Stone) • 2011: Multiple systemic and local therapies for metastatic adenocarcinoma of the lung • October 2013: Right pleural biopsy again revealed adenocarcinoma – Molecular profiling identified an ALK gene fusion • Crizotinib for almost 2 years • Ceritinib initiated on disease progression • Imaging has revealed a response to treatment 54-Year-Old Man with ALK-Positive Metastatic NSCLC (Ms Stone) 6/26/15 – Progression on crizotinib 1/18/16 – Response to ceritinib Case discussion points (Ms Stone) • What were some of the key patient education points that you addressed when the patient was started on crizotinib? • How did you explain how it works? • What are the most common toxicity/tolerability issues with crizotinib? • How did the patient tolerate treatment with crizotinib? ALK Rearrangement in Cancer • Chromosomal translocation: Most common ALK abnormality in cancer • Rearrangement of genetic info: Parts of one chromosome break off and fuse with another or flip around (inversion) • Result: New gene and expression of fusion protein Cancer Genome Atlas, National Cancer Institute EML4-ALK Alterations in NSCLC • In ~4% of NSCLC cases • Enriched in younger, never or light smokers with adenocarcinoma • Rarely overlaps with EGFR and KRAS mutations Soda M et al. Nature 2007;448(7153):561-6. Decrease or increase from baseline (%) Activity of Crizotinib in ALK-Positive NSCLC Update of the Phase II Study (N = 240) 100 80 60 PD SD PR CR 40 20 0 -20 -40 -60 -80 -100 -120 Kim DW et al. Proc ASCO 2012;Abstract 7533. + + ++ Visual Disorders with Crizotinib “Trails” coming off lights in peripheral vision, in low light conditions Also at edges of vision in low light conditions: • Image persistence • Flashes of light, which don’t appear to be connected to a real light source • High contrast images (eg, stripes) flip registration Camidge DR. The International Journal of Targeted Therapies in Cancer 2012;6.12:30-3. Case discussion points (Ms Stone) • What were some of the key patient education points that you addressed when the patient was started on ceritinib? • What are the most common toxicity/tolerability issues with ceritinib? • How did the patient tolerate treatment with ceritinib? New Agent Profile: Ceritinib • Mechanism of action: – An orally available inhibitor of the receptor tyrosine kinase activity of anaplastic lymphoma kinase (ALK) • Indication: – For the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib • Recommended dose: – 750 mg orally once daily on an empty stomach (ie, do not administer within 2 hours of a meal) www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=694589 Ceritinib package insert, April 2016 Ceritinib (LDK378) Induces Responses in the Majority of Patients with Crizotinib-Resistant Disease Common Side Effects • Diarrhea • Nausea and vomiting • Dehydration • Elevated ALT/AST Shaw AT et al. N Engl J Med 2014;370(13):1189-97. 49-Year-Old Woman with ALK-Positive Metastatic NSCLC (Ms Stone) • March 2015: Diagnosis of adenocarcinoma of the lung metastatic to the brain and T7 – Possible leptomeningeal disease – ALK gene fusion • Crizotinib – Vision problems and headache – Workup results equivocal for leptomeningeal disease • Optic nerve radiation therapy and continued crizotinib • October 2015: Alectinib on an expanded access program Case discussion points (Ms Stone) • What were some of the key patient education points that you addressed when the patient was started on alectinib? • What are the most common toxicity/tolerability issues with alectinib? • How did the patient tolerate treatment with alectinib? New Agent Profile: Alectinib • Mechanism of action: – An orally available inhibitor of the receptor tyrosine kinase ALK • Indication: – For the treatment of patients with ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib • Recommended dose: – 600 mg orally twice daily. Administer with food www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=733572 Alectinib package insert, April 2016 Updated Analysis of Alectinib in Advanced ALK-Positive, Crizotinib-Resistant NSCLC Most AEs Grade 1-2 • Fatigue • Edema • Myalgia Grade ≥3: Reduction in neutrophils Shaw AT et al. Lancet Oncol 2016;17(2):234-42. ALEX Phase III Study Design • ALK+ • Stage IIIB/IV or recurrent NSCLC • Chemotherap y naïve • ECOG PS 0-2 Alectinib 600 mg BID (n = 143) R 1:1 Crizotinib 250 mg BID (n = 143) * Determined by investigators, based on RECIST v1.1 Ou SHI et al. Proc ASCO 2015;Abstract 8008. Until PD* or premature withdrawal (eg, due to toxicity) Subsequent therapy and survival follow-up Case discussion points (Ms Stone) • What is it like interacting with the patient’s daughter who is an oncology nurse practitioner? • What motivated the patient to start the Facebook group “Living with … ALK Mutation”? 62-Year-Old Woman with BRAF V600E MutationPositive Metastatic NSCLC (Ms Stone) • February 2012: Diagnosis of metastatic lung adenocarcinoma • Carboplatin/pemetrexed/bevacizumab x 6 cycles – Maintenance bevacizumab/pemetrexed • September 2012: Bevacizumab discontinued due to recurrent epistaxis • October 2014: New biopsy upon disease progression revealed a BRAF V600E tumor mutation • Vemurafenib on a clinical trial and no current evidence of active disease Case discussion points (Ms Stone) • What were some of the key patient education points that you addressed when the patient was started on vemurafenib? • What are the most common toxicity/tolerability issues with vemurafenib? • How did the patient tolerate treatment with vemurafenib? Case discussion points (Ms Stone) • What is the nature of the clinical responses and side effects you have observed in your patients who have BRAF-mutated NSCLC and are receiving a BRAF inhibitor? • What is the nature of the clinical responses and side effects you have observed in your patients who have BRAF-mutated NSCLC and are receiving a BRAF inhibitor in combination with a MEK inhibitor? Dabrafenib Combined with Trametinib in BRAF V600E-Mutated Metastatic NSCLC • The median duration of response was not reached Planchard D et al. Proc ASCO 2015;Abstract 8006. ROS1 Alterations in NSCLC ROS1 alterations • In ~1% of NSCLC cases • Enriched in younger, never or light smokers with adenocarcinoma • No overlap with other oncogenic drivers Bergethon K et al. J Clin Oncol 2012;30(8):863-70; Takeuchi K et al. Nat Med 2012;18(3):37881. Crizotinib in Advanced ROS1-Positive NSCLC Disease progression Stable disease Change from baseline (%) Partial response Complete response N = 50 evaluable ORR: 72% The safety profile of crizotinib was similar to that observed in ALK-positive advanced NSCLC Shaw AT et al. N Engl J Med 2014;371(21):1963-71. Case discussion points (Ms Stone) • What are some of this patient’s most important current goals? • How has this patient being the caregiver for her mother who has dementia affected how you approach her cancer care? Module 3: Management of Pan-Wild-Type Metastatic Adenocarcinoma of the Lung Discussion Topics • Systemic treatment of metastatic pan-wild-type NSCLC: Choice of chemotherapy regimen and role of bevacizumab • Recognition and management of hypertension and proteinuria with bevacizumab; risk of cardiovascular events • Maintenance strategies in NSCLC: Biologic therapy, chemotherapy or both 62-Year-Old Man with Metastatic NSCLC (Ms Magnoli) • Stage IV, poorly differentiated metastatic adenocarcinoma – Metastases to mediastinum, adrenal gland and pelvis • Palliative radiation therapy to the pelvis with improvement in bone pain • Carboplatin and pemetrexed • Carboplatin/nab paclitaxel/bevacizumab followed by maintenance bevacizumab Case discussion points (Ms Magnoli) • What were some of the key patient education points that you addressed when the patient was started on carboplatin/pemetrexed? • What are the most common toxicity/tolerability issues with carboplatin/pemetrexed? • How did the patient tolerate treatment with carboplatin/pemetrexed? Case discussion points (Ms Magnoli) • What were some of the key patient education points that you addressed when the patient was started on carboplatin/nab paclitaxel/bevacizumab? • What are the most common toxicity/tolerability issues with carboplatin/nab paclitaxel/bevacizumab? • How did the patient tolerate treatment with carboplatin/nab paclitaxel/bevacizumab? Sequencing of Commonly Used Chemotherapy/Biologic Regimens in Pan-WildType Lung Adenocarcinoma Pem/carbo/bev Paclitaxel/carbo/bev Carbo/pem Pem/bev OR pem OR bev maintenance Bev maintenance Pem maintenance PD-1/PD-L1 antibody PD-1/PD-L1 antibody PD-1/PD-L1 antibody Docetaxel ramucirumab Docetaxel ramucirumab Docetaxel ramucirumab Case discussion points (Ms Magnoli) • What are some of this patient’s most important current goals? • What type of end-of-life planning, if any, have you discussed with the patient? Discussion Topics • Predictors of response and efficacy of newly FDAapproved immune checkpoint inhibitor therapies in NSCLC • Current sequencing of immunotherapy • Pseudoprogression versus disease progression with checkpoint inhibitors 76-Year-Old Man with Metastatic NSCLC Receives Nivolumab (Ms Magnoli) • March 2014: Ex-boilermaker and current smoker (>100 pack years) is diagnosed with Stage IV panwild-type lung adenocarcinoma – Family history of lung cancer • Carboplatin/pemetrexed/bevacizumab – Maintenance bevacizumab • Nivolumab – Major response and improved quality of life with relief of dyspnea 76-Year-Old Man with Metastatic NSCLC Receives Nivolumab (Ms Magnoli) 10/21/2015 1/14/ 2016 After nivolumab x 4 cycles (2 months) Case discussion points (Ms Magnoli) • What was the time course for the patient’s response to nivolumab? • How did he tolerate treatment with nivolumab? Role of PD-1 in Suppressing Antitumor Immunity Patient’s T cells Tumor cell TCR MHC T Cell PD-L1 PD-1 B7.1 T-cell inhibition T Cells TCR MHC Tumor cell growth PD-1 PD-L1 Engineered Fc-domain B7.1 Tumor cell death T-cell activation + Anti-PDL1 Granzymes and perforin • Blocking PD-L1 restores T-cell activity, resulting in tumor regression in preclinical models • Binding to PD-L1 leaves PD-1/PD-L2 interaction intact and may enhance efficacy and safety Adapted from Spigel et al. Proc ASCO 2013;Abstract 8008. New Agent Profile: Nivolumab • Mechanism of action: – A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1) • Indication: – For the treatment of patients with metastatic NSCLC and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab • Recommended dose: – 3 mg/kg every 2 weeks www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=539733 Nivolumab package insert, April 2016 CheckMate 057: Duration of Response with Nivolumab Borghaei H et al. N Engl J Med 2015;373(17):1627-39. New Agent Profile: Pembrolizumab • Mechanism of action: – A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against human cell surface receptor PD-1 • Indication: – For patients with metastatic NSCLC whose tumors express PDL1 as determined by an FDA-approved test and who have disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab • Recommended dose: – 2 mg/kg as intravenous infusion over 30 minutes every 3 weeks www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=695789 Pembrolizumab package insert, April 2016 KEYNOTE-001: OS with Pembrolizumab by PD-L1 Proportion Score (PS) in NSCLC PS is the percentage of neoplastic cells positive for PD-L1 staining Garon EB et al. N Engl J Med 2015;372(21):2018-28. Percentage change from baseline Response to First-Line Nivolumab Combined with Ipilimumab in NSCLC ORR: 13%-39% mPFS: 4.9-10.6 mo a Based PD-L1 expression N (%) ≥1% PD-L1a <1% PD-L1a Unknownb 77 (68) 36 (32) 35 (24) on patients with known PD-L1 expression; b Based on all treated patients Rizvi NA et al. Proc IASLC 2015;Abstract ORAL02.05. New Agent in Development: Atezolizumab (MPDL3280A) • Mechanism of action: – A human, Fc optimized, monoclonal antibody directed against the protein ligand PD-L1 • Priority Review (April 10, 2016): – For patients with locally advanced or metastatic NSCLC whose disease expresses the protein PD-L1, as determined by an FDAapproved test, and who have progressed on or after platinumcontaining chemotherapy • Breakthrough Therapy Designation (February 2015): – For patients whose NSCLC expresses PD-L1 and whose disease progressed during or after standard treatments (e.g., platinum-based chemotherapy and appropriate targeted therapy for EGFR mutationpositive or ALK-positive disease) • Investigational Dose: – 1200-mg intravenous dose every 3 weeks www.cancertherapyadvisor.com/lung-cancer/lung-cancer-nsclc-fda-atezolizumab-priority-review/article/488800/ www.medscape.com/viewarticle/851625 Module 4: Management of Metastatic Squamous Cell Carcinoma of the Lung Discussion Topics • First-line treatment of metastatic squamous cell NSCLC: Role of nab paclitaxel • Second-line treatment options for metastatic squamous cell NSCLC • Lung-MAP trial and implications for future research • Incidence and management of immune-related adverse events associated with checkpoint inhibitor therapy • Use of corticosteroids and other immune suppressants for autoimmune complications of checkpoint inhibitors • Use of checkpoint inhibitors for patients with a history of autoimmune disease 68-Year-Old Man with Squamous Cell Carcinoma of the Lung (Ms Stone) • August 2014: Diagnosis of bilateral squamous cell carcinoma of the lung • Carboplatin/paclitaxel x 6 cycles • Durvalumab on SWOG-S1400 (Lung-MAP) clinical trial S1400: Master Lung-1: Squamous Lung Cancer Second-Line Therapy Common Biomarker Profiling Biomarker-Driven Sub-Studies Non-match Sub-Studies S1400B PI3K S1400C CCGA S1400D FGFR Taselisib Palbociclib AZD4547 S1400I Checkpoint Naive Durvalumab Nivolumab + Ipilimumab vs vs Docetaxel Nivolumab www.lung-map.org; www.clinicaltrials.gov; Accessed April 2016; (NCT02154490). Common Treatment Options for Pan-Wild-Type Metastatic Squamous Cell NSCLC First Line • Carboplatin/gemcitabine • Carboplatin/paclitaxel • Carboplatin/nab paclitaxel • Cisplatin/gemcitabine + necitumumab Second Line • Nivolumab • Pembrolizumab • Docetaxel ± ramucirumab • Gemcitabine NCCN Clinical Practice Guidelines in Oncology – Non-Small Cell Lung Cancer. V4.2016 Nanoparticle Albumin-Bound Paclitaxel (Nab/P) in Metastatic Squamous Cell Carcinoma of the Lung • FDA approval October 12, 2012 as first-line therapy for locally advanced or metastatic NSCLC, in combination with carboplatin • Phase III study (N = 1,052) in previously untreated Stage IIIB/IV NSCLC – Higher response rate with nab/P in squamous cell NSCLC – Overall survival benefit for older patients (≥70 years) Socinski MA et al. J Clin Oncol 2012;30(17):2055-62. Socinski MA et al. Ann Oncol 2013;24(2):314-21. Socinski MA et al. Ann Oncol 2013;24(9):2390-6. Common Treatment-Related Grade ≥3 Adverse Events with Nab Paclitaxel Nab paclitaxel (n = 514) Standard paclitaxel (n = 524) Adverse event Grade 3 Grade 4 Grade 3 Grade 4 p-value Neutropenia 33% 14% 32% 26% <0.001 Thrombocytopenia 13% 5% 7% 2% <0.001 Anemia 22% 5% 6% <1% <0.001 Sensory neuropathy 3% 0% 11% <1% <0.001 Socinski MA et al. J Clin Oncol 2012;30(17):2055-62. Differences between Nab Paclitaxel (Nab/P) and Cremophor®-Based Paclitaxel • No corticosteroid premedication with nab/P • Shorter infusion time with nab/P • Incidence, severity and reversibility of neuropathy? • Myelosupression? • Less Grade ≥3 neutropenia, arthralgias and neuropathy with nab/P • More Grade ≥3 thrombocytopenia and anemia with nab/P Immune-Related Adverse Events (IRAEs) Associated with Immune Checkpoint Inhibitors • Hypophysitis • Thyroiditis • Adrenal insufficiency • Colitis • Dermatitis • Pneumonitis • Hepatitis • Pancreatitis • Motor and sensory neuropathies • Arthritis Less common: hematologic; cardiovascular; ocular; renal Courtesy of Julie R Brahmer, MD.