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Non-Small Cell Lung Cancer Year in Review 2012

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Non-Small Cell Lung Cancer Year in Review 2012

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  1. 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. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

  2. Non-Small Cell Lung CancerYear in Review 2012 Corey J Langer, MD Director of Thoracic Oncology Abramson Cancer Center Professor of Medicine University of Pennsylvania Vice Chair, Radiation Therapy Oncology Group

  3. Have you attempted to obtain a ROS1 mutational analysis for any of your patients with non-small cell lung cancer (NSCLC)?

  4. Clinical Activity of Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring ROS1 Gene Rearrangement Shaw AT et al. Proc ASCO 2012;Abstract 7508

  5. ROS1 • New “driver” mutation: ROS1 • ROS1: 18/1,073 (1.7%) tumors • Receptor Tyrosine Kinase • ATP binding like ALK • 77% identical • Detected by Break-apart FISH • Younger pts • Never-smokers • Adenocarcinoma Bergethon JCO 30:863, 2012: Janne JCO 30:878; 2012

  6. ROS1 — Crizotinib Activity • ROS1 included in crizotinib dose escalation • At 250 mg bid dosing • Reported on 15 pts • 7/15 had PR; 1 CR and only 1 with PD • Very similar RR and toxicity as in ALK+ pts

  7. Clinical tumor responses in ROS1+ NSCLC treated with crizotinib • Restaging scans at 8 weeks demonstrated near complete resolution of multifocal lung tumor, which was subsequently confirmed at 12 weeks1 • 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib2 1. Bergethon et al. JCO 2012 2. Davies et al., accepted AACR 2012

  8. Study Design Phase II, single-arm, multicenter study; ~1100 patients (enrollment ongoing) Treatment • Key eligibility criteria: • ALK+ NSCLC by central laboratory • Local test allowed on case-by-case basis per protocol amendment (January 2011) • ECOG PS: 0–3 • ≥1 prior line of chemotherapy • Stable/controlled brain metastases allowed Crizotinib 250 mg po BIDcontinuous daily dosing • Primary endpoints: • ORR • safety/tolerability • Secondary endpoints include: • OS • PFS • Duration of response • Time to response • PRO/HRQOL Riely G et al. Chicago IASLC/ASTRO 2012;Abstract 3.

  9. Patient Characteristics Riely G et al. Chicago IASLC/ASTRO 2012;Abstract 3.

  10. Best Response of Indicator Lesions Mature population* 100 PD SD PR^ CR+ 80 60 40 20 0 Decrease or increase from baseline (%) –20 –40 –60 + + –80 –100 + + –120 *n=240 response-evaluable patients from the mature population, and excludes patients with early death, indeterminate response and non-measurable disease ^ Responses observed in untreated CNS mets +Per RECIST 1.1, percent change from baseline for subjects with best overall response of CR can be less than 100% when lymph nodes are included as target lesions With permission from Riely G et al. Chicago IASLC/ASTRO 2012;Abstract 3.

  11. ESMO 2012 – NSCLC • PROFILE 1007: Phase III study of crizotinib vs pemetrexed or docetaxel chemotherapy in advanced ALK-positive NSCLC. Shaw AT et al. Abstract LBA1_PR. • Median PFS: 7.7 mo vs 3.0 mo (HR 0.49; P<0.0001) • ORR: 65% vs 20% (P<0.0001) • These findings establish crizotinib as the standard of care for pts with previously treated advanced ALK-positive NSCLC

  12. A 60-year-old patient with adenocarcinoma of the lung, PS 0 and exon 19 EGFR mutation experiences a 1-year response to erlotinib but then develops slow, objective, asymptomatic disease progression. What is your likely approach?

  13. In a recent Phase III study, afatinib was shown to be superior to __________ as first-line treatment for patients with advanced EGFR mutation-positive NSCLC.

  14. 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 Rosell R et al. Lancet Oncology 2012;13(3):239-46.

  15. EURTAC Study Design Erlotinib 150mg/day PD Primary endpoint • Progression-free survival (PFS) • interim analysis planned at 88 events Secondary endpoints • Objective response rate • Overall survival (OS) • Location of progression • Safety • EGFR mutation analysis in serum • Quality of life • Chemonaїve • Stage IIIB/IV NSCLC • EGFR exon 19 deletion or exon 21 L858R mutation • ECOG PS 0–2 (n = 174) • Stratification • Mutation type • ECOG PS (0 vs 1 vs 2) R Platinum-based doublet chemotherapy q3wks x 4 cycles* PD ECOG = Eastern Cooperative Oncology Group; PS = performance status; PD = progressive disease*Cisplatin 75mg/m2 d1 / docetaxel 75mg/m2 d1; cisplatin 75mg/m2 d1 / gemcitabine 1250mg/m2 d1,8;carboplatin AUC6 d1 / docetaxel 75mg/m2 d1; carboplatin AUC5 d1 / gemcitabine 1000mg/m2 d1,8

  16. PFS in ITT Population PFS: • Erlotinib (n = 86), 9.7 months • Chemotherapy (n = 87), 5.2 months • HR = 0.37 (0.25-0.54) • Log-rank p<0.0001 (data cut-off 1-26-11) OS HR 1.04, NS; MST 19.3mo-E vs 19.5mo-C Rosell R et al. Lancet Oncology 2012;13(3):239-46.

  17. EGFR TKI vs Platinum-Based Therapy *Numbers represent EGFR mutation positive subsets Mok et al. NEJM 2009; Fukuoka et al. JCO 2011; Maemondo et al. NEJM 2010; Mitsudomi et al. Lancet Oncology 2010; Zhou et al. Lancet Oncology 2011; Lee 13th WLC 2009, Rosell et al. Lancet Oncology 2012

  18. LUX-Lung 3: A Randomized, Open-Label, Phase III Study of Afatinib vs Cisplatin/Pemetrexed as 1st-Line Treatment for Patients with Advanced Adenocarcinoma of the Lung Harboring EGFR-Activating Mutations Yang JCH et al. Proc ASCO 2012;Abstract LBA7500.

  19. LUX LUNG3 Study Design Stage IIIB (wet)/IV lung adenocarcinoma (AJCC version 6) EGFR mutation in tumor (central lab testing; Therascreen EGFR29 RGQ PCR) Randomization 2:1 Stratified by: EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian) Afatinib 40 mg/day† Cisplatin + Pemetrexed 75 mg/m2 + 500 mg/m2 i.v. q21 days, up to 6 cycles Primary endpoint: PFS (RECIST 1.1, independent review) Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, PRO, safety, PK 72% Asian, 65% women, 68% NS 49% del19, 40% L858R, 11% other Yang JC et al. Proc ASCO 2012;Abstract LBA7500.

  20. Primary Endpoint: PFS Independent review — all randomized patients 1.0 0.8 0.6 Progression-free survival (probability) HR 0.47 if “other” excluded 47% 0.4 0.2 22% 0.0 0 3 6 9 12 15 18 21 24 27 Progression-free survival (months) With permission from Yang JC et al. Proc ASCO 2012;Abstract LBA7500.

  21. Most Frequent Related Adverse Events>20% difference between treatment arms *Grouped term. †No grade 5 events for the presented AEs. Yang JC et al. Proc ASCO 2012;Abstract LBA7500.

  22. SELECT: A Multicenter Phase II Trial of Adjuvant Erlotinib in Resected EGFR Mutation Positive NSCLC Joel Neal1, Nathan Pennell2, Ramaswamy Govindan3, Rebecca Heist4, Alice Shaw4, Alona Muzikansky4, Pasi Jänne5, Thomas Lynch6, Jerry Azzoli4,7, Lecia Sequist4 Proc ASCO 2012;Abstract 7010 1 Stanford Cancer Institute, Stanford, CA ; 2 Cleveland Clinic, Cleveland, OH; 3 Washington University, St. Louis, MO; 4 Massachusetts General Hospital, Boston, MA; 5 Dana-Farber Cancer Institute, Boston, MA; 6 Yale Cancer Center, New Haven, CT; 7 Memorial Sloan-Kettering Cancer Center, New York, NY

  23. SELECT: Study Design • Single arm Phase II study • Adjuvant erlotinib following surgery and “standard” therapy CT surveillance: - Every 6 mo x 3 years - Annually years 4 and 5 • Stage IA-IIIA NSCLC • Surgically resected • EGFR mutation positive • Completed routine adjuvant chemotherapy and/or XRT Erlotinib 150 mg PO daily Observation • Primary Endpoint: • Disease Free Survival: • Goal: 2-year >86% • Secondary Endpoints: • Safety and Tolerability • Overall Survival 2 years duration Total N = 100 This report on 36 pts

  24. SELECT: Disease Free Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median follow-up time: 2.7 years Survival Probability Censored observation 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Time from initiating adjuvant erlotinib (Years) Patients at Risk 36 35 34 34 33 19 7 3 1 0 With permission from Neal J et al. Proc Chicago Multidisciplinary Symposium in Thoracic Oncology 2012;Abstract 16.

  25. What is your usual front-line and maintenance strategy for patients with EGFR wild-type tumors without contraindications to bevacizumab? Carbo/paclitaxel/bev bev Carbo/paclitaxel/bev pemetrexed Carbo/paclitaxel/bev pemetrexed/bev Carbo/pemetrexed/bev bev Carbo/pemetrexed/bev pemetrexed Carbo/pemetrexed/bev bev/pemetrexed

  26. A Randomized, Open-Label, Phase III, Superiority Study of Pemetrexed (Pem) + Carboplatin (Cb) + Bevacizumab (Bev) Followed by Maintenance Pem + Bev versus Paclitaxel (Pac) + Cb + Bev Followed by Maintenance Bev in Patients with Stage IIIB or IV Non-Squamous Non-Small Cell Lung Cancer (NS-NSCLC) Patel JD et al. 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology;Abstract LBPL1.

  27. PointBreak: Study Design • Randomized, open-label, Phase III superiority study conducted in US • Pemetrexed 500 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg • Paclitaxel 200 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg Maintenance Phase q21d until PD Induction Phaseq21d, 4 cycles • Inclusion: • - No prior systemic therapy for lung cancer • - PS 0/1 • - Stage IIIB-IV NS-NSCLC • - Stable tx’t brain mets • Exclusion: • Peripheral neuropathy • ≥ Gr 1 • - Uncontrolled pleural effusions Pemetrexed (folic acid & vitamin B12) + Carboplatin + Bevacizumab Pemetrexed (folic acid & vitamin B12) + Bevacizumab R1:1 450 patients each Bevacizumab Paclitaxel + Carboplatin + Bevacizumab Stratified for: PS (0 vs 1); sex (M vs F); disease stage (IIIB vs IV); measurable vs nonmeasurable disease Note Randomization BEFORE initiation of therapy

  28. Two POINT-BREAK Questions: • Would it POINT the way to a new treatment paradigm? • If Pemetrexed/Bevacizumab became a new standard during induction and maintenance, would the combination BREAK the bank?

  29. PointBreak: Kaplan-Meier (KM) OS from Randomization (ITT) With permission from Patel J et al. Chicago IASLC/ASTRO 2012;Abstract LBPL1.

  30. Carboplatin-Based, Bevacizumab-Based Trials in Advanced NSCLC 1Mok et al, ESMO 2011 2Sandler et al, NEJM 2006 3Patel et al, JCO 2009 4Stevenson, Cancer 2011 5Patel et al, Chicago IASLC/ASTRO, 2012

  31. Carboplatin-Based, Bevacizumab-Based Trials in Advanced NSCLC 1Mok et al, ESMO 2011 2Sandler et al, NEJM 2006 3Patel et al, JCO 2009 4Stevenson, Cancer 2011 5Patel et al, Chicago IASLC/ASTRO, 2012

  32. PointBreak: KM PFS from Randomization (ITT) Exploratory analysisCensoring rate for Pem + Cb + Bev was 26.9%; for Pac + Cb + Bev was 23.3% With permission from Patel JD et al. 2012 Chicago Multidisciplinary Symp in Thoracic Oncol;Abstract LBPL1.

  33. PointBreak: Pre-specified Exploratory Analysis of KM OS from Randomization: Maintenance Group Pre-specified exploratory non-comparative subgroup analyses Censoring rate for Pem + Cb + Bev was 36.0%; for Pac + Cb + Bev was 30.2% With permission from Patel JD et al. 2012 Chicago Multidisciplinary Symp in Thoracic Oncol;Abstract LBPL1.

  34. ECOG-E5508: Phase III Study of Maintenance Bevacizumab, Pemetrexed or the Combination in NSCLC Study Start Date: August 2010 Target Accrual: 1,282 Bevacizumab Bevacizumab + Pemetrexed Pemetrexed • Eligibility • Stage IIIB/IV • Nonsquamous • NSCLC • No brain mets • ≥ stable or response after carbo/paclitaxel + bevacizumab R Primary Endpoint: Overall survival www.clinicaltrials.gov, October 2012

  35. Multidisciplinary Symposium in Thoracic Oncology 2012 (ASCO) 06-08 September 2012 Hirsch V et al. Weekly nab-Paclitaxel in Combination with Carboplatin as First-Line Therapy in Patients (pts) with Advanced Non-Small Cell Lung Cancer(NSCLC): Analysis of Patient-Reported Neuropathy and Taxane-Associated Symptoms. Abstract 108; Thoracic Oncology 2012 Socinski MA et al. Weekly nab-Paclitaxel In Combination With Carboplatin As First-line Therapy In Elderly Patients (pts) With Advanced Non-small Cell Lung Cancer (NSCLC). Abstract 109; Thoracic Oncology 2012. Renschler MF et al. Safety and Efficacy by Histology of Weekly nab-Paclitaxel in Combination with Carboplatin as First-line Therapy in Patients (pts) with Advanced Non-Small Cell Lung Cancer (NSCLC). Abstract 110; Thoracic Oncology 2012

  36. October 15, 2012 • The FDA has approved nab-paclitaxel plus carboplatin for patients with untreated locally advanced or metastatic non-small cell lung cancer (NSCLC) who are not candidates for surgery or radiation • The approval was based on results from the phase III CA031 trial, which showed that weekly nab-paclitaxel combined with carboplatin significantly improved overall response rate (ORR), when compared with solvent-based (sb) paclitaxel plus carboplatin Source: FDA Press Release

  37. What is your usual first-line chemotherapy regimen for patients with metastatic squamous cell NSCLC? Carboplatin/paclitaxel Carboplatin/gemcitabine Carboplatin/nanoparticle albumin-bound (nab) paclitaxel Carboplatin/pemetrexed Other

  38. Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients with Advanced Non-Small-Cell Lung Cancer J.R. Brahmer,1 L. Horn,2 S.J. Antonia,3 D. Spigel,4 L. Gandhi,5 L.V. Sequist,6 J.M. Wigginton,7 D. McDonald,7 G. Kollia,7 A. Gupta,7 S. Gettinger8 Proc ASCO 2012;Abstract 7509. 1Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD; 2Vanderbilt-Ingram Cancer Center, Nashville, TN; 3H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 4Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; 5Dana-Farber Cancer Institute, Boston, MA; 6Massachusetts General Hospital Cancer Center, Boston, MA; 7Bristol-Myers Squibb, Princeton, NJ; 8Yale University School of Medicine, New Haven, CT

  39. Response of Metastatic NSCLC (BMS-936558, 10 mg/kg) • Initial progression in pulmonary lesions of a NSCLC patient with non-squamous histology was followed by regression • Dx ‘04, EGFR mutation+; Rx gem/carbo, erlotinib, erlotinib + LBH589 (trial for T790 mutation), and lastly pemetrexed With permission from Brahmer JR et al. Proc ASCO 2012;Abstract 7509.

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