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.

Lung Cancer 2012 – Where We Are and Where We’re Heading Pasi A. Jänne, M.D., Ph.D. Lowe Center for Thoracic Oncology Dana-Farber Cancer Institute

Strategies to Improve Outcome of Lung Cancer Patients Move away from approaching lung cancer as one disease Develop treatment strategies for different subsets of lung cancer Treatment improvements based on Histology Oncogenic alterations

Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine for Advanced NSCLC Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1 Randomization Factors Stage Performance status Gender Histologic vs cytologic diagnosis History of brain metastases R Each cycle repeated q3 weeks up to 6 cycles Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8 Vitamin B12, folate, and dexamethasone given in both arms Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-3551.

Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine for Advanced NSCLC Breakdown by Histology: Cis/Pem vs Cis/Gem Nonsquamous Squamous Survival Probability Median CP 11.8 months 95% CI 10.4, 13.2 9.4 months 95% CI 8.4, 10.2 Median CG 10.4 months 95% CI 9.6, 11.2 10.8 months 95% CI 9.5, 12.1 CP v CG adjusted HR; 95% CI 0.81; 0.70, 0.94 1.23; 1.00, 1.51 PFS Probability 5.3 months 95% CI 4.8, 5.7 4.4 months 95% CI 4.1, 4.0 4.7 months 95% CI 4.4, 5.4 5.5 months 95% CI 4.6, 5.9 0.90; 0.79, 1.02 1.36; 1.12, 1.65 Scagliotti GV, et al. J Clin Oncol, 2008;26(21):3543-3551.

Non Small Cell Lung Cancer: From Histology To Genomics Squamous cell cancer “Druggable” genomic alterations Kinases Critical to growth & survival of NSCLC Adenocarcinoma BRAF

OPTIMAL: Erlotinib vs. Chemotherapy in EGFR Mutant NSCLC Median progression-free survival Erlotinib (N = 82): 13.1 months Chemotherapy (N = 72): 4.6 months HR 0.16 (95% CI 0.10-0.26) Log-rank p < 0.0001 Zhou et al. Lancet Oncol 2011

EGFR Kinase Inhibitors 2012 Clinical activity in EGFR mutant NSCLC 1,2 1st line response rate: 60%-80% 1st line progression free survival 10–14 months Gefitinib and erlotinib superior to 1st line chemotherapy1,3 Higher RR and longer PFS; no OS improvement Better toxicity profile However – resistance develops in most if not all patients 1Mok et al. NEJM 2009; 2Rosell et al. NEJM 2009; 3Zhou et al. Lancet Oncol 2011

Soda et al. Nature 2007

Crizotinib is Clinically Effective in EML4-ALK NSCLC Kwak E et al. N Engl J Med 2010;363(18):1693-703. Copyright © 2012 Massachusetts Medical Society.

Randomized phase III trial of crizotinib vs chemotherapy in previously treated EML4-ALK NSCLC Key Entry Criteria Positive for ALK gene translocation Brain mets allowed 1 prior chemo (platinum-based) N = 159 Pemetrexed or Docetaxel N = 318 N = 159 Primary endpoint: PFS Secondary endpoints: ORR, DR, DCR, OS, Safety, QoL, Biomarkers

Phase 3 study in previously untreated NSCLC: A8081014 Trial design Endpoints Stratification World-wide, multicenter, randomized, open-label, focused screening Primary: PFS* Secondary: 6- and 12-month OS; OS; ORR*; DCR; DR; Safety; HRQoL; Lung cancer-specific symptoms; General health status; Biomarkers; TTD; HCRU ECOG PS (0/1 vs 2) Ethnicity (Asian vs non-Asian) Brain metastases *Based on RECIST v 1.1 and confirmed by independent radiology review Key entry criteria Diagnosis of locally advanced/metastatic non-squamous NSCLC; ECOG 0-2 Positive for ALK No prior treatment for advanced disease Brain metastases allowed R A N D O M I Z E Arm A: Crizotinib 250 mg BID administered on a continuous dosing schedule N = 160 Arm B: Pemetrexed/cisplatin or pemetrexed/carboplatin Day 1 of a 21-day cycle N = 160 N=320 Patients in Arm B who have RECIST-defined PD as determined by the independent radiology review will be allowed to cross over to Arm A www.clinicaltrials.gov (NCT01154140) 12 12

Non small cell lung cancer – from histology to genomics Squamous cell cancer Adenocarcinoma BRAF

Dacomitinib (PF299804) in ERBB2 amplified NSCLC Molecular analysis revealed a HER2-positive tumor Patient was commenced on dacomitinib in December 2008 and experienced a partial response after 4 weeks of 45 mg orally once daily with 21 days per cycle Of particular interest was a notable reduction in the patient's soluble extracellular domain HER2 levels (non-invasive method for tracking treatment efficacy) Kelly R J et al. JCO 2010

Pre-clinical efficacy of neratinib and afatinib in ERBB2 mutant NSCLC The subset of NSCLC patients with tumors carrying the ERBB2 mutation may benefit from treatment with neratinib1 The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor neratinib2 Clinical testing of afatinib/rapamycin in NSCLC patients with tumors expressing HER2 mutations is warranted3 1 Shimamura Cancer Res 2006 2 Minami Oncogene 2007 3 Perera PNAS 2009

Clinical activity of neratinib and temsirolimus in ERBB2 mutant NSCLC "The combination of NER and TEM has demonstrated preliminary antitumor activity in pts with HER2-dependent NSCLC and BC, as well as other solid tumors." Leena Gandhi – ASCO 2011

Ongoing Phase II Trial of Dacomitinib Cohort A: Non- or former light smoker or EGFR mu (1st line) Cohort B: HER-2 mu or HER-2 amp* Dacomitinib 45 mg QD N=80 Until Progression Serial T790M in blood Cohort A; * [gene]/[centromere of chromosome 17] ratio >2 Cohort B: no limit on prior number of regimens

Summary of BRAF mutations from DFCI NSCLC patients V600E G466V G466R G469 del G469A Inst T D594G D594N Exon 11 mutations

Efficacy of Vemurafenib in BRAF V600E Melanoma Chapman PB et al. N Engl J Med 2011;364:2507-2516. Copyright © 2012 Massachusetts Medical Society.

Will BRAF inhibitors demonstrate activity in lung/colon/etc tumors with BRAF V600E? Vemurafenib (PLX4032) shows activity at 960 mg BID in metastatic CRC patients (n=19)* with the BRAF V600E mutation With permission from Kopetz et al. ASCO, 2010

Phase II trial of dabrafenib (GSK2118436) Primary endpoint Response Rate Secondary PFS OS Toxicity Dabrafenib Stage IV NSCLC Previously treated BRAF V600E mutant Sample size: 40 patients Mutation testing can be done in any CLIA lab Correlative biomarkers: serum DNA for BRAF V600E

Adopted from Schubber et al, Nature Cancer Review 2007 RAS Signaling Adopted from Schubber et al, Nature Cancer Review 2007

Efficacy of trametinib (GSK1120212) in BRAF mutant melanoma and KRAS mutant NSCLC KRAS mutant NSCLC (n=14) 2 PR (20+ and 33+ wks) 7 SD (3 > 16 wks) and 5 PD With permission from Falchook et al. ESMO 2010

Trametinib: KRAS-mutant NSCLC K-ras mutations (n = 22) PFS: Median (95% CI) = 3.8 (1.9-5.5) months K-ras wild type (n = 8) PFS: Median (95% CI) = 2.1 (1.8-5.2) months Blumenschein. Proc Santa Monica Meeting, 2011

MEK114654 Phase II Study in KRAS-Mutant NSCLC Trametinib (2 mg QD) n=80 Docetaxel (75 mg/m2 every 3 wks i.v.) Trametinib 2 mg QD Screen KRAS- MUT PFS PFS2 n=40 Key study design features: 2:1 randomization; cross-over after PD Population: - KRAS-mutant Adenocarcinoma Stage IIIb / IV - 2nd line population - ECOG 0 or 1 Primary endpoints: PFS Secondary endpoints: OS, ORR, DR, safety, biomarker validation

MEK114654 Phase II Study in KRAS-Mutant NSCLC Trametinib (2 mg QD) n=80 Docetaxel (75 mg/m2 every 3 wks i.v.) Trametinib 2 mg QD Screen KRAS- MUT PFS PFS2 n=40 Key study design features: 2:1 randomization; cross-over after PD Population: - KRAS-mutant Adenocarcinoma Stage IIIb / IV - 2nd line population - ECOG 0 or 1 Primary endpoints: PFS Secondary endpoints: OS, ORR, DR, safety, biomarker validation Additional cohort of 25 patients: BRAF mutant (both exon 11 and 15) MEK 1 mutant NRAS mutant

Randomized Phase II trial of Selumetinib (AZD6224) vs. Chemotherapy Selumetinib in combination with docetaxel Primary Overall Survival Secondary Progression Free Survival Objective Response Rate Duration of Response Use of plasma & serum as source of CFDNA for analysis of KRAS mutation status Investigate PK of selumetinib Patients: NSCLC (IIIB–IV) 2nd line patients KRAS mutant WHO PS 0–1 1:1 randomisation Placebo in combination with docetaxel Sample size: 87 Study completed accrual; data will be presented at ASCO 2012 27

Randomized Phase II trial of Selumetinib (AZD6224) vs. Chemotherapy Selumetinib in combination with docetaxel Primary Overall Survival Secondary Progression Free Survival Objective Response Rate Duration of Response Use of plasma & serum as source of CFDNA for analysis of KRAS mutation status Investigate PK of selumetinib Patients: NSCLC (IIIB–IV) 2nd line patients KRAS mutant WHO PS 0–1 “…progression-free survival, objective response rate, and alive and progression-free at 6 months were all demonstrated with statistical significance, showing improvement in favor of selumetinib in combination with docetaxel versus docetaxel alone.” ARRAY press release Sep 30th 2011 1:1 randomisation Placebo in combination with docetaxel Sample size: 87 Study completed accrual; data will be presented at ASCO 2012

Squamous Cell Lung Cancer A significant minority of NSCLC No effective targeted therapy Lack of efficacy or toxicity for Pemetrexed Bevacizumab Some KRAS and PIK3CA mutations Ongoing systematic genomics efforts The Cancer Genome Atlas

DDR2 Mutations in Squamous Cell Cancer "DDR2 mutations are present in 4% of lung SCCs, and DDR2 mutations are associated with sensitivity to dasatinib." Hammerman et al. Cancer Discovery 2011

Continue until disease progression or development of toxicity Phase II Trial of Dasatinib in Squamous Cell Lung Cancer – DF/HCC #11-142 Stage IV Squamous cell histology 1 prior systemic therapy Tissue available Dasatinib Continue until disease progression or development of toxicity 100 mg daily Continuous Primary objective: Response Rate Secondary objectives: Types/Frequencies of DDR2 Mutations, Correlation of DDR2 Mutations with RR, PFS, OS and Tox PI: Hammerman/Johnson

FGFR1 Amplification in a Subset of Squamous Cell Cancers "Focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients." Weiss J et al. Sci Transl Med 2010

FGFR1 Inhibitor is Effective in FGFR1 Amplified Cells Phase I trial of BGJ398 (Pan FGFR inhibitor) is currently underway (NCT01004224) Weiss J et al. Sci Transl Med 2010

DFCI Thoracic Program Genomics Initiative Aim to provide routine genotyping to all lung cancer patients EGFR 2004; KRAS 2008 Comprehensive July 2009 Partly supported by philanthropy EGFR, KRAS, BRAF, PIK3CA, ERBB2 & EML4-ALK > 900 patients genotyped to date 4 dedicated CRCs

DFCI Thoracic Program Genomics Initiative contd. Limited to “non-squamous cell” carcinoma Squamous cell carcinoma to start 2012 Failure rate ~10% Insufficient tumor, bad quality DNA Bone biopsies are bad for genotyping ~50% of the patients with known alterations have received a molecularly targeted therapy

Systematic Genotyping of Lung Adenocarcinomas at DFCI Erlotinib Second generation EGFR TKI PF00299804 Lapatinib/Temsirolimus XL147, PKI587 GDC 0980, ZSTK474 Docetaxel +/- AZD6244 GSK 1120212 vs. Docetaxel GDC 0973/GDC0941 AZD6244 GSK2118436 GSK 1120212 Crizotinib vs. Chemotherapy Crizotinib, 2nd Generation ALK Inhibitors

Lung Cancer Mutation Consortium

Patients and Study Plan Lung Cancer Mutation Consortium Patients and Study Plan 1000 patients Stage IV ECOG PS 0-2 Lung Adenocarcinoma Sufficient Tissue (Paraffin) Informed Consent Central Confirmation of Adenocarcinoma Diagnosis (1 slide) Report to LCMC Virtual Database Use Data to Select Therapy (Erlotinib with EGFR Mutation) Mutational Analysis CLIA-certified lab at LCMC site: KRAS, EGFR, EML4-ALK, BRAF, HER2, PIK3CA, NRAS, MEK1, AKT1, MET amplification Report to Physician Recommend Clinical Trial of Agent Specific for Target Kris et al. ASCO 2011

Incidence of Single Driver Mutations Lung Cancer Mutation Consortium Incidence of Single Driver Mutations Mutation found in 54% (280/516) of tumors completely tested (CI 50-59%) Kris et al. ASCO 2011

Evolution of Lung Cancer Genotyping Current – sequencing based (6 genes) Currently limited to lung cancer Mass spec based genotyping (Oncomap) All cancers; started in 2011 Whole exome sequencing in development U01 grant Lung cancer and colorectal cancer

Lung Cancer 2012 – Where We Are and Where We’re Heading “One size fits all” era of treatment and drug development is over for lung cancer Two validated genomic targets Mutant EGFR and ALK rearrangements Ongoing - ? use in earlier disease & drug resistance Rapid pace of pre-clinical discoveries Goal to find and develop effective therapies for all subsets of NSCLC patients

Lung Cancer 2012 – Where We Are and Where We’re Heading Pasi A. Jänne, M.D., Ph.D. Lowe Center for Thoracic Oncology Dana-Farber Cancer Institute 42