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Corey J. Langer MD, FACP Director of Thoracic Oncology Abramson Cancer Center

KRAS in Non-Small Cell Lung Cancer (NSCLC) Is it Prognostic or Predictive? Is it an Actionable Target?. Corey J. Langer MD, FACP Director of Thoracic Oncology Abramson Cancer Center Professor of Medicine University of Pennsylvania Philadelphia, PA 19104. Langer Disclosures: Past 5 yrs.

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Corey J. Langer MD, FACP Director of Thoracic Oncology Abramson Cancer Center

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  1. KRAS in Non-Small Cell Lung Cancer (NSCLC)Is it Prognostic or Predictive?Is it an Actionable Target? Corey J. Langer MD, FACP Director of Thoracic Oncology Abramson Cancer Center Professor of Medicine University of Pennsylvania Philadelphia, PA 19104

  2. Langer Disclosures: Past 5 yrs • Grant/Research Support: • BMS, Pfizer, Imclone, Lilly, SPRI, SanofiAventis, Amgen, CTI, Celgene, Vertex, Genentech (Roche), OSI, AstraZeneca, Pfizer, Medimmune, GSK, Merck, EMD-Serono, Pharmacyclics • DSMC: • Amgen, Synta, Lilly, Agennix • Scientific Advisor: • BMS, Imclone, Sanofi-Aventis, Pfizer, GSK, AstraZeneca, Novartis, Genentech, OSI, Bayer/Onyx, Celgene, Clarient, Morphotek, Biodesix, Abbott • Speakers Bureau: curtailed as of Dec, 2010 • BMS, Imclone, Sanofi-Aventis, Lilly, Genentech, OSI

  3. Numerous Molecular Changes Drive Lung Cancer No mutation detected KRAS 25% AKT1 NRAS MEK1 MET AMP HER2 PIK3CA BRAF EML4-ALK 7% EGFR 17% Double 3% Kris, et al. J Clin Oncol 2011;29:Suppl(Abstr 7506).

  4. Signaling through kRAS Roberts P J , and Stinchcombe T E JCO 2013;31:1112-1121

  5. KRAS Is Not a Single Entity Data: COSMIC database at Sanger Institute, http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=gene&ln=KRAS

  6. KRAS Mutation & Smoking Status 35 % 30 25 20 15 10 5 0 Riely 481 Sugio 322 Sequist 546 Ortiz 331 (100% ADK) (100% ADK) (78% ADK) (85%ADK)* Never Smoker Former smoker Current smoker Riely et al. Clin Can Res 2008; Sugio et al. Br J Cancer 2006; Ortiz #7517 ASCO 2011, Sequist #7518 ASCO 2011

  7. KRAS mutation in NSCLCSmokers vs. Nonsmokers

  8. Prognostic Significance of KRAS Mutation

  9. Prognostic Significance of KRAS in Surgical Series JBR.10 HR 1.23 p=0.40 N=113 ECOG 4592 HR 0.82, P=0.38 N=19 N=44 Slebos NEJM J Med 323: 561, 1990 Tsao. JCO 25:5240, 2007 Schiller. J Clin Oncol 19: 448, 2001

  10. Pooled Analysis of KRAS Mutation in LACE-Bio Tsao et al, Proc ESMO, 2010 ADC: adenocarcinoma; SCC: squamous cell carcinoma

  11. Distribution of KRAS Mutations by Histology

  12. No. Deaths / No. Entered Category Hazard Ratio HR [95% CI] Mutated Wild-type Squamous cell carcinoma 20/44 325/661 1.05 [0.66;1.67] Adjusted HR=1.19 95%CI=[0.75;1.88] P-value=0.46 Adenocarcinoma 98/206 187/396 1.03 [0.80;1.32] Adjusted HR=1.01 95%CI=[0.79;1.30] P-value=0.93 Other NSCLC 31/53 90/176 1.35 [0.87;2.11] Adjusted HR=1.56 95%CI=[1.0;2.40] P-value=0.05 Total 149/303 602/1233 1.09 [0.90;1.33] 0.1 1.0 4.0 | Mutated better Wild-type better Test for interaction: p=0.60 Prognostic Effect of KRAS Mutation in LACE-Bio P=0.39

  13. No. Deaths / No. Entered Category Hazard Ratio HR [95% CI] Mutated Wild-type Squamous cell carcinoma 20/44 325/661 1.05 [0.66;1.67] Adjusted HR=1.19 95%CI=[0.75;1.88] P-value=0.46 Adenocarcinoma 98/206 187/396 1.03 [0.80;1.32] Adjusted HR=1.01 95%CI=[0.79;1.30] P-value=0.93 Other NSCLC 31/53 90/176 1.35 [0.87;2.11] Adjusted HR=1.56 95%CI=[1.0;2.40] P-value=0.05 Total 149/303 602/1233 1.09 [0.90;1.33] 0.1 1.0 4.0 | Mutated better Wild-type better Test for interaction: p=0.60 Prognostic Effect of KRAS Mutation in LACE-Bio 1.03 [0.80-1.32] P=0.39

  14. KRAS and Other Mutations EGFR P53

  15. Prognostic Effect of KRAS Mutation in EGFR Wild-type Adeno in LACE-Bio Janne et al, Proc ESMO, 2012

  16. Prognostic Value of TP53 and KRAS Mutations on OS in Observation Patients *7 patients with missing covariates are excluded Janne et al, Proc ESMO, 2012

  17. LACE-Bio: KRAS Mutation Type * One codon 14 mutation, 3 double mutations on codon 12

  18. Prognostic Effect of KRAS Codon 12 &13 Mutations on OS (Obs. Arm) • Variable HR • KRAS WT 1 • Codon 12 mut 1.04 • Codon 13 mut 1.01 • p=0.96 Logrank p=0.83 Shepherd et al. Proc ASCO, 2012

  19. LACE-Bio: KRAS Mutation Type Shepherd et al. Proc ASCO, 2012

  20. Prognostic Effect of Specific Codon 12 AA Substitutions on OS All patients Observation arm Shepherd et al. Proc ASCO, 2012

  21. Is kRAS a marker of adverse prognosis? Weakly vs. Not Mascuax, Br. J. Cancer 2005 Janne, Proc ESMO 2012

  22. Predictive Value of KRAS EGFR Inhibitors Chemotherapy

  23. KRAS and its Impact on EGFR Inhibitors EGFR TKIs TRIBUTE BR.21 ATLAS SATURN INTEREST Cetuximab Trials BMS 099 FLEX

  24. 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 5 5 10 10 15 15 20 20 Months KRAS Gene Mutations in TRIBUTE Progression-Free Survival Overall Survival KRAS mutant Months Chemotherapy, wild type (n=103) Erlotinib + chemotherapy, wild type (n=104) Chemotherapy, mutant (n=30) Erlotinib + chemotherapy, mutant (n=25) Eberhard D, et al. J Clin Oncol 2005;25:5900.

  25. BR.21 Survival According to Updated KRAS Mutation Status KRAS Mutation KRAS Wild Type 100 100 Median: 7.5 (5.4, 10.7) 3.4 (3.0, 7.1) HR=0.69 (0.49-0.97) P=0.0311 Median: 3.7 (1.9, 7.9) 7.0 (1.7, 19.5) HR=1.67 (0.62-4.50) P=0.3096 80 80 60 60 Percentage Placebo Percentage Erlotinib 40 40 20 20 Placebo Erlotinib 0 0 0 6 12 18 24 0 6 12 18 24 Time (months) Time (months) Despite the large numerical differences in the HRs, no significant interaction could be demonstrated Interaction p value 0.09 Interaction P value = 0.09 Zhu et al. J Clin Oncol, 2008.

  26. ATLAS: PFS by KRAS Mutation Status KRAS Wild-Type KRAS Mutant B+E (n=124) B+E (n=47) B+P (n=115) B+P (n=46) Censored value Censored value HR = 0.666 (CI: 0.485 - 0.914) Log-rank P=0.0105 HR = 0.925 (CI: 0.548 - 1.562) Log-rank P=0.7697 Johnson et al. Proc IASLC, 2009

  27. SATURN – PFS KRAS MUTATIONS KRAS Mutation +ve KRAS Wild-type HR=0.77 (0.50-1.19) LR P=0.679 HR=0.70 (0.57-0.87) LR P=0.698 Brugger et al. Proc ASCO, 2009

  28. Gefitinib (n = 94) Docetaxel (n = 109) INTEREST: PFS byKRAS Mutation Status KRAS wild-type KRAS mutation 1.0 1.0 Gefitinib (n = 20) Docetaxel (n = 27) 0.8 0.8 HR 1.16 ( CI 0.56, 2.41) p = 0.68 HR 1.23 ( CI 0.90, 1.68) p = 0.199 0.6 0.6 Probability of PFS Probability of PFS 0.4 0.4 0.2 0.2 0.0 0.0 0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40 Months Months HR (95% CI) = 1.16 (0.56, 2.41) p = 0.6824 Median PFS (mo): gefitinib 1.4, docetaxel 1.5 HR (95% CI) = 1.23 (0.90, 1.68) p = 0.1998 Median PFS (mo): gefitinib 2.6, docetaxel 3.3 Cox analysis with covariates Douillard et al. J Clin Oncol 28: 744, 2009

  29. The Effect of KRAS Mutation Status on EGFR Antibody Therapy in Colon Cancer Panitumumab Cetuximab KRAS Mutant KRAS Mutant KRAS Wild type KRAS Wild type Amado et al. J Clin Oncol: 26: 1626, 2008 Jonker D et al. N Engl J Med: 359: 1757, 2008

  30. BMS099: Overall Survival by KRAS Status HR 0.93, P=0.88 HR 0.97, p=0.93 Khambata-Ford et al. J Clin Oncol 28: 918, 2010

  31. FLEX: Overall Survival by KRAS Status C225 C225 HR 0.96, P=0.75 HR 1.00, P=1.00 O’Byrne et al. Lancet Oncol 12: 795, 2011

  32. Predictive Value of KRAS on Survival Benefit from Adjuvant Chemotherapy Test for interaction KRAS *Treatment p=0.50 Interaction HR (95% CI): 1.16 [0.81 ; 1.67] Between trial heterogeneity: p=0.65 Tsao et al, Proc ESMO, 2010

  33. Predictive Value of KRAS on Survival Benefit from Adjuvant Chemotherapy Is this evidence sufficient to withhold adjuvant chemotherapy in patients with KRAS mutations? We must be held to a very high level of evidence to withhold any treatment!! Test for interaction KRAS *Treatment p=0.50 Interaction HR (95% CI): 1.16 [0.81 ; 1.67] Between trial heterogeneity: p=0.65 Tsao et al, Proc ESMO, 2010

  34. LACE-Bio: Predictive Value of KRAS Status in Adenocarcinoma (OS) Category Deaths/Entered Hazard Ratio HR (95% CI) ChemoRx Control KRAS WT 85/189 102/207 0.87 (0.65-1.16) KRAS Mut 48/105 50/101 0.87 (0.58-1.30) All Adeno 133/294 152/308 0.87 (0.69-1.10) 0.2 1.0 5.0 Interaction HR= 0.99 (95%CI .61-1.65), p= 0.99

  35. Is KRAS Prognostic or Predictive? • Inconsistent Results • Weak (-) Prognostic Variable in surgical setting, but more recent studies, especially in context of systemic Tx, call this into question • KRAS wt pts have somewhat greater relative benefit with EGFR TKIs c/w mt (+) pts in placebo-controlled trials, but KRAS mutation does not reliably predict inferior outcome • Unlike CRC, neither wt nor mt (+) KRAS has any bearing on outcome in NSCLC pts receiving EGFR MAbs in combination with chemo

  36. KRAS as Therapeutic Target MET Inhibition MTOR Inhibition MEK Inhibitors

  37. Tivantinib (ARQ 197) forKRAS-mutant NSCLC

  38. Tivantinib: a Selective MET TKI Non-ATP competitive oral inhibitor of MET Stabilizes inactive conformation of MET • Broad-spectrum anti-tumor activity in xenografts (including NSCLC) • In vivo anti-tumor activity of ARQ 197 + EGFR inhibitor greater than either drug alone • Safety and linear PK in phase I combination with erlotinib Munshi , Mol Cancer Ther 2010;Epub ahead of print Unpublished; courtesy of ArQule, Inc. and Kyowa Hakko Kirin Co., Ltd Laux , ASCO 2009 Goldman, IASLC 2009

  39. Tivantinib (ARQ 197) Randomized, placebo-controlled, double-blind, Phase II study of erlotinib ± tivantinib as second or later line therapy of locally advanced or metastatic NSCLC • NSCLC • N=167 • Age ≥18 years • Inoperable LA/ metastatic disease • ≥1 prior chemo (no prior EGFR agent) R A N D O M I Z E Tivantinib @ 360 mg PO BID + Erlotinib 150 mg PO QD Continuous Dosing Placebo PO BID + Erlotinib 150 mg PO QD Continuous Dosing Primary endpoint: PFS Sequist et al., ESMO 2010

  40. Tivantinib (ARQ 197): Progression-Free Survival (ITT Population) • * Pre-planned Cox regression model adjusting for sex, prior chemotherapy, best prior response, time from diagnosis, and EGFR mutation status • PFS also measured by independent radiographic review: • - median 3.6 vs. 2.0 mos. • - unadjusted/adjusted HR= 0.74/0.51 Sequist et al. ESMO 2010

  41. Tivantinib (ARQ 197): PFS and OS in Non-Squamous Cell Patients (n=117) • Cox regression model • Note: treatment cross-over from placebo to tivantinib allowed. Sequist et al. ESMO 2010

  42. Tivantinib & KRAS • Biomarker analyses included EGFR & KRAS genotyping and MET FISH • Sequist et al, JCO, 2011

  43. Tivantinib (ARQ 197): PFS in Histologic and Molecular Subgroups Sequist et al. ESMO 2010

  44. Tivantinib (ARQ 197): PFS in Histologic and Molecular Subgroups Sequist et al. ESMO 2010

  45. Tivantinib & KRAS • Exploratory analysis identified a longer PFS in KRAS-mutant pts receiving tivantinib • Sequist et al, JCO, 2011

  46. Tivantinib (MARQUEE) Phase III study design A multicenter, phase 3, randomized, double-blind, placebo-controlled clinical trial RANDOMI ZE • Phase III in NSCLC • Inoperable, locally advanced or metastatic disease • Non-squamous histology • 1 - 2 regimens of prior chemo (no prior EGFR TKI) • Prior platinum-based doublet therapy required Arm A: Tivantinib360 mg PO BID Erlotinib150 mg PO QD + Arm B: PlaceboPO BID Erlotinib150 mg PO QD + • Endpoints • 1°: OS (ITT population) • 2°/Exploratory: • PFS (ITT population) • PK and PD analysis • OS in EGFR wt patients • Safety and toxicity • QOL/FACT-L • Biologic subgroup analysis • Stratification by: • Gender • Smoking history • Number of prior systemic therapies • EGFR genotype • KRAS genotype Scagliotti et al., ECCO 2013

  47. FOR IMMEDIATE RELEASE ARQULE AND DAIICHI SANKYO ANNOUNCE DISCONTINUATION OF PHASE 3 MARQUEE CLINICAL TRIAL IN NON-SMALL CELL LUNG CANCER DMC Recommends Discontinuation of Study for Futility No Unexpected Safety Findings from Interim Analysis Woburn, MA and Tokyo, Japan, October 2, 2012 – ArQule, Inc. (Nasdaq: ARQL) and Daiichi Sankyo, Co., Ltd. (TSE 4568) today announced that the independent Data Monitoring Committee (DMC) of the Phase 3 MARQUEE (Met inhibitor ARQ 197 plus Erlotinib vs Erlotinib plus placebo in NSCLC) trial recommended the study be stopped early following a planned interim analysis, when they concluded that the study would not meet its primary endpoint of improved overall survival. Although the interim analysis showed a statistically significant improvement in progression-free survival (PFS) in the intent-to-treat (ITT) population, this benefit did not carry over to overall survival. There were no safety concerns identified by the DMC to Daiichi Sankyo or ArQule during this interim analysis.

  48. MARQUEE: PFS – ITT Population Scagliotti et al., ECCO 2013

  49. MARQUEE: OS - ITT Population Scagliotti et al., ECCO 2013

  50. MARQUEE: Tumor Biomarker Analysis Scagliotti et al., ECCO 2013

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