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Abstract: 3508

Abstract: 3508.

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Abstract: 3508

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  1. Abstract: 3508 A Randomized, Placebo-Controlled, Phase 2 Study of Tivantinib (ARQ 197) in Combination With Cetuximab and Irinotecan as Second-Line Therapy in Patients With KRAS Wild‑Type Metastatic Colorectal Cancer Cathy Eng,1 Lowell L. Hart,2 Aleksey Severtsev,3 Oleg Gladkov,4Lothar Muller,5 Mikhail V. Kopp,6 Vladimir Vladimirov,7 Robert Langdon,8 Bogdan Kotiv,9 Sandro Barni,10 Ching Hsu,11 Ellen Bolotin,11Reinhard von Roemeling,11 Brian Schwartz,12 Johanna C. Bendell131The University of Texas M.D. Anderson Cancer Center, Houston, TX; 2Florida Cancer Specialists/Sarah Cannon Research Institute, Fort Myers, FL; 3The Central Clinical Hospital #1, Moscow, Russia; 4Chelyabinsk Regional Clinical Oncological Dispensary, Chelyabinsk, Russia; 5Onkologische Schwerpunktpraxis Leer-Emden, Leer, Germany; 6Samara Regional Clinical Oncology Dispensary, Samara, Russia; 7Pyatigorsk Oncological Dispensary, Pyatigorsk, Russia; 8Nebraska Methodist Hospital Cancer Center, Omaha, NE; 9Military Medical Academy, St. Petersburg, Russia; 10Azienda Ospedaliera di Treviglio Ospedale, Treviglio, Italy; 11Daiichi Sankyo, Inc., Edison, NJ; 12ArQule, Inc., Woburn, MA; 13Sarah Cannon Research Institute, Nashville, TN

  2. Disclosures • The trial was funded by Daiichi Sankyo, Inc., a member of the Daiichi Sankyo Group, and ArQule, Inc. • I have received research funding from Daiichi Sankyo for this trial Study ARQ197-A-U252; Presented by C. Eng, MD

  3. CRC Background • Colorectal cancer (CRC) is the fourth most common cancer and second leading cause of cancer death in the US (for men and women combined)1 • Approximately 40% of patients develop metastatic disease2 • Current standard treatments are administered as single agents or in combination and may include3 • Chemotherapy (fluoropyrimidines, oxaliplatin, irinotecan/CPT-11) • Monoclonal antibodies (bevacizumab, cetuximab, panitumumab) • Small molecules (regorafenib) • American Cancer Society Cancer. Colorectal Cancer Facts and Figures 2013. http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013. • Fedorowicz Z, et al. Cochrane Database Syst Rev. 2008;(2):CD006039. DOI: 10.1002/14651858.CD006039.pub4. • National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. V.3.2013. www.nccn.org. Study ARQ197-A-U252; Presented by C. Eng, MD

  4. MET in CRC • MET overexpression may occur in 30% to 70% of CRC tumors, and is associated with poor prognosis and resistance to radiation1 • MET plays an important role in CRC progression and metastasis2 • Resistance to cetuximab has been associated with activation of alternative RTK pathways, including MET3 • We hypothesized that adding tivantinib to cetuximab plus irinotecan may decrease resistance to cetuximab and improve patient outcomes Takeuchi H, et al. Clin Cancer Res. 2003;9(4):1480-1488. Zeng ZS, et al. Cancer Lett. 2008;265(2):258-269. Walther A, et al. Nat Rev Cancer. 2009;9(7):489-499. Study ARQ197-A-U252; Presented by C. Eng, MD

  5. Tivantinib (ARQ 197) • A selective oral MET inhibitor with a novel ATP-independent binding mechanism1 • Broad-spectrum antitumor activity was demonstrated in preclinical studies including MET-high CRC cell lines2,3 when provided as a single-agent and when combined with chemotherapy • Promising phase 1b data in CRC showed safety of the combination at full dose and included 4 objective responses in 9 patients4 Reprinted from Eathiraj et al. Eathiraj S, et al. J Biol Chem. 2011;286(23):20666-20676. Munshi N, et al. Mol Cancer Ther. 2010;9(6):1544-1553. Lu S, et al. Z Gastroenterol. 2012;50:P5_31. DOI: 10.1055/s-0031-1295987. Eng C, et al. Ann Oncol. 2012;23(suppl 4). Abstract PD-0018. Study ARQ197-A-U252; Presented by C. Eng, MD

  6. Phase 2 Study Design • Eligibility • Age ≥ 18 years • Inoperable, locally advanced or metastatic disease • KRAS WT • 1 line of prior systemic Tx • ECOG PS 0-1 • No prior anti-EGFR therapy RANDOMIZE Cetuximab 500 mg/m2 IV q14 days DOUBLE BLIND Tivantinib(ARQ 197)360 mg PO BID + Irinotecan 180 mg/m2 IV q14 days Cetuximab 500 mg/m2 IV q14 days PlaceboPO BID + Irinotecan 180 mg/m2 IV q14 days N = 150 1:1 Stratification Factors: 1) ECOG PS (0 vs 1) 2) Best response to 1st-line therapy (CR/PR/SD vs PD) Primary Endpoint: PFS Secondary Endpoints: OS, ORR, safety Study ARQ197-A-U252; Presented by C. Eng, MD

  7. Accrual and Statistics • Accrual: Jul 2010 to Feb 2012 in US, Russia, France, Italy, Germany • Recruitment was discontinued early before the pre-specified goal of 150 patients was reached. The number of PFS events for analysis was decreased from 110 to 80, providing 70% power to detect a 50% improvement in median PFS at P = 0.10 (1-sided) Study ARQ197-A-U252; Presented by C. Eng, MD

  8. Patient Disposition a Other includes clinical progression, investigator discretion, patient decision, patient relocation. Study ARQ197-A-U252; Presented by C. Eng, MD

  9. Patient CharacteristicsFull Analysis Set Study ARQ197-A-U252; Presented by C. Eng, MD

  10. Patient DemographicsFull Analysis Set Study ARQ197-A-U252; Presented by C. Eng, MD

  11. Progression-Free SurvivalFull Analysis Set (median follow-up: 15.9 mo) HR = 0.85 (95% CI, 0.55 - 1.33) Stratified log-rank P = 0.38 100 75 50 Progression-Free Survival, % 25 Tivantinib (n = 60) Placebo (n = 57) 0 0 3 6 9 12 15 18 21 Time Since Randomization, mo Study ARQ197-A-U252; Presented by C. Eng, MD

  12. Overall SurvivalFull Analysis Set (median follow-up: 21.5 mo) HR = 0.70 (95% CI, 0.42 - 1.17) Stratified log-rank P = 0.25 100 75 50 Overall Survival, % 25 • Tivantinib (n = 60) Placebo (n = 57) 0 0 4 8 12 16 20 24 28 32 Time Since Randomization, mo Study ARQ197-A-U252; Presented by C. Eng, MD

  13. Best Overall ResponseFull Analysis Set Study ARQ197-A-U252; Presented by C. Eng, MD

  14. Tumor ResponseInvestigator Assessed 120 110 100 Tivantinib 90 Placebo 80 70 60 50 40 30 20 10 0 Change From Baseline, % - 10 - 20 - 30 - 40 - 50 - 60 - 70 - 80 - 90 - 100 - 110 - 120 Study ARQ197-A-U252; Presented by C. Eng, MD

  15. Adverse Events (> 15% Frequency)Safety Population Study ARQ197-A-U252; Presented by C. Eng, MD

  16. Outcomes in Key Subgroups a HR/OR < 1.0 favors tivantinib; HR/OR > 1.0 favors placebo. Study ARQ197-A-U252; Presented by C. Eng, MD

  17. Outcomes in Patients Treated With Prior Oxaliplatin PFS OS HR = 0.58 (95% CI, 0.33 - 1.02) Stratified log-rank P = 0.06 HR = 0.66 (95% CI, 0.41 - 1.09) Stratified log-rank P = 0.10 1.0 1.0 0.8 0.8 0.6 0.6 Progression-Free Survival, % Overall Survival, % 0.4 0.4 0.2 0.2 Tivantinib(n = 47; 33 events) Tivantinib(23 events) Placebo(n = 48; 33 events) Placebo(28 events) 0.0 0.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28 32 Time Since Randomization, mo Time Since Randomization, mo TivantinibPlacebo ORR 42.6% 27.1% Study ARQ197-A-U252; Presented by C. Eng, MD

  18. Biomarkers • MET IHC • Available archival tissue tested centrally for total MET expression using the anti-MET (SP44) antibody (Spring Biosciences) • High: ≥ 50% of tumor cells with immunostaining intensity of 2+ or 3+ • N = 67 (59 primary tumors; 8 metastatic lesions) • HGF serum concentration • N=115 • High: > mean baseline concentration for the subgroup • Low: ≤ mean baseline concentration Study ARQ197-A-U252; Presented by C. Eng, MD

  19. PFS and OS by MET Expression MET-High MET-Low PFS ORR: T = 54.2%; P = 30.0% ORR: T = 27.3%; P = 41.7% 100 100 HR = 0.74 (95% CI, 0.36 - 1.52) Log-rank P = 0.41 HR = 0.22 (95% CI, 0.06 - 0.80) Log-rank P = 0.01 75 75 50 Progression-Free Survival, % Progression-Free Survival, % 50 Tivantinib (n = 11) Tivantinib (n = 24) 25 25 Placebo (n = 12) Placebo (n = 20) 0 0 0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 21 OS 100 100 HR = 0.58 (95% CI, 0.25 - 1.36) Log-rank P = 0.20 HR = 0.78 (95% CI, 0.24 - 2.47) Log-rank P = 0.67 75 75 Overall Survival, % 50 50 Overall Survival, % 25 25 0 0 0 4 8 12 16 20 24 28 32 0 4 8 12 16 20 24 28 32 Time Since Randomization, mo Time Since Randomization, mo Study ARQ197-A-U252; Presented by C. Eng, MD

  20. PFS and OS by Serum HGF Level HGF-High HGF-Low PFS ORR: T = 44.8%; P = 25.0% ORR: T = 46.7%; P = 39.3% 100 100 HR = 0.70 (95% CI, 0.37 - 1.32) Log-rank P = 0.27 HR = 0.94 (95% CI, 0.50 - 1.80) Log-rank P = 0.86 75 75 Progression-Free Survival, % Progression-Free Survival, % 50 50 Tivantinib (n = 30) Tivantinib (n = 29) 25 25 Placebo (n = 28) Placebo (n = 28) 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 OS 100 100 HR = 0.61 (95% CI, 0.30 - 1.23) Log-rank P = 0.16 HR = 0.70 (95% CI, 0.31 - 1.57) Log-rank P = 0.38 75 75 Overall Survival, % Overall Survival, % 50 50 25 25 0 0 0 4 8 12 16 20 24 28 32 0 4 8 12 16 20 24 28 32 Time Since Randomization, mo Time Since Randomization, mo Study ARQ197-A-U252; Presented by C. Eng, MD

  21. Overall Survival by Baseline Serum HGF Level in Placebo Patients 100 High (n = 28) Low (n = 28) 80 60 Overall survival, % 40 HR = 2.14 (95% CI: 1.01, 4.53) 20 0 0 5 10 15 20 25 Time Since Randomization, mo Study ARQ197-A-U252; Presented by C. Eng, MD

  22. Conclusions • Tivantinib in combination with cetuximab and irinotecan had a similar safety profile to cetuximab and irinotecan alone, except for a higher incidence of neutropenia • PFS, ORR, and OS all trended in favor of tivantinib, particularly among patients who received prior oxaliplatin • Efficacy signals in the small MET-high (by IHC) subgroup were inconclusive; require further validation with a larger sample size • HGF serum concentration appears to be a prognostic indicator of OS and warrants further analysis • While results are encouraging, they highlight the need for uniform tissue and blood collection prior to enrollment to allow more robust correlative outcome assessments in the MET pathway Study ARQ197-A-U252; Presented by C. Eng, MD

  23. Next Steps for Tivantinib • These encouraging findings will be informed by additional data from ongoing studies: • Phase 1 study of tivantinib in combination with FOLFOX in the US(ASCO 2013, abstract 2544) • Phase 2 study of tivantinib in combination with cetuximab in patients who failed cetuximab, currently enrolling in Italy • Phase 3 study of tivantinib vs placebo in MET-high HCC (2nd-line) (ASCO 2013, poster TPS4519) • Additional work is needed to better characterize changes in MET expression from diagnosis through treatment and following progression of disease, particularly in oxaliplatin-pretreated patients • Prior studies suggest that MET overexpression is a late event, thus MET analysis as predictive biomarker may be best obtained from metastatic lesions • Based on these results the most promising path forward will be determined Study ARQ197-A-U252; Presented by C. Eng, MD

  24. Acknowledgments We thank the patients and their families and all the investigators Principle investigators Francis Arena, Lake Success, NY, USA Alberto Bessudo, San Diego, CA, USA Corrado Boni, Reggio Emilia, Italy Roger Brito, Boynton Beach, FL, USA Brian Choi, Riverside, CA, USA Christophe Desauw, Lille, France Irfan Firdaus, Cincinnati, OH, USA Nashat Gabrail, Canton, OH, USA George Geils, Jr., Charleston, SC, USA Philip Gold, Seattle, WA, USA Jayne Gurtler, Metairie, LA, USA James Hays, Centralia, IL, USA David Hoffman, Beverly Hills, CA, USA Ralf-Dieter Hofheinz, Mannheim, Germany Haresh Jhangiani, Fountain Valley, CA, US Dinesh Kapur, Norwich, CT, USA Omar Kayaleh, Orlando, FL, USA Igor Kiselev, Kursk, Russia • Fred Kudrik, Columbia, SC, USA • Pallavi Kumar, Baltimore, MD, USA • Wen Wee Ma, Buffalo, NY, USA • Robert Marschke, Fort Collins, CO, USA • Michael McCormack, Hagerstown, MD, USA • Shubham Pant, Oklahoma City, OK, USA • Hervé Perrier, Marseille, France • Maciej Rotarski, Bayonne, France • Armando Santoro, Rozzano, Milan, Italy • Hans-Joachim Schmoll, Halle (Saale), Germany • Jens Siveke, Munchen, Germany • DMC members: John Lindsay Marshall, Jean Grem, Mithat Gonen, Vanessa Beddo • ArQule, Inc: Yinpu Chen, Julia Kazakin, Matt McLeod • Daiichi Sankyo: Abdel-Baset Halim, Taina Lopez, Dale Shuster, Koichi Tazaki, Hamim Zahir • Editorial support provided by Accuverus This study was sponsored by Daiichi Sankyo, Inc., a member of the Daiichi Sankyo Group, and ArQule, Inc. Study ARQ197-A-U252; Presented by C. Eng, MD

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