Second Line Therapy in Hepatocellular Carcinoma (HCC): A Randomized Controlled Phase 2 Trial (RCT) with Tivantinib (ARQ 197)

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1 Second Line Therapy in Hepatocellular Carcinoma (HCC): A Randomized Controlled Phase 2 Trial (RCT) with Tivantinib (ARQ 197) C Porta, I Borbath, L Rimassa, B Daniele, S Salvagni, JL Van Laethem, H Van Vlierberghe, J Trojan, F Kolligs, A Gasbarrini, M Lencioni, R Von Roemeling G Abbadessa, B Schwartz, A Santoro Abstract ESMO GI Barcelona, Spain Supported by ArQule, Inc., and Daiichi Sankyo

2 Disclosures Camillo Porta, MD No conflict of interest to disclose.

3 Background HCC is among the leading cause of cancer-related death, and sorafenib is the only approved systemic agent for patients with unresectable disease 1-3 MET, the receptor tyrosine kinase for hepatocyte-growth factor (HGF), involved in cancer progression and metastasis, is often dysregulated in HCC and correlated with poor prognosis in HCC patients who underwent resection 4-8 Tivantinib, an oral tyrosine kinase inhibitor targeting MET with a novel ATPindependent mechanism, has activity as single agent and in combination in several cancer types in preclinical and clinical studies (including NSCLC, where a phase 3 study just completed enrollment). Promising phase 1b data have been reported in HCC as monotherapy and with sorafenib Globocan Llovet JM, et al. N Engl J Med Jul 24;359(4): Cheng AL, et al. Lancet Oncol. 2009; 10: Birchmeier C, et al. Nat Rev Mol Cell Biol. 2003;4: Tavian D, et al. Int J Cancer. 2000;87: Son G, et al. J Hepatol. 2006;45: You H, et al. Hepatol. 2011;54: Chau G-Y, et al. Eur J Surg Oncol. 2008;34: Eathiraj S, et al. Biol Chem. 2011;286: Munshi N, et al. Mol Cancer Ther. 2010;9(6): Sequist L, et al. J Clin Oncol. 2011;29(24): ASCO 2012 abstract #4117.

4 Study Design Advanced HCC Child Pugh A Stratified by: ECOG PS Vascular Invasion 2:1 Randomization 107 pts Tivantinib PO BID 71 pts Placebo PO BID Crossover AFTER Rx PD 23 pts 36 pts Endpoints a 1 TTP 2 PFS, OS, ORR, DCR, crossover ORR, safety, PK 3 TTP, PFS, OS in subgroups by: - MET Diagnostic status - Viral infection (HBV, HCV) - Duration of prior systemic therapy a On ITT population. Efficacy assessment based on independent radiology review by RECIST 1.1. Scans performed every 6 weeks. Data cut-off: 21 Oct 2011 (18 Apr 2012 for OS)

5 Study Design and Conduct Key Eligibility Criteria: Locally advanced or metastatic HCC One prior systemic regimen for 3 wks Progressed or intolerant to prior thx Child Pugh A, ECOG PS 0-1 Adequate marrow, liver, renal tests No HIV, no prior liver transplant RECIST 1.1 measurable disease Enrollment: Oct Aug 2011 in Italy, Belgium, Germany, US, Canada Dosing: After 57 patients were enrolled, due to drug-related G 3 neutropenia, tivantinib dose of 360mg BID was modified to 240mg BID and a modified dose reduction schema was implemented Characteristics of Study Patients: Generally well balanced across groups; the tivantinib arm, compared to the placebo arm, included slightly fewer patients with metastases (61 vs 78%), more patients with HBV (23 vs 14%), more with HCV (51 vs 39%), and less with baseline AFP baseline values 200 IU/mL (44 vs 59%). All patients had received prior sorafenib except 4, who had received sunitinib.

6 Patient Disposition and Treatment 240mg BID (N=33) 360mg BID (N=38) % of Patients Tivantinib Total (N=71) Placebo (N=36) Reason for Discontinuation Progressive Disease Death* Adverse Event Withdrawal Of Consent Other** Ongoing as of 21 Oct Dose reductions due to AEs * Most common causes on placebo: PD, cachexia; on tivantinib: PD, liver failure (unrelated), neutropenic sepsis ** Other includes: 1 compliance, 1 investigator s decision, 4 clinical progression Dose reduction schema was modified for the 240mg BID group 240mg BID (N=33) 360mg BID (N=38) % of Patients Tivantinib Total (N=71) Placebo (N=36) Post-study treatment Any systemic anti-cancer therapy Sorafenib Any local therapy Unknown

7 Efficacy in ITT Population Median TTP Patients Events Tivantinib 6.9 wks Placebo 6.0 wks HR: 0.64 (90% CI: ) Log Rank: P=0.04 Study powered to detect a treatment difference with a 1-sided type I error α = 0.05 PFS consistent with TTP: HR 0.67 (95% CI: ) Log Rank: P=0.06 RR: 1 PR observed in the 240mg BID group. DCR: 44% on tivantinib (32-56) vs 31% (16-48) Of 23 crossed-over patients, 11 showed best response of SD (3 ongoing at time of data cut-off), 8 PD, 4 non evaluable OS on tivantinib vs placebo non significant (6.6 vs 6.2 mos, HR: 0.90 (95% CI: ) P=0.63) and slightly better at 240mg BID (7.5 mos, HR: 0.71 (95% CI: ) P=0.24)

8 MET IHC as Companion Diagnostic (Dx) in HCC MET expression was evaluated by IHC assay using the CONFIRM anti-total MET(SP44) antibody - Ventana (Roche) Analyzed at an independent CLIA certified laboratory by a board certified pathologist after randomization and prior to un-blinding MET Dx High was defined as majority ( 50%) of tumor cells with moderate or strong (2+ or 3+) staining intensity % of Evaluable Patients 240mg BID 360mg BID Tivantinib Placebo 77/107 Evaluable (N eval=24/33) (N eval=25/38) (N eval=49/71) (N eval=28/36) Tumor MET High Tumor MET Low When grouped by MET status, patients characteristics were well balanced. In ITT, MET High vs Low key baseline differences: presence of vascular invasion (76% vs 63%), HCV (49% vs 30%). In MET High patients, tivantinib vs placebo key baseline differences: presence of metastases (55% vs 73%), HBV (27% vs 13%).

9 MET as a Prognostic Factor (Patients on Placebo) Median OS Patients Events MET Dx Low MET Dx High HR: 2.94 (95% CI: ) Log Rank: P=0.02

10 Improved TTP in MET Diagnostic High Group Median TTP Patients Events Tivantinib 11.7 wks Placebo 6.1 wks HR: 0.43 (95% CI: ) Log Rank: P=0.03 PFS: HR 0.45 (95% CI: ) Log Rank: P=0.02 DCR: 50% on tivantinib (28-72) vs 20% (4-48)

11 Improved OS in MET Diagnostic High Group Median OS Patients Events Tivantinib 7.2 mos Placebo* 3.8 mos HR: 0.38 (95% CI: ) Log Rank: P=0.01 *8 MET Dx High patients crossed-over, 5 remained on open-label tivantinib for at least 6 weeks (1 non-evaluable at cut-off date)

12 TTP and OS in MET Diagnostic Low Group Median TTP Patients Events Tivantinib 6.3 wks Placebo 6.0 wks HR: 0.96 (95% CI: ) Log Rank: P=0.92 Median OS Patients Events Tivantinib 5.0 mos Placebo 9.0 mos 13 9 HR: 1.33 (95% CI: ) Log Rank: P=0.50 No statistical difference observed, with curves crossing multiple times.

13 OS of Selected Subgroups in ITT Patients / Events Favors Tivantinib Favors Placebo Tivantinib Placebo HR (95% CI) MET Dx High 22/17 15/ ( ) Low 27/20 13/ ( ) Starting Dose 240mg BID 33/21 36/ ( ) 360mg BID 38/35 36/ ( ) Vascular Invasion Yes 22/21 13/ ( ) No 49/35 23/ ( ) Distant Metastasis Yes 43/34 28/ ( ) No 28/22 8/ ( ) ECOG PS 0 41/29 21/ ( ) 1 30/27 15/ ( ) HBV Pos* 16/15 5/ ( ) HCV Pos (HBV Neg) 31/23 14/ ( ) HBV / HCV Neg / Neg 24/18 17/ ( ) Baseline AFP (IU/mL) <200 37/30 15/ ( ) /23 21/ ( ) Prior sorafenib therapy 60 days 15/13 4/ ( ) *5 HBV Pos patients are also HCV Pos >60 days 55/42 29/ ( )

14 Adverse Events Summary % of Patients Preferred Term Tivantinib 240mg BID N=33 Tivantinib 360mg BID N=38 Placebo N=36 AEs resulting in death All SAEs (all grades) All Grades Grade 3-5 All Grades Grade 3-5 All Grades Grade 3-5 All AEs Most common relevant AEs: Asthenia Neutropenia* Decreased appetite Anaemia Fatigue Less frequent AEs of particular relevance: Thrombocytopenia Hepatic failure** *Includes 5 patients (4 at 360mg BID) who developed sepsis ** Reported as non-treatment related by Investigators; all but one took place after experimental therapy was suspended Incidence of AEs was similar across groups, besides hematological events (particularly G 3 neutropenia at 360mg BID)

15 Conclusions Single agent treatment with tivantinib met the primary endpoint in ITT, with a statistically significant 56% improvement in TTP (HR=0.64, log rank p=0.04) in second-line HCC Pronounced benefit was observed in MET Dx High patients, who experienced a 133% improvement in TTP and a 163% improvement in OS compared to placebo TTP and OS in MET Dx Low patients were statistically similar on tivantinib and placebo MET expression was defined as a prognostic factor in 2 nd line HCC Adverse events were reported at similar rates in tivantinib and placebo arms except for a higher incidence of hematologic events in the tivantinib arm A predictable and manageable safety profile emerged following dose reduction to 240mg BID from 360mg BID, and comparable clinical benefit was observed with both doses These are the first randomized data in HCC showing OS advantage with a MET inhibitor and identifying a biological subgroup responding to a targeted therapy A Phase 3 study in the MET Dx High HCC population is being planned

16 Acknowledgments The Patients and Their Families Arcispedale S. Maria Nuova, Italy C Boni Azienda Ospedaliera SG Moscati, Italy C Gridelli Azienda Ospedaliera G Rummo, Italy B Daniele, D Germano, S Competiello Azienda Ospedaliera di Parma, Italy S Salvagni, E Rapacchi Azienda Ospedaliero-Universitaria di Pisa, Italy M Lencioni, A Falcone Cedar Sinai, USA N Barahona, S Miles Clinique Universitaires Saint Luc, Belgium I Borbath, A Ceratti Klinikum der Universitat Munchen, Germany F Kolligs, E De Toni Policlinico Gemelli, Italy A Gasbarrini, A Piscaglia, M Campanale Toronto General Hospital, Canada M Sherman, K Poldre Universitatsklinikum Essen, Germany G Gerken University Hospital Gent, Belgium H Van Vlieberghe University of Texas, USA L Cicalese, A Duchini Vancouver General Hospital, British Columbia Cancer Clinic, Canada A Weiss, K Earnshaw Erasme University Hospital, Belgium JL Van Laethem, V Duthie Humanitas Cancer Center, Italy A Santoro, L Rimassa, N Personeni IFI Studien un Projekt GmbH, Germany P Buggisch IRCCS Policlinico San Matteo, Italy C Porta, C Ganini JW Goethe-University Hospital, Germany J Trojan, S Zeuzem Klinikum Rechts der Isar, Germany R Schmid ArQule, Inc G Abbadessa, S Cacciaguerra, F Cattaneo, F Chai, D Franklin, Y Chen, M Lamar, M McLeod, B Schwartz ACM Central Pathology Lab K Bowers, D Liu Daiichi-Sankyo R Von Roemeling, Y Wang, H Zahir IMI Independent Radiology L Schwartz