Disclosures. 2 Study ARQ197-A-U252; Presented by C. Eng, MD

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1 Abstract: 358 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, 4 Lothar Muller, 5 Mikhail V. Kopp, 6 Vladimir Vladimirov, 7 Robert Langdon, 8 Bogdan Kotiv, 9 Sandro Barni, 1 Ching Hsu, 11 Ellen Bolotin, 11 Reinhard von Roemeling, 11 Brian Schwartz, 12 Johanna C. Bendell 13 1 The University of Texas M.D. Anderson Cancer Center, Houston, TX; 2 Florida Cancer Specialists/Sarah Cannon Research Institute, Fort Myers, FL; 3 The Central Clinical Hospital #1, Moscow, Russia; 4 Chelyabinsk Regional Clinical Oncological Dispensary, Chelyabinsk, Russia; 5 Onkologische Schwerpunktpraxis Leer-Emden, Leer, Germany; 6 Samara Regional Clinical Oncology Dispensary, Samara, Russia; 7 Pyatigorsk Oncological Dispensary, Pyatigorsk, Russia; 8 Nebraska Methodist Hospital Cancer Center, Omaha, NE; 9 Military Medical Academy, St. Petersburg, Russia; 1 Azienda Ospedaliera di Treviglio Ospedale, Treviglio, Italy; 11 Daiichi Sankyo, Inc., Edison, NJ; 12 ArQule, Inc., Woburn, MA; 13 Sarah 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 2

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 4% of patients develop metastatic disease 2 Current standard treatments are administered in combination or as single agents and include 3 Chemotherapy (fluoropyrimidines, oxaliplatin, irinotecan/cpt-11) Monoclonal antibodies (bevacizumab, cetuximab, panitumumab) Small molecules (regorafenib) 1. American Cancer Society Cancer. Colorectal Cancer Facts and Figures Fedorowicz Z, et al. Cochrane Database Syst Rev. 28;(2):CD639. DOI: 1.12/ CD639.pub4. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. V

4 MET in CRC MET overexpression may occur in 3% to 7% of CRC tumors, and is associated with poor prognosis and resistance to radiation 1 MET plays an important role in CRC progression and metastasis 2 Resistance to cetuximab has been associated with activation of alternative RTK pathways, including MET 3 We hypothesized that adding tivantinib to cetuximab plus irinotecan may decrease resistance to cetuximab and improve patient outcomes 1. Takeuchi H, et al. Clin Cancer Res. 23;9(4): Zeng ZS, et al. Cancer Lett. 28;265(2): Walther A, et al. Nat Rev Cancer. 29;9(7):

5 Tivantinib (ARQ 197) A selective oral MET inhibitor with a novel ATP-independent binding mechanism 1 Broad-spectrum antitumor activity as single-agent and combination therapy demonstrated in preclinical studies, including MET-high CRC cell lines 2,3 Promising phase 1b data in CRC showed safety of the combination at full dose and included 4 objective responses in 9 patients 4 Reprinted from Eathiraj et al. 1. Eathiraj S, et al. J Biol Chem. 211;286(23): Munshi N, et al. Mol Cancer Ther. 21;9(6): Lu S, et al. Z Gastroenterol. 212;5:P5_31. DOI: 1.155/s Eng C, et al. Ann Oncol. 212;23(suppl 4). Abstract PD-18. 5

6 Phase 2 Study Design Eligibility Age 18 years Inoperable, locally advanced or metastatic disease KRAS WT 1 line of prior systemic Tx ECOG -1 No prior anti-egfr therapy Stratification Factors: 1) ECOG ( vs 1) 2) Best response to 1st-line therapy (CR/PR/SD vs PD) R A N D O M I Z E D O U B L E B L I N D N = 15 1:1 Tivantinib (ARQ 197) 36 mg PO BID Placebo PO BID + + Primary Endpoint: PFS Secondary Endpoints: OS, ORR, safety Cetuximab 5 mg/m 2 IV q14 days Irinotecan 18 mg/m 2 IV q14 days Cetuximab 5 mg/m 2 IV q14 days Irinotecan 18 mg/m 2 IV q14 days 6

7 Accrual and Statistics Accrual: Jul 21 to Feb 212 in US, Russia, France, Italy, Germany Total Patients Randomized 122 Full Analysis Set: pts with postbaseline scan eligible for efficacy analysis 117 Safety Data Set: pts who received study drug 121 Recruitment was discontinued early before the pre-specified goal of 15 was reached. The number of PFS events for analysis was decreased from 11 to 8, which provides 7% power to detect a 5% improvement in median PFS at P =.1 (1-sided) 7

8 Patient Disposition Tivantinib Placebo Randomized, n 62 6 Full analysis set, n 6 57 Treatment discontinuation, n (%) 53 (85.5) 47 (78.3) Progressive disease 34 (54.8) 28 (46.7) Adverse event 12 (19.4) 6 (1.) Patient withdrew consent 1 (1.6) 3 (5.) Lost to follow-up 1 (1.6) Death 1 (1.7) Other a 5 (8.1) 9 (15.) Treatment ongoing, n (%) 9 (14.5) 13 (21.7) a Other includes clinical progression, investigator discretion, patient decision, patient relocation. 8

9 Patient Demographics Full Analysis Set Mean age, y (min - max) SD Tivantinib (n = 6) Placebo (n = 57) (29-79) (27-79) Gender, n (%) Male 26 (43.3) 32 (56.1) Female 34 (56.7) 25 (43.9) Race, n (%) Caucasian 57 (95.) 54 (94.7) Black 2 (3.3) 1 (1.8) Asian 1 (1.7) 2 (3.5) ECOG score, n (%) 36 (6.) 28 (49.1) 1 24 (4.) 29 (5.9) 9

10 Patient Characteristics Full Analysis Set Tivantinib (n = 6) Placebo (n = 57) Prior radiation, n (%) 9 (15.) 1 (17.5) Prior surgery, n (%) 53 (88.3) 48 (84.2) Time from diagnosis to treatment, d SD Prior systemic cancer therapy, n (%) Fluoropyrimidine 6 (1) 55 (97) Oxaliplatin 47 (78) 48 (84) Bevacizumab 33 (55) 25 (44) Irinotecan 1 (17) 11 (19) Other 6 (1) 8 (14) Best response to prior therapy, n (%) CR, PR, SD 44 (73.3) 35 (61.4) PD 16 (26.7) 22 (38.6) 1

11 Progression-Free Survival, % Progression-Free Survival Full Analysis Set (median follow-up: 15.9 mo) 1 75 HR =.85 (95% CI, ) Stratified log-rank P =.38 Events Median, mo 95% CI T P Tivantinib (n = 6) Placebo (n = 57) Time Since Randomization, mo 11

12 Overall Survival, % Overall Survival Full Analysis Set (median follow-up: 21.5 mo) 1 75 HR =.7 (95% CI, ) Stratified log-rank P =.25 Events Median, mo 95% CI T P Tivantinib (n = 6) Placebo (n = 57) Time Since Randomization, mo 12

13 Best Overall Response Full Analysis Set Best Response, n (%) Tivantinib (n = 6) Placebo (n = 57) Complete response Partial response 27 (45.) 19 (33.3) Stable disease 22 (36.7) 22 (38.6) Progressive disease 9 (15.) 13 (22.8) Not evaluable 2 (3.3) 3 (5.3) Objective response rate (CR + PR) [95% CI] Stable disease or better [95% CI] 27 (45.) [ ] 49 (81.7) [ ] 19 (33.3) [ ] 41 (71.9) [ ] 13

14 Change From Baseline, % Tumor Response Investigator Assessed Tivantinib Placebo 14

15 Adverse Events (> 15% Frequency) Safety Population Tivantinib (n = 62) Placebo (n = 59) Preferred Term, n (%) All Grades Grade 3 All Grades Grade 3 Rash 36 (58) 5 (8) 34 (58) 5 (9) Diarrhea 33 (53) 8 (13) 3 (51) 5 (9) Nausea 27 (44) 6 (1) 27 (46) 4 (7) Fatigue 24 (39) 3 (5) 2 (34) 2 (3) Vomiting 2 (32) 3 (5) 18 (31) 3 (5) Neutropenia 18 (29) 12 (19) 12 (2) 6 (1) Abdominal pain 12 (19) 15 (25) 4 (7) Decreased appetite 11 (18) 1 (2) 7 (12) 1 (2) Dry skin 11 (18) 1 (17) Constipation 1 (16) 11 (19) Dermatitis acneform 8 (13) 1 (1) 9 (15) 1 (2) Anemia 7 (11) 18 (31) 1 (2) 15

16 Outcomes in Key Subgroups Group Tivantinib, n (%) Placebo, n (%) PFS HR (95% CI) a OS HR (95% CI) a All ( ).68 ( ) Male 26 (43) 32 (56) 1.28 ( ) 1.9 ( ) Female 34 (57) 25 (44).52 ( ).45 ( ) ECOG 36 (6) 28 (49) 1.1 (.6-2.1).75 ( ) ECOG 1 24 (4) 29 (51).69 ( ).63 ( ) Age 65 y 45 (75) 41 (72).81 ( ).6 ( ) Age > 65 y 15 (25) 16 (28).88 ( ).99 ( ) Prior systemic therapy Oxaliplatin 47 (78) 48 (84).66 ( ).58 ( ) Fluoropyrimidine 6 (1) 55 (96).8 ( ).66 (.4-1.1) Irinotecan 1 (17) 11 (19) 3.36 ( ) 1. (.3-3.3) Bevacizumab 33 (55) 25 (44).61 ( ).73 ( ) a HR/OR < 1. favors tivantinib; HR/OR > 1. favors placebo. 16

17 Progression-Free Survival, % Overall Survival, % Outcomes in Patients Treated With Prior Oxaliplatin PFS HR =.66 (95% CI, ) Stratified log-rank P =.1 Median 95% CI T 8.3 mo P 7.2 mo OS HR =.58 (95% CI, ) Stratified log-rank P =.6 Median 95% CI T 22.3 mo P 14.1 mo Tivantinib (n = 47; 33 events) Placebo (n = 48; 33 events). Tivantinib (23 events) Placebo (28 events) Time Since Randomization, mo Time Since Randomization, mo Tivantinib Placebo ORR 42.6% 27.1% 17

18 Biomarkers MET IHC Available archival tissue tested centrally for total MET expression using the anti-met (SP44) antibody (Spring Biosciences) High: 5% of tumor cells with immunostaining intensity of 2 + or 3 + N = 67 (59 primary tumors; 8 metastatic lesions) HGF serum concentration High: > mean baseline concentration for the subgroup Low: mean baseline concentration 18

19 Overall Survival, % Overall Survival, % Progression-Free Survival, % Progression-Free Survival, % PFS and OS by MET Expression 1 75 PFS MET-High MET-Low ORR: T = 54.2%; P = 3.% ORR: T = 27.3%; P = 41.7% HR =.74 (95% CI, ) Log-rank P = HR =.22 (95% CI,.6 -.8) Log-rank P = Tivantinib (n = 24) Placebo (n = 2) OS 21 HR =.58 (95% CI, ) Log-rank P = Tivantinib (n = 11) Placebo (n = 12) HR =.78 (95% CI, ) Log-rank P = Time Since Randomization, mo Time Since Randomization, mo 19

20 Overall Survival, % Overall Survival, % Progression-Free Survival, % Progression-Free Survival, % PFS and OS by Serum HGF Level 1 PFS HGF-High HGF-Low ORR: T = 44.8%; P = 25.% ORR: T = 46.7%; P = 39.3% 1 75 HR =.7 (95% CI, ) Log-rank P = HR =.94 (95% CI,.5-1.8) Log-rank P = OS Tivantinib (n = 29) Placebo (n = 28) HR =.61 (95% CI, ) Log-rank P = Tivantinib (n = 3) Placebo (n = 28) HR =.7 (95% CI, ) Log-rank P = Time Since Randomization, mo Time Since Randomization, mo 2

21 Overall survival, % Overall Survival by Baseline Serum HGF Level in Placebo Patients 1 8 High (n = 28) Low (n = 28) HR = 2.14 (95% CI: 1.1, 4.53) Events Median, mo 95% CI High , 19.2 Low , Time Since Randomization, mo 21

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 concentration is 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 22

23 Next Steps for Tivantinib These encouraging findings will be informed by additional data from ongoing studies: Phase 2 study of tivantinib in combination with cetuximab in patients who failed cetuximab, currently enrolling in Italy Phase 1 study of tivantinib in combination with FOLFOX in the US (ASCO 213, abstract 2544) Phase 3 study of tivantinib vs placebo in MET-high HCC (2 nd -line) (ASCO 213, 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 23

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. 24