MEETING SUMMARY ASCO GI, SATURDAY JANUARY 17 TH 2015

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1 Supported by an Independent Educa1onal Grant from

2 MEETING SUMMARY ASCO GI, SATURDAY JANUARY 17 TH 2015 BY DR. GUILLEM ARGILES, BARCELONA, SPAIN Cancers of the Lower GI Tract

3 RAISE: A RANDOMIZED, DOUBLE-BLIND, MULTICENTER PHASE III STUDY OF IRINOTECAN, FOLINIC ACID, AND 5- FLUOROURACIL () PLUS RAMUCIRUMAB OR PLACEBO IN PATIENTS WITH METASTATIC COLORECTAL CARCINOMA PROGRESSION DURING FOR FOLLOWING FIRST-LINE COMBINATION THERAPY WITH BEVACIZUMAB, OXALIPLATIN, AND A FLUOROPYRIMIDINE Josep Tabernero*, Allen Lee Cohn, Radka Obermannova, Gyorgy Bodoky, Rocio Garcia-Carbonero, Tudor-Eliade Ciuleanu, David C. Portnoy, Eric Van Cutsem, Axel Grothey, Jana Prausová, Pilart Garcia-Alfonso, Kentaro Yamazaki, Philip R. Clingan, Vittorina Zagonel, Tae Won Kim, Lorrinda Simms, Shao-Chun Chang, Federico Nasroulah, Takayuki Yoshino *On behalf of the RAISE Investigators

4 RAISE: STUDY DESIGN Progression during or after bevacizumab, oxaliplatin, and a fluoropyrimidine Stratification factors Geograpic regions KRAS mutation status Time to disease progression after beginning first-line therapy R A N D O M I Z E 1:1 Ramucirumab (8 mg/kg) and * every 2 weeks per cycle N=525 Placebo and * every 2 weeks per cycle N=525 Treatment until disease progression or unacceptable toxicity Primary endpoint: Overall survival Secondary endpoints: PFS, ORR, PRO, Safety, PI, IG Sample size assumptions Hazard ratio of 0.8 Median overall survival of 10 months in the control arm vs 12.5 months with ramucirumab with a 2-sided a level of 0.05 Enrollment of 1050 patients with 756 events for 85% power Gatekeeping from OS to PFS to ORR

5 RAISE: STUDY DESIGN Median, months (95% CI) Ramucirumab + N= (12.4, 14.5) Placebo + N= (10.8, 12.7) Overall survival HR (95% CI) P- value (log- rank) 0.84 (0.73, 0.98) (stra1fied) (stra1fied) Patients at risk Ram + Placebo Time (months) CI, confidence interval; HR, hazard ratio; Ram, Ramucirumab.

6 RAISE: PROGRESSION-FREE SURVIVAL Progression-free survival Median, months (95% CI) HR (95% CI) P- value (log- rank) Ramucirumab + N= (5.5, 6.2) Placebo + N= (4.2, 5.4) 0.79 (0.70, 0.90) (stra1fied) (stra1fied) Patients at risk Ram + Placebo Time (months) CI, confidence interval; HR, hazard ratio; Ram, Ramucirumab.

7 TREATMENT-EMERGENT ADVERSE EVENTS (ALL GRADES 20% OR HIGHER, OR GRADE 3-5 5% OR HIGHER IN EITHER TREATMENT ARM) Any Grade Grade 3 Preferred Term Ramucirumab + N=529 Placebo + N=528 Ramucirumab + N=529 Placebo + N=528 n % n % n % n % Any TEAE Neutropenia Fatigue Diarrhea Hypertension Stomatitis Abdominal pain Thrombocytopenia Vomiting Nausea Decreased appetite Anemia Constipation Peripheral edema Epistaxis Alopecia The febrile neutropenia rate (any grade) was 3.6% in ramucirumab patients and 2.7% in placebo patients

8 RAISE: ADVERSE EVENTS OF SPECIAL INTEREST Any Grade Grade 3 Ramucirumab + N=529 Placebo + N=528 Ramucirumab + N=529 Placebo + N=528 n % n % n % n % Bleeding/hemorrhage event Hypertension Proteinuria GI hemorrhage Venous thromboembolic events Infusion-related reaction Renal failure GI perforation Arterial thromboembolic event Pulmonary hemorrhage events Healing complication Congestive heart failure Fistula RPLS Thrombotic microangiopathy Hepatic hemorrhage event GI, gastrointestinal; RPLS, reversible posterior leukoencephalopathy syndrome.

9 CONCLUSIONS RAISE met its primary endpoint Demonstrated a statistically significant improvement in overall survival for ramucirumab and vs placebo and In second-line metastatic CRC patients who progressed after first-line treatment wit bevacizumab, oxaliplatin, and a fluoropyrimidine Consistent survival benefits were observed across subgroups Ramucirumab in combination with was well tolerated in patients with mcrc. Overall, the adverse events were considered manageable

10 PREOPERATIVE HEPATIC AND REGIONAL ARTERIAL CHEMOTHERAPY (PHRAC) REDUCES THE OCCURRENCE OF METACHRONOUS LIVER METASTASIS AFTER CURATIVE COLORECTAL CANCER RESECTION A PROSPECTIVE, MULTI-CENTER, RANDOMIZED CONTROLLED TRIAL Jianmin Xu Zhongshan Hospital, Fudan University Shanghai, China

11 PHRAC Right colon cancer Brain tumor supplying artery chemotherapy + Common hepatic artery chemotherapy SMA HA FUDR 650 mg/m2, Oxaliplatin 75 mg/m 2, MMC 8 mg/m 2 Half in each artery Presented By Jianmin Xu at 2015 Gastrointestinal Cancers Symposium

12 STUDY DESIGN CRC patients years old ctnm Stage II/III No distand metastases No contraindications to chemo No previous cancer therapy R PHRAC 7d before primary surgery (PHRAC arm) Primary surgery (Control arm) Primary surgery(phra C arm) Adjuvant therapy(contr ol arm) Adjuvant therapy(phra C arm) Presented By Jianmin Xu at 2015 Gastrointestinal Cancers Symposium

13 OUTCOMES Primary outcome DFS Secondary outcome Cumulative incidence of liver metastasis OS Safety Presented By Jianmin Xu at 2015 Gastrointestinal Cancers Symposium

14 PRIMARY OUTCOME DFS ITT population Eligible population Probability of survival PHRAC Control Hazard ra1o (95% CI) Events n/n (%) 3y- DFS 5y- DFS 78/341 (22.9%) 80% 75% 120/347 (34.6%) 68% 61% 0.60 ( ) Log- rank p<0.001 Probability of survival PHRAC Control Hazard ra1o (95% CI) Events n/n (%) 3y- DFS 5y- DFS 66/313 (21.1%) 82% 77% 99/314 (31.5%) 72% 63% 0.62 ( ) Log- rank p<0.002 No. at risk PHRAC Control Time (months) No. at risk PHRAC Control Time (months) Presented By Jianmin Xu at 2015 Gastrointestinal Cancers Symposium

15 VITAMIN D STATUS AND SURVIVAL OF METASTATIC COLORECTAL CANCER PATIENTS: RESULTS FROM CALGB/SWOG (ALLIANCE) Kimmie Ng, Alan P. Venook, Kaori Sato, Bruce W. Hollis, Donna Niedzwiecki, Cynthia Ye, I-Wen Chang, Bert H. O Neil, Federico Innocenti, Heinz-Josef Lenz, Charles D. Blanke, Robert J. Mayer, Charles S. Fuchs, Jeffrey A. Meyerhardt

16 CALGB/SWOG 80405: FINAL DESIGN ORIGINAL mcrc 1 st -line KP wildtype (con 13 Strata: FOLFOX/ Prior adjuvant chemo Prior XRT or FOLFOX MD choice Chemo + Cetuximab Chemo + Bevacizumab Chemo + Bevacizumab and Cetuximab N = Endpoint: Overall Survival Presented By Kimmie Ng at 2015 Gastrointestinal Cancers Symposium

17 STATISTICAL METHODS Pre-planned, prospective, observational cohort study Primary endpoint: Overall survival Kaplan-Meier method Log rank test Plasma 25(OH)D measured by radioimmunoassay prior to treatment Validated diet and lifestyle questionnaires prior to treatment Multivariable analyses using Cox proportional hazards models All P values two-sided and considered significant at the 0.05 level Presented By Kimmie Ng at 2015 Gastrointestinal Cancers Symposium

18 BASELINE CHARACTERISTICS Median 25(OH)D = 17.2 ng/ml Median 25(OH)D, ng/ml (range) Median age, years Q1 (n=208) ) Q2 (n=209) 13.6 ( ) Q3 (n=208) 17.2 ( ) Q4 (n=210) 21.4 ( ) Q5 (n=208) 27.5 ( ) P Male, % Black, % < ECOG 0 / 1, % 49 / / / / / RAS WT / mut / unknown, % 33 / 30 / / 30 / / 39 / / 29 / / 21 / Presented By Kimmie Ng at 2015 Gastrointestinal Cancers Symposium

19 Overall survival probability HIGHER VITAMIN D LEVELS ASSOCIATED WITH BETTER SURVIVAL QuinFle mos (months) 95% CI Log-rank P = No. at risk Quintiles 1 & 2 Quintiles 3 & 4 Quintile Time (years) Presented By Kimmie Ng at 2015 Gastrointestinal Cancers Symposium