ECCO ESMO 2011 GI Cancer Updates TAS102 and BSC vs. Placebo and BSC Reviewer: Dr. Scott Berry Date posted: October 2011

A multicenter, randomized, double-blind, phase II study of TAS-102 plus best supportive care (BSC) versus Placebo plus BSC in patients with chemotherapy- refractory metastatic colorectal cancer ( study) Presenter: Y. Kuboki (The Cancer Institute Hospital of JFCR, Tokyo, Japan)

Background TAS-102 is a new oral anticancer agent that combines trifluorothymidine and thymidine phosphorylase inhibitor at a molar ratio of 1:0.5 –trifluorothymidine inhibits thymidylate synthase and DNA synthesis –thymidine phosphorylase inhibitor prevents the degradation of trifluorothymidine

R n=112 TAS-102+BSC 70mg/m 2 b.i.d q4wks (d 1-5, 8-12) n=57 Placebo + BSC Patient Population 2 or more prior regimens Refractory/Intolerant of: fluoropyrimidine irinotecan oxaliplatin ECOG PS 0-2 TAS-102+BSC vs P+BSC N= 169 Primary Outcome: Overall Survival 2:1

Prior Chemotherapy TAS-102 (N=112) Placebo (N = 57) p-value % # of Chemotherapy Regimens 2 ≥ N.S. Oxaliplatin Base100.0 Irinotecan Base100.0 Bevacizumab N.S. Anti-EGFR N.S.

RESULTS TAS102Placebo HR p-value Response Rate (%) 1%0% Disease Control Rate (%) 43.8%10.5% P< PFS (median, mos) 2 mos1 mos HR=0.41 P< OS (median, mos) 9 mos6.6 mos HR=0.56 P=0.0011

Major Adverse Events (Grade 3/4) TAS-102 (N=112) Placebo (N = 57) Grade 3/4 % Hematological Neutropenia Leukopenia Anemia Lymphopenia Thrombopenia Non-Hematological Fatigue Diarrhea Nausea Anorexia Febrile neutropenia Vomiting There were no treatment related deaths

Post-Treatment TAS-102 (N=112) Placebo (N = 57) p-value N%N% Post-Treatment N.S. # of Chemotherapy Regimens N.S. Fluoropyrimidine base N.S. Oxaliplatin Base N.S. Irinotecan Base P=0.012 Bevacizumab N.S. Anti-EGFR N.S.

STUDY COMMENTARY Interesting subset analysis based on the KRAS status of the patients’ tumours: KRAS WT OS HR = 0.70 KRAS MUT OS HR = 0.44 However: –? Biologic rationale –Needs to be validated in future trials Given that this study was done solely in Japan – would be good to have clinical data from a broader patient population

BOTTOM LINE FOR MEDICAL ONCOLOGISTS We are seeing more treatment refractory patients like the patients in this trial that are fit for further therapy – especially patients with KRAS Mutant tumours This randomized phase II trial of this novel agent demonstrated a statistically and clinically significant improvement in OS in this group of patients However a larger, confirmatory phase III trial is needed before it could be considered a standard of care