ISY-17-3Subgroup analysis in RAISE: a phase III study of FOLFIRI + ramucirumab or placebo in patients with advanced mCRC

Background: The RAISE prespecified subgroup analyses included 3 stratification factors: KRAS status, time to first-line PD (TTP, <6 months and ≥6 months) and geographic region. These analyses evaluated outcomes of ramucirumab (RAM) + FOLFIRI according to the variables considered most informative: KRAS and TTP. Materials and Methods: In RAISE, mCRC patients with disease progression during or after a first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine were randomized 1:1 to RAM 8mg/kg I.V. or placebo (PBO) in combination with FOLFIRI every 2 weeks. Overall survival (OS) and progression-free survival (PFS) for each of the KRAS and TTP subgroups were evaluated by Kaplan-Meier. Hazard ratios (HR) were calculated by unstratified Cox proportional hazards model; p-values were calculated by unstratified log rank test. The interaction was tested to determine if treatment effect was consistent among subgroups. Results: OS and PFS were greater for patients receiving RAM+FOLFIRI in each subgroup, compared with patients receiving PBO+FOLFIRI: KRAS wild-type: OS HR: 0.82, 95% CI: 0.67-1.00, p=0.049, PFS HR: 0.77, 95% CI: 0.65-0.92, p=0.004; KRAS mutant: OS HR: 0.89, 95% CI: 0.73-1.09, p=0.263, PFS HR: 0.84, 95% CI: 0.70,1.00, p=0.056. TTP <6 months: OS HR: 0.86, 95% CI: 0.64-1.13, p=0.275, PFS HR: 0.68, 95% CI: 0.52-0.89, p=0.004; TTP ≥6 months: OS HR: 0.86, 95% CI: 0.73-1.01, p=0.061, PFS HR: 0.83, 95% CI: 0.72, 0.96, p=0.013, respectively. Regardless of the numerical differences in the subgroups, there was a lack of treatment-by-subgroup interaction. Conclusions: The addition of ramucirumab to FOLFIRI demonstrated a consistent and clinically meaningful treatment effect for the RAISE patient population. The KRAS and TTP subgroup analyses revealed no efficacy difference among patients with differing KRAS mutation status, and longer or shorter first line TTP. RAM+FOLFIRI is an effective second-line treatment for a wide range of patients with mCRC.