Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression

Abstract

Background: The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ≥65 years), and time to progression (TTP) on first-line therapy (<6 versus ≥6 months).

Patients and methods: OS and PFS were evaluated by the Kaplan-Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs.

Results: Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ≥6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ≥65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (≥65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was similar across subgroups.

Conclusions: These analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC.

Trial registration: ClinicalTrials.gov, NCT01183780.

Keywords: CRC; RAISE; VEGFR-2; metastatic colorectal carcinoma; phase III clinical trial; ramucirumab.

Figure 1.

Forest plots for (A) overall survival and (B) progression-free survival in subgroups. Hazard ratios (HRs) and 95% confidence intervals (CIs) are shown for subgroups as defined by baseline patient and tumor characteristics. CEA, carcinoembryonic antigen; ECOG PS, Eastern Cooperative Oncology Group performance status; RAM, ramucirumab; PBO, placebo; TTP, time to progression.

Figure 1.

Forest plots for (A) overall survival and (B) progression-free survival in subgroups. Hazard ratios (HRs) and 95% confidence intervals (CIs) are shown for subgroups as defined by baseline patient and tumor characteristics. CEA, carcinoembryonic antigen; ECOG PS, Eastern Cooperative Oncology Group performance status; RAM, ramucirumab; PBO, placebo; TTP, time to progression.

Figure 2.

Graphs of the Kaplan–Meier estimates of (A and B) overall survival and (C and D) progression-free survival by wild-type (A and C) and mutant (B and D) KRAS status. CI, confidence interval; HR, hazard ratio; RAM, ramucirumab; PBO, placebo; n, number of patients; OS, overall survival (months); PFS, progression-free survival (months).

Figure 3.

Graphs of the Kaplan–Meier estimates of (A and B) overall survival and (C and D) progression-free survival by time to progression on first-line therapy ≥6 months (A and C) and <6 months (B and D). CI, confidence interval; HR, hazard ratio; RAM, ramucirumab; PBO, placebo; n, number of patients; OS, overall survival (months); PFS, progression-free survival (months); TTP, time to progression.

Figure 4.

Graphs of the Kaplan–Meier estimates of (A and B) overall survival and (C and D) progression-free survival by age ≥65 (A and C) and <65 (B and D) years. CI, confidence interval; HR, hazard ratio; RAM, ramucirumab; PBO, placebo; n, number of patients; OS, overall survival (months); PFS, progression-free survival (months).