O-010 KRAS and BRAF gene subgroup analysis in the Phase 3 RECOURSE trial of TAS-102 versus placebo in patients with metastatic colorectal cancer

Abstract

Introduction: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride, at a molar ratio of 1:0.5 (weight ratio, 1:0.471). The efficacy and safety of TAS-102 in patients with metastatic colorectal cancer refractory/intolerant to standard therapies were evaluated in the RECOURSE trial; enrollment criteria included ≥2 prior lines of standard chemotherapy (including prior fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an anti-EGFR antibody in patients with KRAS wild-type [WT] tumors). Primary results of RECOURSE demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 vs placebo (hazard ratio [HR] = 0.68 and 0.48 for OS and PFS, respectively; both P < 0.0001). We report on the efficacy and safety in the RECOURSE trial based on KRAS and BRAF mutation gene status. Methods: These prespecified analyses of RECOURSE compared efficacy and safety of TAS-102 vs placebo in subgroups of patients who had tumors that were WT or mutant, and status was determined according to site practice. Patients were initially stratified by status; status was collected if available. The primary endpoint (OS) and key secondary efficacy endpoint (PFS) were evaluated using univariate and multivariate analyses for stratification (eg, status) and prespecified (eg, status) factors. Results: Of the 800 RECOURSE patients, 394* (49.3%) had KRAS WT tumors (63.7% male, mean age 62.0 years); 406* (50.8%) had KRAS mutant tumors (59.1% male, mean age 61.1 years). Treatment groups were well balanced with respect to KRAS status, including KRAS mutation types. BRAF status was provided for approximately 15% of intent-to-treat patients: 116 (14.5%) had BRAF WT, 8 (1.0%) had BRAF mutant tumors. OS favored TAS-102 vs placebo across both KRAS subgroups, although this difference did not achieve statistical significance in the KRAS mutant group (Table). Results for PFS also favored TAS-102 across KRAS gene status. The small number of patients with BRAF status identified, especially BRAF mutant, precludes any meaningful analysis. There were no overall differences in incidence of adverse events (AEs), ≥ Grade 3 AEs, or serious AEs for patient subgroups based on KRAS status, and no consistent differences in incidence of specific AEs and clinical laboratory abnormalities. In the TAS-102 group, patients with KRAS mutant vs WT tumors had a higher incidence (≥5%) of diarrhea (35.2% vs 28.5%), asthenia (21.6% vs 14.6%), and decreased appetite (43.2% vs 34.6%); patients with KRAS WT tumors had a higher incidence of decreased neutrophil (30.4% vs 25.3%) and white blood cell count (31.5% vs 23.4%). Statistical analysis was not planned for AEs. The small BRAF status sample size makes it difficult to draw any conclusions regarding differences in incidence of AEs or clinical laboratory abnormalities. Conclusion: As in the overall RECOURSE study group, TAS-102 was associated with improved OS and PFS vs placebo in patients with KRAS WT and mutant tumors, along with a favorable safety profile. Survival benefit in patients with KRAS mutant tumors showed borderline statistical significance. Although similar results were obtained with respect to BRAF status, the small patient sample size precludes evaluation.