Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE, a global phase 3 study

Abstract

Background

Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (mCRC) (hazard ratio [HR]=0.84, 95%CI=0.73–0.98, P=0.022). Post-hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters.

Patients and methods

Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS ("RAS") mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon and cecum.

Results

RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI = 0.71–1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI = 0.64–1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI = 0.25–1.13), although, as with the other genetic subgroup analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P=0.523, PFS P=0.655) indicated that the ramucirumab benefit was not statistically different among the mutation subgroups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI = 0.68–0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI = 0.75–1.26). The treatment-by-subgroup interaction was not statistically significant for tumour sidedness (P = 0.276).

Conclusions

In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the p-values were not statistically significant. ClinicalTrials.gov, NCT01183780