Exploratory biomarker analysis for predicting treatment effects of aflibercept in the VELOUR trial.

Abstract

3592 Background: Second-line treatment with aflibercept and FOLFIRI in patients with metastatic colorectal carcinoma (mCRC) previously treated with oxaliplatin improved overall survival (OS) versus placebo [Hazard ratio (HR), 0.81; 95% CI, 0.71–0.93; P=0.003]1. However, colorectal cancer (CRC) is a heterogenous disease and the new intrinsic consensus molecular (iCMS) allows for tumours to be subtyped into unique genetic and transcriptional features2. We present a post hoc analysis of VELOUR patient data, to assess the impact of KRAS or BRAF mutation status and iCMS on efficacy parameters. Methods: Patient samples were classified as either KRAS or BRAF mutant or wild-type (WT) via a targeted mutation panel1. Gene expression data was used to classify samples as either iCMS2 or iCMS3 using a modified classifier based on iCMS signatures which are specifically up-regulated in tumour samples2. Results: Of the 439 patients with available RNA data, 54.9% (241/439) were classified as iCMS2; 45.1% (198/439) as iCMS3; 48.3% (212/439) as RAS mutant and 8.4% (37/439) as RAF mutant. A favourable aflibercept treatment effect was observed for patients within the KRAS WT group (Median OS from 11 to 17.7 months; HR 0.87; 95% CI 0.79-0.96, P=0.005), particularly for patients with KRAS WT iCMS2 tumours (Median OS from 15.5 to 30.4 months; HR 0.81; 95% CI 0.70-0.94, P=0.004). This is in comparison to the KRAS WT iCMS3 patients where no treatment benefit was seen (HR 0.97; 95% CI 0.82-1.14, P=0.683). In addition, no treatment benefit was seen in the KRAS mutant group (OS HR 1.03; 95% CI 0.96-1.12, P=0.405). Progression-free survival (PFS) data followed the same trend. Aflibercept seemed to also strongly benefit the 37 patients with BRAF-mutated tumours, (PFS HR 0.46, 95% CI 0.20-1.09; OS HR 0.65, 95% CI 0.29-1.48), although differences were not statistically significant. Irrespective of treatment, improved OS (HR 0.60; 95% CI 0.48-0.75, P< 0.001) and PFS (HR 0.75; 95% CI 0.60-0.94, P=0.011) were observed in all patients with iCMS2 versus iCMS3 tumours, as expected. Treatment-by-mutation status interaction tests (OS P=0.40, PFS P=0.33) indicated that the aflibercept benefit was not statistically different among the mutation sub-groups, although the small sample size limited the analysis. Conclusions: In the VELOUR study, the benefit of the addition of aflibercept to FOLFIRI appears to be primarily in patients with KRAS WT tumours, especially those with KRAS WT iCMS2. The improved OS and PFS seen in all patients with iCMS2 tumours in comparison to iCMS3 is prognostic but not predictive of aflibercept treatment response in addition to FOLFIRI. On the contrary, the addition of aflibercept to FOLFIRI provided a numerical benefit in BRAF-mutated tumours, however the P-values were not statistically significant.