Beyond VEGF inhibition: Comparative efficacy analysis of novel VEGF and non-VEGF therapeutic agents in phase I trials for patients with metastatic colorectal cancer (mCRC).

Abstract

3541 Background: Recently, regorafenib (RGF), an oral multikinase inhibitor, was approved for patients (pts) with mCRC who have failed standard therapies. Compared to placebo, the phase III CORRECT study showed RGF improved median overall survival (mOS) from 5.0 to 6.4 months (mo) and median progression-free survival (mPFS) from 1.7 to 1.9 mo, regardless of K-Ras status. This suggests further VEGF inhibition is crucial in controlling mCRC progression. Many mCRC pts enroll on phase I studies with efficacy reported by some; however, a collective efficacy assessment aimed solely for mCRC in relation to class of agents has not been done. Methods: A historical cohort analysis included pts with mCRC enrolled amongst 28 phase I trials at the IDD, from 7/2008 – 9/2012. PFS and OS were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Results: A total of 75 pts were included. Median age 59 (33–80), males 61 %, K-ras mutated 39 %. ECOG PS 0–1 96 %. ≥3 prior lines of therapy 68 %. Class of drugs included: VEGF Inhibitors 32 %, Cytotoxic 25 %, Microenvironment Inhibitors 13 %, Apoptosis/Autophagy Inhibitors 11 %, EGFR/Growth Factor TKIs 8 %, others 11 %. For the whole cohort of 75 pts, mPFS was 2.8 mo (95% CI: 2.0–3.7). As of 12/1/12, among 65 pts, mOS was 5.6 mo (95% CI: 4.4-7.0). In subgroup analysis, mPFS was 3.4 (95% CI: 1.4–4.5) vs 2.8 months (95% CI: 2.0–3.5) for pts on VEGF and non-VEGF Inhibitors (HR 0.79, 95% CI: 0.43–1.44, p = 0.44), respectively. VEGF Inhibitor treated pts had a mOS of 5.5 months (95% CI: 1.6–10.0 months) vs 5.6 months (95% CI: 4.4–7.6) with non-VEGF Inhibitors (HR 1.02, 95% CI: 0.58–1.78, p = 0.96). Efficacy was similar regardless of K-Ras status. Conclusions: In pretreated mCRC, median PFS and OS for pts enrolled in phase I trials, irrespective of agent, was comparable to efficacy of RGF. Therefore, after failure of standard therapies, mCRC pts should be encouraged to enroll in clinical trials with efficacy reported in both VEGF and non-VEGF inhibitors.