Abstract A3: Beyond VEGF inhibition: Comparative efficacy analysis of novel VEGF and non-VEGF therapeutic agents in phase I trials for patients with metastatic colorectal cancer.
Authors: Patel Sukeshi R. , Karnad Anand B. , Ketchum Norma S. , Pollock Brad H. , Sarantopoulos John , Weitman Steven , Mahalingam Devalingam 
Published: August 2014

Background: Agents targeting the angiogenic pathway have been the cornerstone of metastatic colorectal cancer (mCRC) treatment for the last 10 years. Recently, regorafenib (RGF), an oral multikinase inhibitor with angiogenic inhibition, was approved for patients (pts) with mCRC who have failed standard therapies. This suggests VEGF inhibition has a continued therapeutic role in the third line setting in mCRC pts, despite progression on previous anti-angiogenic agents. Prior to RGF, mCRC pts were often enrolled on phase I clinical studies, with efficacy reported by many novel agents. We chose to further assess efficacy of VEGF versus non-VEGF Inhibitors amongst pts with refractory mCRC enrolled in early phase studies prior to RGF approval.

Methods: A historical cohort analysis included pts with mCRC enrolled amongst 44 phase I trials at the IDD, from 3/2004 - 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 139 pts were included. Median age 59 (33-81), males 67.6%, K-ras mutated 38.7 %. ECOG PS 0-1 94.9 %. ≥3 prior lines of therapy 73.9 %. Class of drugs included: VEGF Inhibitors 19.4%, Cytotoxic 36.7%, Cell Cycle Inhibitors 12.2%, Microenvironment Inhibitors 7.2%, Apoptosis/Autophagy Inhibitors 7.9%, EGFR/Growth Factor I / TKIs 10.7 %, others 5.8 %. For the whole cohort of 139 pts, mPFS was 2.0 mo (95% CI: 1.8 - 2.8). As of 4/1/13, among 130 pts (9 lost to follow-up), mOS was 6.1 mo (95% CI: 5.1 - 6.9). In subgroup analysis, mPFS was 3.7 (95% CI: 1.8-7.4) vs 1.9 months (95% CI: 1.8-2.3) for pts on VEGF (n=27) and non-VEGF Inhibitors (n=112), respectively (HR 0.60; 95% CI: 0.36-1.01; p = 0.05). VEGF Inhibitor (n=25) treated pts had a mOS of 6.0 months (95% CI: 2.0-10.0 mo) vs 6.2 months (95% CI: 5.1-7.0) with non-VEGF Inhibitors (n=105) (HR 1.02; 95% CI: 0.64-1.63; p = 0.92). Sub-group analysis was done based on classes of drugs. Grade 3-4 treatment-related adverse events occurred in 34 (24.4%) pts.

Conclusions: In pretreated mCRC, mPFS and mOS for pts enrolled in phase 1 trials, irrespective of agent, were comparable to efficacy of RGF. K-RAS status or progression on prior VEGF Inhibitors did not affect efficacy; however, elderly pts had worse mOS. Phase I agents were well tolerated with minimal grade 3-4 toxicities. 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.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A3.

Citation Format: Sukeshi R. Patel, Anand B. Karnad, Norma S. Ketchum, Brad H. Pollock, John Sarantopoulos, Steven Weitman, Devalingam Mahalingam. Beyond VEGF inhibition: Comparative efficacy analysis of novel VEGF and non-VEGF therapeutic agents in phase I trials for patients with metastatic colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A3.