Cancer Therapy: Clinical Synergy Between VEGF/VEGFR Inhibitors and Chemotherapy Agents in the Phase I Clinic

Purpose: We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies. Experimental Design: Patients treated on phase I protocols between December 2004 and July 2013 (n1⁄4 1,498)were included in this analysis. The primary outcomewas clinical benefit, defined as stable disease 6 months, complete response, or partial response. Two odds ratios (OR) for achieving clinical benefit were calculated: one for patients treatedwithVEGF/R inhibitors (ORwithVEGF/R) and another for patients treated without (OR without VEGF/R). To compare these two ORs, an interaction term was included in the multivariate model: (chemotherapy/factor of interest) (VEGF/R). We took significant interaction terms (Pinteraction < 0.05) to suggest effect modification (either synergy or antagonism) with VEGF/R inhibitors. Results: All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [OR 1⁄4 1.9; 95% confidence interval (CI), 1.5–2.4; P < 0.0001]. Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [OR with VEGF/R 1⁄4 1.6 (95% CI, 1.1–2.5) vs.ORwithout VEGF/R1⁄40.4 (95%CI, 0.3–0.6),Pinteraction1⁄40.02]. Specifically, the antimetabolite class was associated with the greatest increase in OR for clinical benefit [OR with VEGF/R 1⁄4 2.7 (95% CI, 1.5–4.7) vs. OR without VEGF/R 1⁄4 0.2 (95% CI 0.1–0.3), Pinteraction 1⁄4 0.004]. Conclusions: VEGF/R inhibitor was found to synergize with chemotherapeutics. This effect was most pronounced with the antimetabolite class. Clin Cancer Res; 20(23); 5956–63. 2014 AACR.