Phase I/II trial evaluating the anti-VEGF MAb bevacizumab in combination with erlotinib, a HER1/EGFR-TK inhibitor, for patients with recurrent non-small cell lung cancer

Abstract

2000 Background VEGF and HER1/EGFR play a pivotal role in many types of cancer. Bevacizumab (Avastin) is a recombinant, humanized anti-VEGF MAb, and erlotinib HCl (Tarceva) is a potent, reversible, and highly selective HER1/EGFR tyrosine-kinase inhibitor. Both have demonstrated antitumor activity in patients with previously treated non-small cell lung cancer (NSCLC). In addition, xenograft experiments performed in various tumor types suggest that growth inhibition using bevacizumab plus erlotinib (AT) is greater than with either agent alone. Therefore, there is compelling rationale for using AT as a therapy for NSCLC. Methods A multicenter, Phase I/II study examined AT in patients with either Stage IIIB/IV or recurrent NSCLC treated with at =1 prior chemotherapy regimen. In Phase I, erlotinib 150mg/day p.o. plus bevacizumab 15mg/kg i.v. every 21 days was established as the Phase II dose, although no true dose-limiting toxicities were observed. Phase II examined the efficacy and tolerability of the combination. Pharmacokinetic and pharmacodynamic parameters were monitored. Results Forty patients have been enrolled and treated, including 34 patients at the Phase II dose level. Patient characteristics (n=40) were: median age 59 (range 36–72), 21 female/19 male, 30 with adenocarcinoma histology, and 24 received =2 prior regimens and 3 =3. The most commonly reported adverse events were rash, diarrhea, and proteinuria, which were never more than mild to moderate. Preliminary data indicate no pharmacokinetic interaction between these two agents. Seven patients (17.5%) had partial responses, two (5%) had minor responses, and 14 (35%) had stable disease. The median overall survival and time to progression for patients on the Phase II dose level (n=31) was 9.3 and 4.6 months, respectively. Conclusions The encouraging antitumor activity and favorable safety profile of AT support further development of this combination for advanced NSCLC. A randomized Phase II trial is planned comparing AT with docetaxel plus bevacizumab and docetaxel plus placebo in advanced NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc. Genentech; OSI Genentech, Inc. Aventis; Genentech