Bevacizumab, erlotinib, and imatinib in the treatment of patients (pts) with advanced renal cell carcinoma (RCC): A Minnie Pearl Cancer Research Network phase I/II trial

Abstract

4542 Background: Most pts with clear cell RCC have loss of Von Hippel Lindau (VHL) protein primarily due to gene mutation, ultimately resulting in overexpression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF-:), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). In a previous phase II trial, we demonstrated that combined VEGF/EGF receptor inhibition with bevacizumab and erlotinib was an active and well tolerated treatment for pts with metastatic RCC. In this phase I/II trial, we add imatinib, a PDGF receptor antagonist, to the combination of bevacizumab/erlotinib. Methods: Eligibility: metastatic clear cell RCC, 0–2 previous systemic regimens, ECOG PS 0–1, no previous anti-angiogenesis or EGF receptor inhibitor therapy, no active CNS metastases, adequate organ function, no history of thromboembolic disease, informed consent. All pts received bevacizumab 10mg/kg IV q 2 weeks, and erlotinib 150mg po daily. In the phase I portion of the trial, imatinib levels were escalated: 300mg qd (cohort 1), 400mg qd (cohort 2), and 600mg qd (cohort 3). Pts were evaluated for response after 8 weeks; treatment continued until tumor progression. Results: In the phase I portion of the trial, imatinib 400mg qd was identified as the maximum tolerated dose. At this dose level, 2 of 10 patients had reversible dose-limiting toxicity (diarrhea). Other grade 3 toxicity (1 pt each): nausea, vomiting, rash, pruritus, fatigue, arthralgia. Grade 1/2 toxicities included rash (77%), diarrhea (69%), nausea (61%), fatigue (54%), vomiting (31%), and proteinuria (23%). Amongst the 15 pts treated in the phase I portion of the study, 2 pts had partial response and 9 pts had minor response/stable disease after 8 weeks. At present, 25 pts have been entered on the phase II portion of the study, and accrual is expected to be completed within the next 2 months. Conclusions: The combination of bevacizumab 10mg/kg IV q 2 weeks, erlotinib 150mg po qd, and imatinib 400mg po qd is tolerable therapy for pts with metastatic RCC. Preliminary results also indicate activity with this 3-drug regimen. Updated results on the phase II study will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech