NASHVILLE, Tennessee- Preliminary results of a phase II study of bevacizumab(Drug information on bevacizumab) (Avastin) and erlotinib (Tarceva) in patients with meta- static renal carcinoma show a substantial number of durable partial responses and support further study of this regimen, said John D. Hainsworth, MD, of the Sarah Cannon Cancer Center/ Tennessee Oncology in Nashville (abstract 4502). "This tumor is refractory to standard chemotherapy, and only a small percentage of patients benefit from cytotoxic therapy," he told Oncology News International. Dr. Hainsworth explained that most patients with clear cell renal carcinoma have loss of the VHL protein, resulting in overexpression of a number of genes including vascular endothelial growth factor (VEGF), tumor growth factor (TGF)-beta, epithelial growth factor (EGF), and platelet derived growth factor (PDGF). In second- line use, bevacizumab, an anti- VEGF antibody, prolongs time to progression in advanced renal carcinoma. "Based on renal carcinoma biology, we hypothesized that combined VEGF and EGFR inhibition would enhance biological and clinical effects," Dr. Hainsworth said. Original Protocol Amended In this phase II trial, bevacizumab was combined with the EGFR antagonist erlotinib. The study enrolled patients with metastatic clear cell renal carcinoma, and 0 or 1 previous systemic regimen. Patients were treated with bevacizumab at 10 mg/kg IV q 2 weeks and erlotinib at 150 mg/d po. Patients were evaluated for response after 8 weeks. The investigators had originally intended to continue treatment for 12 months, but the original study protocol was amended to permit continuation in patients until disease progression. Dr. Hainsworth reported data for 58 treated patients with median follow- up of 11 months. In contrast to several other trials, 68% had no prior treatment. Eighteen percent had pre- pavious interferon, 8% had previous interleukin- 2 (IL-2) plus interferon, and 6% had previous IL-2. Fifty three patients had previous nephrectomies. Sites of metastases included lungs (41), liver (17), bone (15), adrenals (10), and other sites (14). "Nine of 12 patients with partial responses and 10 of 12 with minor responses [20% to 30% decrease in tumor size] remain progression-free," said Dr. Hainsworth (see Table 1). "A total of 42% of patients had measurable decreases in their tumor size. Twenty six of the 38 stable or minor response patients remain alive and on treatment for more than 6 months." "Responses have been seen in all areas of metastases and in most cases included reductions of more than 50%. For example, one patient had innumerable bilateral lung metastases that cleared substantially with treatment, " Dr. Hainsworth said. Twelve Month PFS of 50% Six-month progression-free survival (PFS) was 67%, and 12-month PFS was 50%. Six-month overall survival was 92%, and 12-month overall survival was 81%. Treatment was tolerable in most patients but with a number of minor side effects, Dr. Hainsworth noted. Twenty-five patients (63%) had no grade 3 or 4 toxicity. Only two patients stopped treatment because of toxicity, both as a result of rash. Grade 3 or 4 toxicity included rash in eight patients (13%), diarrhea in six (10%), and nausea and vomiting in six (10%). Grade 1 or 2 bleeding occurred in 24 patients (39%) and grade 3 or 4 bleeding was reported in 3 patients (5%). "The number of bleeding occurrences may seem out of proportion. We were somewhat concerned about bleeding, which has been a problem with bevacizumab, but most instances were minor hemorrhoidal bleeding or minor nosebleeds. We feel that this is probably not a true level of treatmentrelated toxicity," Dr. Hainsworth said. "Most of the side effects were the rash and diarrhea typical of EGF receptor inhibitors." Good Major Response Rate The investigators concluded that bevacizumab/erlotinib produced a major response rate of 21% in this group of 58 evaluable patients with advanced renal carcinoma. An additional 45% of patients had stable disease or minor response for more than 6 months, and Dr. Hainsworth said that an increasing number of patients have now maintained this result for more than 12 months with continued treatment. One-year PFS was 50%, and overall survival was 81%. "This regimen appears to be one of the most active and best tolerated regimens in the treatment of advanced renal carcinoma. The activity of this combination of two targeted agents appears greater than the activity of either agent used alone in clear cell renal carcinoma. Comparison of this regimen to standard regimens is certainly indicated. The results of this trial also support further development of combinations of targeted agents to exploit tumor-specific biologic mechanisms in renal cancer and other malignancies," Dr. Hainsworth concluded.