NASHVILLE, Tennessee- Promising outcomes in a phase I/II trial of the bevacizumab(Drug information on bevacizumab) (Avastin) and erlotinib (Tarceva) combination against recurrent non-small-cell lung cancer (NSCLC) have prompted a phase II study testing bevacizumab/ erlotinib against bevacizumab/docetaxel (Taxotere) and docetaxel(Drug information on docetaxel)/placebo. Alan B. Sandler, MD, of Vanderbilt University Medical Center, Nashville, Tennessee, described the results of the phase I/II bevacizumab/ erlotinib study (abstract 2000). The rationale for combining bevacizumab, a vascular endothelial growth factor blocker, and erlotinib, an HER1/epithelial growth factor receptor tyrosine kinase blocker, is grounded in preclinical work showing synergy for these two targeted agents used together in mice with human tumor xenografts, Dr. Sandler explained. Dosing and Toxicities The primary objective of the phase I/II study was to establish the maximum tolerated doses of the combination and to examine dose-limiting toxicities. The secondary objective was to evaluate the pharmacokinetics for potential drug interactions. The phase I/II trial enrolled 40 patients (21 female, 19 male) with recurrent, nonsquamous, stage IIIB (with pleural effusion), stage IV, or recur- rent NSCLC. All had received at least one prior chemotherapy regimen. Thirty (75%) had adenocarcinomas, one (5%) had bronchoalveolar carcinoma (BAC), and nine (22.5%) had NSCLC not otherwise specified. Median age was 59 (range 36-72). The phase I part of the study was toxicity analysis in the first 12 patients. The main toxicities reported were mild rash, diarrhea, and proteinuria. There were no hemorrhages in any of these patients. The highest dose tested in this phase I part of the study, erlotinib 150 mg/d po plus be vacizumab 15 mg/kg IV every 21 days, was selected as the phase II dose, although no true dose-limiting toxicities were seen. There were also no pharmacokinetic indications of drug interactions. Among the 12 patients treated in the phase I segment were 4 with partial responses (PR) and 6 with stable disease (SD). These promising outcomes encouraged the investigators to press on with bethe phase II part of the study. Among the 34 patients in this phase were 1 patient with grade 4 pulmonary toxicity that is still under investigation, 2 patients (6%) with grade 3 hypertension, and 1 with grade 3 vomiting. The phase II treatment produced 20% PR and 65% SD, for a clinical control rate of 85%. Median time to progression was 7.0 months (see Table 1). Dr. Sandler said that response was quite durable in many patients, including one patient who has continued on treatment without progression for almost 2 years. "The response rate was 20% and median survival was 12.6 months, but it is important to remember that a high number of patients had adenocarcinomas, and patients with brain metastases were excluded," he said. Dr. Sandler reported that a randomized phase II trial was expected to begin in summer 2004 and would seek to enroll about 200 patients.