Erlotinib Plus Bevacizumab Combination Safe and Promising Against NSCLC

CHICAGO-Encouraging early results reported from a phase I trial of bevacizumab(Drug information on bevacizumab) (Avastin) plus erlotinib (OSI-774, Tarceva) in patients with recurrent non-small-cell lung cancer (NSCLC) has boosted interest in testing combinations of novel agents (ASCO abstract 2521). The combination not only showed antitumor activity, but also was well tolerated by the first 12 patients in the study. Three had a partial response (producing a response rate of 25%), and five had stable disease (a rate of 42%). Although a majority of patients experienced rash, diarrhea, and/or nausea, no adverse events reached grades 3 or 4, and no bleeding was recorded (see Table 1). "We're very excited," senior investigator Roy S. Herbst, MD, of the University of Texas M. D. Anderson Cancer Center, Houston, told ONI. "Now we have 25 patients. Twenty have been evaluated, and we still have a response rate of 25%. Even more importantly the drugs are safe. You can give a full dose of Avastin, a full dose of Tarceva." Eric D. Mininberg, MD, a senior medical oncology fellow at M. D. Anderson Cancer Center, reported the preliminary results in a poster session and Dr. Herbst used them as the basis for his presentation at a post-ASCO, industry-sponsored, satellite symposium, "Targeting Critical Pathways in Oncology." Synergism Sought
An antiangiogenic agent, bevacizumab is a monoclonal antibody that disrupts the supply of blood to tumors by neutralizing the vascular endothelial growth factor (VEGF) receptor. Erlotinib is a small molecule that blocks a key signaling pathway in tumor growth by targeting the HER1/ epidermal growth factor receptor (HER1/EGFR) tyrosine kinase (see Figure 1). The investigators hoped for a synergistic effect between the two agents, according to Dr. Mininberg. "As we are learning more and more about targeted therapies, there's a lot of crosstalk between these two mechanisms and especially in lung cancer, we know there's overexpression of EGFR as well as VEGF," he said. In a discussion of NSCLC results, Alex Adjei, MD, PhD, a medical oncologist at the Mayo Clinic in Rochester, Minnesota, singled out the approach in the bevacizumab/erlotinib trial as the most promising. He called the combination of novel targeted agents "an important move forward and probably the way we should be going." Emphasizing the complexity of cancer cells, Dr. Adjei told ONI that blocking one pathway would probably have limited effect because cancer can bypass that pathway and find another way to activate downstream signaling molecules such as ERK. "If you have these agents that block different pathways, then you can block ways of the tumor escaping," he said, describing multiple target inhibition as the key to improving survival rates for patients with lung cancer. New Approaches Needed
Dr. Adjei, Dr. Herbst, and Dr. Mininberg each emphasized the need for a new approach in light of the low success rate and high toxicity of chemotherapy in lung cancer patients. "We have targeted therapies that we talk about being less toxic and easier to give, so the first thing we do is com- bine them with chemotherapy," Dr. Herbst said, calling for more studies of novel agents in combination with each other. "Combinations should have a rationale," he added, cautioning that researchers should not "just start to mix and match indiscriminately." Conducted with investigators from Genentech Inc. and Vanderbilt University, the ongoing bevacizumab/ erlotinib study is expanding to 48 patients for phase II. Inclusion criteria include histologically proven stage IIIB, IV, or recurrent nonsquamous cell NSCLC, Karnofsky performance status of ≥ 70, and at least one prior chemotherapy regimen for recurrent or metastatic disease. Patients with prior therapy targeting EGFR or VEGF are excluded. Based on phase I, the investigators are examining a maximum tolerated dose of 150 mg per day of erlotinib and 15 mg/kg of bevacizumab given intravenously every 21 days. Dr. Mininberg said the researchers hope to do proteomic studies in phase II. The protocol includes baseline and follow-up biopsies for measurement of blood vessel counts, EGFR and VEGF expression, and other markers.