Clinical Targeting of VEGF and EGFR Effective in Non-Small Cell Lung Cancer

Abstract

Results of the first clinical trial to combine two new targeted cancer drugs suggest that the combination may provide a powerful "one-two punch" against lung cancer, the nation's leading cancer killer.The work, led by researchers at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and The University of Texas M.D. Anderson Cancer Center in Houston, was presented June 5, 2004, at the 40th annual meeting of the American Society of Clinical Oncology in New Orleans.Tumors were controlled among 85 percent of the 40 patients with advanced non-small cell lung cancer (NSCLC) who entered the Phase I/II trial of a combined regimen of bevacizumab (Avastin TM) and erlotinib (Tarceva TM).The response rate - proportion of patients whose tumors shrank in size by more than half - was about 20 percent, while median survival was 12.5 months. This compares to about 10 percent response and between six and eight months median survival with traditional therapy or erlotinib alone, said Alan Sandler, M.D., associate professor of Medicine and director of the lung cancer clinical program at Vanderbilt-Ingram.The treatment resulted in only mild side effects, including rash and diarrhea, and the drugs did not appear to interact adversely with one another, the investigators report."The anti-tumor activity was encouraging" said Sandler, who presented the research at the meeting. "These findings suggest not only that combining these two agents is feasible, but that this approach may provide a one-two punch against tumors that should be further examined in larger clinical trials."Lung cancer is the leading cause of cancer death in the United States, killing more than 157,000 people each year, more than the next four leading cancers (colorectal, breast, prostate and pancreas) combined. About 85 percent of all lung cancers are non-small cell cancers, and nearly half of these patients are diagnosed with advanced disease and receive only chemotherapy or supportive care, the investigators say.Despite newer third-generation chemotherapies, most of these patients become resistant to treatment or develop side effects so severe that they cannot continue treatment. "Less toxic and more effective treatments are clearly needed," Sandler said.The two drugs are among newer so-called targeted cancer agents that focus on specific molecular features of cancer cells. Because they potentially target cancer cells while sparing healthy cells, the hope for these new agents is more effective cancer therapy with fewer side effects.Bevacizumab blocks the vascular endothelial growth factor (VEGF), which is involved in making new blood vessels (a process called angiogenesis) that help feed tumor growth and spread. Erlotinib inhibits the epidermal growth factor receptor (EGFr), a key player in delivery of signals that prompt the runaway cell growth that characterizes cancers.Increased activity of the EGFr pathway, as well as increased number of tumor blood vessels resulting from VEGF expression, are associated with poorer outcomes for patients with NSCLC, the investigators note.Other research has suggested that activities of EGFr and VEGF are related - EGFr appears to play a role in angiogenesis, while blocking VEGF appears to interrupt EGFr signaling. As a result, the researchers suspect that a dual blockade of these targets may be synergistic.Interim results from this research were presented at last year's ASCO meeting in Chicago, prompting other investigators across the country to examine this combination in other tumor types as well as combine other targeted agents in clinical trials, Sandler said.At the time the study was launched, it was the first time two drugs that had not yet been approved by the U.S. Food and Drug Administration were combined in a trial. Since that time, bevacizumab has been approved for use in advanced colorectal cancer in combination with chemotherapy. Erlotinib is pending FDA approval.Co-investigators include Roy Herbst, Eric Mininberg, Ted Henderson, Edward Kim, George Blumenschein Jr., Jack Lee, Mylene Truong, and Waun Hong of M.D. Anderson; David Johnson and David Carbone of Vanderbilt-Ingram; Ben Garcia of the University of Texas Southwestern Medical Center; and Dong Xie and Sean Kelley of Genentech Inc., which makes both drugs and funded the clinical trial.