ATLANTA — A year after research on bevacizumab proved that angiogenesis inhibition can help patients with non-small cell lung cancer live longer, a second generation of antiangiogenesis agents is showing activity against advanced, metastatic lung cancer.
Phase II trials of sunitinib (Sutent), sorafenib (Nexavar), and an experimental drug called ZD6474 (Zactima) all reported progression-free survival rates of 11% or more at the annual meeting of the American Society of Clinical Oncology.
Because each drug hits more cellular targets than does bevacizumab (Avastin), investigators voiced hope that the new agents will be more effective. Two of the drugs—sunitinib and sorafenib—have already been approved for renal cell carcinoma. Sunitinib also has an indication for gastrointestinal stromal tumors that are refractory to imatinib (Gleevec).
Along with the possibility of better therapies, however, the three trials renewed concerns about the toxicity of antiangiogenic agents. Investigators reported cavitation and hemorrhage leading to treatment-related deaths. Rash, hand-foot syndrome, and controllable hypertension also were seen.
“More than ever, we need pulmonologists to look at the risk of bleeding and to look at cavitation,” Dr. Roy S. Herbst said in an interview after presenting a review of the new drugs and the state of antiangiogenic therapy against lung cancer.
“We need to find some sort of risk factors to stratify these patients,” said Dr. Herbst, of the department of thoracic/head and neck medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston and the senior investigator of a series of lung cancer trials testing the combination of bevacizumab and erlotinib (Tarceva).
Dr. Herbst cited the survival advantages reported last year in a phase III trial combining bevacizumab with chemotherapy, as well as early results from his study. “Despite these advances, few, if any, metastatic patients are cured,” he cautioned.
He called the three new agents “quite comparable” and noted that “signs of early activity are seen,” but said that whether the new multitargeted tyrosine kinase inhibitors are more effective than single-targeted bevacizumab is “not clear yet” in non-small cell lung cancer.
Among the potential advantages of multitargeted agents, Dr. Herbst cited convenience, single-agent activity, the ability to act on both tumor and blood vessels, and the potential to lower the cost of treatment. Whether these agents can be used alone or should be combined with chemotherapy or other targeted agents still has to be worked out in clinical trials, he said.
“Angiogenesis inhibition has become a mainstay in cancer therapy, and it will be very interesting in the next few years as we figure out how to optimize its use and use it safely,” Dr. Herbst said. “It is a perfect therapy to add to our existing methods.”
Sunitinib
Dr. Mark A. Socinski reported that sunitinib controlled tumor growth in more than half of 63 patients who had failed previous regimens for advanced non-small cell lung cancer. Six patients (9.5%) had partial responses, and 27 patients (42.9%) had stable disease in the study. Median progression-free survival reached 11.3 weeks, and overall survival was 23.9 weeks.
Three patients died of hemorrhages, however: Two were pulmonary—only one of which was attributed to treatment—and one was cerebral. Fatigue led the list of grades III and IV toxicity. Other adverse events included myalgia, neutropenia, stomatitis, headaches, and hypertension.
Patients received 50 mg of sunitinib daily for 4 weeks followed by 2 weeks off therapy before starting another cycle in the trial. Dr. Socinski, director of the multidisciplinary thoracic oncology program at the University of North Carolina at Chapel Hill, announced that the study has been extended with a revised dosing schedule of 37.5 mg daily.
Sorafenib
Dr. Ulrich Gatzemeier reported that 30 (59%) of 51 patients with advanced non-small cell lung cancer had stable disease while they were treated with 400 mg twice a day of sorafenib. No partial responses were recorded in the study.
Another 18 patients (35%) progressed, and 3 patients died before they could be evaluated. Median progression-free survival reached 11.3 months, and median survival 29.5 weeks. Two patients have been on therapy for 2 years, according to Dr. Gatzemeier, head of thoracic oncology at Grosshansdorf Hospital in Hamburg, Germany.
Four patients, all with squamous cell carcinoma, had tumor cavitation, and four patients had bleeding events. Three hemorrhages were described as minor, but a fatal hemorrhage occurred in a cavitary lesion while the patient was receiving radiation therapy 30 days after stopping sorafenib. Other adverse events included diarrhea, hand-foot syndrome, fatigue, and hypertension.
Dr. Gatzemeier said that a phase III trial has already started. It is to randomize 900 patients to a carboplatin/paclitaxel regimen with sorafenib or a placebo.