ATLANTA — A year after 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 disease.

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, chief of thoracic medical oncology at 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 cautioned 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. He cautioned, however, that the inhibition of each target may not be equally effective with just one drug.

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 23.9 weeks.

Three patients died of hemorrhages, however: Two were pulmonary—only one of which was attributed to treatment—and one was cerebral.

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 and 47 additional patients enrolled on 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 three 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.

Dr. Gatzemeier announced that a phase III trial has already started. It is to randomize 900 patients to a carboplatin/paclitaxel regimen with sorafenib or a placebo.

ZD6474

Dr. Ronald B. Natale reported that 83 patients achieved a median progression-free survival of 11 weeks on 300 mg per day of ZD6474. In comparison, only 8.1 weeks was reached by a control arm of 85 patients treated with 250 mg of gefitinib (Iressa) daily. The response rates were 8% and 1%, respectively.

The trial allowed patients who had progressed to cross over to the other agent. There were no additional responses, but 16 of 37 patients who switched from gefitinib to ZD6474 achieved more than 8 weeks' disease control vs. 7 of 29 patients who switched to gefitinib from ZD6474.

Dr. Natale, a medical oncologist at the Cedars-Sinai Comprehensive Cancer Center in Los Angeles, concluded that the data support further investigation of ZD6474 as monotherapy.

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Convenience and the potential to lower treatment costs are among the advantages of these agents. DR. HERBST

New Antiangiogenesis Agents Fight Lung Cancer