At a recent meeting of the National Cancer Institute, the European Organization for Research and Treatment of Cancer, and the American Association for Cancer Research in Amsterdam, results from a phase I/II clinical trial were presented that demonstrated that bexarotene (Targretin), in conjunction with chemotherapy, may be an effective treatment for patients with non-small-cell lung cancer. These results add to the phase II/III results recently reported by Ligand Pharmaceuticals, manufacturers of bexarotene, and to a growing body of data that suggest bexarotene therapy may delay disease progression and extend survival of patients with some forms of solid-tumor cancer.
Survival Extended
Researchers found that bexarotene capsules plus chemotherapy yielded acceptable response rates, with better-than-expected survival in stage III/IV non-small-cell lung cancer patients.
"We believe our 1-, 2-, and projected 3-year survival are the best reported in the literature," said Fadlo R. Khuri, MD, assistant professor of medicine at the University of Texas M. D. Anderson Cancer Center in Houston, Texas, and lead investigator of the study. "While this is a phase II trial with a limited number of patients, these survival data are clinically important and exciting."
"The results from this multicenter study are most notable in terms of the high survival rate, perhaps the best reported for phase II trials of non-small-cell lung cancer, while the tumor response rate is comparable to results of other phase II platinum-based combination trials," said Steven U. Reich, MD, Ligand’s senior vice president of clinical research. "In the trials of patients with non-small-cell lung cancer reporting 2-year survival rates, few have reported 2-year survival rates better than 15%. Our experience with bexarotene capsules for actual 2-year survival was 32%, and the projection for 3-year survival is 30%. At the maximum tolerated dose of 400 mg/m2 of body surface area per day. Bexarotene showed substantial activity in combination with a third-generation chemotherapy regimen with a tolerable safety profile."
"The body of evidence is now large enough to begin initiating large-scale phase III clinical studies to conclusively demonstrate bexarotene capsules’ benefit in the treatment of patients with non-small-cell lung cancer," said Andres Negro-Vilar, MD, senior vice president of research and development and chief scientific officer at Ligand. "After discussions with the FDA, we anticipate launching the phase III trials in the first half of 2001."
Bexarotene Investigated in Combination Therapy
In the phase I/II trial, 43 previously untreated patients with stage IIIb with pleural effusion and stage IV non-small-cell lung cancer (Karnofsky performance status ³ 70) were treated with bexarotene in combination with an active chemotherapy regimen of cisplatin(Drug information on cisplatin) (Platinol, 100 mg/m2) and vinorelbine (Navelbine, alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion of the trial, the dose of bexarotene was escalated from 150 mg/m2 through 600 mg/m2 daily in cohorts of three to six patients, starting 1 week prior to therapy with cisplatin and vinorelbine (PV). After the maximum tolerated dose of bexarotene plus PV was determined to be 400 mg/m2 daily, the phase II portion was initiated.
Response Rates and Adverse Events
Response rate was the primary end point with median survival and 1-year survival as secondary end points. Of 43 patients in the phase I/II trial, 8 had major responses, with 7 of 28 responses (25%) occurring in phase II. Median survival in the phase II trial was 416 days (14 months), with 61% surviving 1 year by life-table analysis and 9 of 28 patients (32%) surviving 24 or more months. The 3-year survival based on a Kaplan-Meier analysis is projected at 30%.
Adverse events included asthenia, nausea, hyperlipemia, vomiting, headache, exfoliative dermatitis, and anorexia. Reported hematologic toxicities were not greater than those reported with PV alone. One death from renal insufficiency occurred during the phase I trial. Toxicities in the phase II portion of the trial were consistent with those reported for bexarotene monotherapy and with what one would expect with combination chemotherapy with cisplatin and vinorelbine.
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