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
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 thatbexarotene (Targretin), in conjunction with chemotherapy, may be an effectivetreatment for patients with non-small-cell lung cancer. These results add tothe phase II/III results recently reported by Ligand Pharmaceuticals,manufacturers of bexarotene, and to a growing body of data that suggestbexarotene therapy may delay disease progression and extend survival of patientswith some forms of solid-tumor cancer.
Researchers found that bexarotene capsules plus chemotherapyyielded acceptable response rates, with better-than-expected survival in stageIII/IV non-small-cell lung cancer patients.
"We believe our 1-, 2-, and projected 3-year survival arethe best reported in the literature," said Fadlo R. Khuri, MD, assistantprofessor of medicine at the University of Texas M. D. Anderson Cancer Center inHouston, Texas, and lead investigator of the study. "While this is a phaseII trial with a limited number of patients, these survival data are clinicallyimportant and exciting."
"The results from this multicenter study are most notablein terms of the high survival rate, perhaps the best reported for phase IItrials of non-small-cell lung cancer, while the tumor response rate iscomparable 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 reporting2-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%, andthe projection for 3-year survival is 30%. At the maximum tolerated dose of 400mg/m2 of body surface area per day. Bexarotene showed substantial activity incombination with a third-generation chemotherapy regimen with a tolerable safetyprofile."
"The body of evidence is now large enough to begininitiating large-scale phase III clinical studies to conclusively demonstratebexarotene capsules’ benefit in the treatment of patients with non-small-celllung cancer," said Andres Negro-Vilar, MD, senior vice president ofresearch and development and chief scientific officer at Ligand. "Afterdiscussions with the FDA, we anticipate launching the phase III trials in thefirst half of 2001."
Bexarotene Investigated in Combination Therapy
In the phase I/II trial, 43 previously untreated patients withstage IIIb with pleural effusion and stage IV non-small-cell lung cancer(Karnofsky performance status ³ 70) were treated with bexarotene incombination with an active chemotherapy regimen of cisplatin (Platinol, 100 mg/m2) and vinorelbine (Navelbine, alternating doses of 30mg/m2 and 15 mg/m2).In the phase I portion of the trial, the dose of bexarotene was escalated from150 mg/m2 through 600 mg/m2 daily in cohorts of three to six patients, starting1 week prior to therapy with cisplatin and vinorelbine (PV). After the maximumtolerated dose of bexarotene plus PV was determined to be 400 mg/m2 daily, thephase II portion was initiated.
Response Rates and Adverse Events
Response rate was the primary end point with median survival and1-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 9of 28 patients (32%) surviving 24 or more months. The3-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 hematologictoxicities were not greater than those reported with PV alone. One death fromrenal insufficiency occurred during the phase I trial. Toxicities in the phaseII portion of the trial were consistent with those reported for bexarotenemonotherapy and with what one would expect with combination chemotherapy withcisplatin and vinorelbine.