Topoisomerase-I Inhibitors With Nonplatinum Combinations Active in NSCLC

NEW HAVEN, Conn—Topoisomerase I inhibitors in combinations not based on platinum have shown significant activity in non–small-cell lung cancer (NSCLC), John R. Murren, MD, reported. These combinations include such drugs as taxanes, gemcitabine (Gemzar), and vinorelbine (Navelbine). Dr. Murren, Associate Professor of Medicine at Yale University School of Medicine, New Haven, Connecticut, reviewed research on these regimens at a clinical investigators’ workshop sponsored by the University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology.

One trial of interest is a phase II study of paclitaxel (Taxol) and irinotecan (Camptosar) in patients who have stage IV NSCLC or malignant pleural effusions and have not been previously treated. Paclitaxel 75 mg/m² is infused over 1 hour, followed immediately by irinotecan 50 mg/m² as a 30-minute infusion. The planned treatment cycle consists of 2 weeks on, 1 week off therapy, with irinotecan doses escalated to 60 mg/m² if toxicity permits.

Thirty-one cycles of treatment have been delivered so far, and Dr. Murren said that 2 patients have been escalated to the higher irinotecan dose. Delivered dose intensity has been 97% of planned.

Responses and Toxicities

Six of seven patients are evaluable for response, including one with a partial response that has lasted for more than 24 weeks, three with stable disease for 17-25 weeks, and one with disease progression. There was one incident of grade 3 diarrhea but no other grade 3 toxicities. Neurotoxicity occurred at grade 2 in one patient and grade 1 in three patients.

“Paclitaxel 75 mg/m² followed by irinotecan 50 mg/m² on a weekly schedule is very well tolerated in advanced NSCLC,” Dr. Murren said. “Neutropenia is the dose-limiting toxicity.” This study found no drug-drug interaction. Among two other studies reported, one also found no drug-drug interaction and the other, reported at the American Society of Clinical Oncology (ASCO) meeting this year, suggested that paclitaxel alters the pharmokinetics of irinotecan. “Further evaluation of this regimen is warranted,” Dr. Murren said.

Irinotecan has also been tested in combination with docetaxel (Taxotere) in NSCLC. Dr. Murren said that the maximum tolerated dose of docetaxel was 35 mg/m² combined with irinotecan 50 mg/m² given weekly for 4 weeks followed by a 2-week rest. “We are currently treating patients on a 2 week on, 1 week off, schedule (similar to the schedule being used with irinotecan and paclitaxel) and have been able to escalate the dose of irinotecan to 60 mg/m² ,” Dr. Murren told ONI.