Irinotecan Plus a Taxane May Surpass Current Treatments for NSCLC

NEW HAVEN, Connecticut—The combination of irinotecan (Camptosar) and a taxane is well tolerated in dose-finding studies and deserves further evaluation in non–small-cell lung cancer, according to Randy S. Rich, MD, of Yale University School of Medicine.

“Continued evaluation of nonplatinum regimens is warranted,” Dr. Rich stated. “They should be better tolerated than platinum regimens, and possibly more effective.”

Dr. Rich and colleagues have conducted two dose-finding studies to identify optimal doses of irinotecan plus paclitaxel (Taxol) and irinotecan plus docetaxel (Taxotere) in patients with histologically confirmed malignancies. The irinotecan plus paclitaxel study was followed by a phase II investigation.

The rationale for these investigations of nonplatinum regimens, according to Dr. Rich, includes the known toxicities of platinum regimens, the noted single-agent activity of new drugs such as irinotecan, and the superior activity of the new agents when they are included in platinum regimens.

Two Paclitaxel Studies

In one initial study, 21 patients with histologically confirmed solid malignancies and no other available treatment options, were treated at recommended doses of irinotecan 50 mg/m²/week (two of the patients received irinotecan 65 mg/m²/week) plus paclitaxel 75 mg/m²/week. All patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The patients had a variety of malignancies, including four non–small-cell lung cancers.

Irinotecan was infused over 90 minutes and then followed immediately by a paclitaxel infusion over 1 hour. Chemotherapy was administered weekly for 4 weeks with a 2- week resting period.

The sequence of drug administration was reversed on the second cycle. This did not produce significant differences in the pharmacokinetics of irinotecan or SN-38 among patients subject to pharmacokinetic studies, suggesting a lack of drug interactions.

Of the 21 patients, 1 had a partial response and 5 had stable disease. The dose-limiting toxicity of the irinotecan/paclitaxel combination was neutropenia, which caused dose delays. Nonhematologic toxicity was acceptable.

A subsequent phase II trial of irinotecan plus paclitaxel in histologically confirmed stage IIIB or IV non–small-cell lung cancer showed similar results. None of the nine patients enrolled in the study had prior chemotherapy. All received paclitaxel 75 mg/m² infused over 1 hour, followed immediately by irinotecan 50 mg/m² infused over 30 minutes (escalation to 60 mg/m² was allowed if well tolerated on the previous cycle).

At the time of analysis, 48 cycles had been delivered. Irinotecan was escalated in four patients and reduced in one due to gastrointestinal toxicity.

Docetaxel Evaluated

Also evaluated was the combination of irinotecan plus docetaxel in a variety of malignancies for which no treatment was available. Again, chemotherapy was administered weekly for 4 weeks with a 2-week resting period.

In this phase-I study, 26 patients with histologically confirmed solid malignancies were enrolled and treated with irinotecan 50 mg/m²/week and docetaxel at 25, 30, 35, or 40 mg/m²/week. Dose-limiting toxicities were low-grade gastrointestinal toxicity and asthenia. Neutropenia of grade 3 or higher was seen in less than 10% of treatment cycles. Investigators determined that the maximum tolerated dose of docetaxel on this schedule was 35 mg/m²/dose.

Dose intensification of docetaxel may be possible with further modification of the schedule, Dr. Rich concluded.