Efficacy data from studies of various combinations of platinum with other cytotoxic drugs in non-small-cell lung cancer suggest that a therapeutic plateau has been reached. The Eastern Cooperative Oncology Group (ECOG) 1594 randomized study demonstrated no efficacy differences among four different platinum-based chemotherapy doublets. Similar results were recently reported for a European phase III trial. The development of non-platinum-containing combinations offers a strategy to lower toxicity and maintain efficacy in the treatment of non-small-cell lung cancer.
The taxane plus gemcitabine(Drug information on gemcitabine) (Gemzar) doublets have been the most explored nonplatinum combinations in non-small-cell lung cancer, and a recent European Organization for Research and Treatment of Cancer (EORTC) trial compared two platinum-containing doublets (standard arm of cisplatin(Drug information on cisplatin)/paclitaxel or cisplatin/gemcitabine) to the gemcitabine plus paclitaxel(Drug information on paclitaxel) combination. Although survival among the three treatment arms was not significantly different, there was a trend toward worse survival with the nonplatinum combination. This disappointing result should not hamper additional studies with other nonplatinum combinations, however.
Several topoisomerase I inhibitors have been studied in patients with non-small-cell lung cancer. One such agent is 9-aminocamptothecin (9-AC), which is a synthetic analog of camptothecin. In a phase II study conducted by Vokes et al, patients with stage IIIB or IV non-small-cell lung cancer with measurable disease received 9-AC at 1,416 µg/m²/d × 3 by continuous intravenous infusion followed by granulocyte colony-stimulating factor (G-CSF [Neupogen]) support. The 9-AC dose was decreased to 1,100 µg/m²/d after the first 13 of 58 accrued patients had been treated. Cycles were repeated every 14 days.
Five patients (8.5%) achieved a partial response. Median time to disease progression was 2.3 months, and median survival for the entire study population was 5.4 months with a 1-year survival rate of 30%. In another study by Vokes and colleagues, non-small-cell lung cancer patients received 9-AC in a different administration schedule, ie, 25 µg/m²/h for 120 hours (3,000 µg/m² over 5 days), given for 2 consecutive weeks of a 3-week cycle. Results were again disappointing, with only 1 of 12 patients responding. The authors recommended no additional studies with 9-AC in non-small-cell lung cancer.
Exatecan mesylate, a synthetic water-soluble topoisomerase I inhibitor, is active as single-agent therapy for non-small-cell lung cancer patients. In a small phase II trial, 23 patients with previously untreated, advanced (11 stage IIIB, 12 stage IV) non-small-cell lung cancer received exatecan at 0.5 mg/m² IV over 30 minutes daily for 5 days, every 3 weeks. Among 16 evaluable patients, 18% responded; survival data were not reported. Further development of this compound in non-small-cell lung cancer may be warranted.
Karenitecin is a highly lipophilic topoisomerase I inhibitor that has undergone limited phase II testing. The Cancer and Leukemia Group B (CALGB) is conducting an ongoing phase II trial of this semisynthetic camptothecin in previously treated non-small-cell lung cancer patients. The karenitecin dose is 1 mg/m²/d administered over 60 minutes by IV infusion for 5 consecutive days, with cycles repeated every 3 weeks. This dose and schedule was identified as the maximum tolerated dose in a previous phase I trial, in which 14 patients (4 pancreatic, 4 colorectal, and 6 other cancers) received a total of 32 (range: 1-9, median: 2) treatment cycles.
In that trial, karenitecin was administered using an accelerated dose titration design, at doses of 0.15 (n = 1), 0.3 (n = 1), 0.6 (n = 1), 1.2 (n = 9), 2.4 (n = 1), and 1.0 (n = 1) mg/m². The dose-limiting toxicity consisted of reversible grade 4 neutropenia and thrombocytopenia in three of nine patients receiving 1.2 mg/m² and one of one patient at 2.4 mg/m²; gastrointestinal toxicities were minimal. Three patients (with colorectal, pancreatic, and tonsillar cancers) exhibited stable disease exceeding two cycles.
The topoisomerase I inhibitors irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) and topotecan(Drug information on topotecan) (Hycamtin) are available commercially in the United States. Although these agents possess similar antitumor mechanisms of action, their single-agent activity in non-small-cell lung cancer differs (Tables 1 and 2).[8-17] As shown in Table 2, the absence of topotecan single-agent activity in non-small-cell lung cancer apparently did not compromise median survival.
The combination of irinotecan and cisplatin has been studied in two phase III trials in non-small-cell lung cancer patients.[18,19] In both trials, irinotecan at 60 mg/m² was administered on days 1, 8, and 15, and cis-platin at 80 mg/m² on day 1. This regimen was compared with the standard regimen of cisplatin at 80 mg/m² given on day 1 plus vindesine(Drug information on vindesine) (Eldisine) at 3 mg/m² on days 1, 8, and 15. One of the trials also included a third arm consisting of single-agent irinotecan at 100 mg/m² on days 1, 8, and 15. As shown in Table 3, survival results for the irinotecan/cisplatin combination compared with vindesine/cisplatin differed in the two trials. No phase III trial results of topotecan in non-small-cell lung cancer are available; phase II data with topotecan/platinum combinations are emerging in this disease (Table 4).[20,21]
Studies of non-platinum-containing combination regimens that include topoisomerase I inhibitors plus gemcitabine or microtubule poisons have been conducted or are under way in patients with non-small-cell lung cancer. Several of these studies are reviewed herein.
Topoisomerase I Inhibitors and Gemcitabine
Preclinical data using breast and lung cancer cell lines suggested that gemcitabine and irinotecan exhibit synergistic activity when used in combination. Isobologram analysis revealed that the combination exerted synergy over a wide range of concentrations in the MCF-7 and SCOG cell lines. Combination index analysis also indicated that at low concentrations, combinations of gemcitabine and irinotecan showed synergistic growth-inhibitory effects on MCF-7. In SCOG cells, however, combination index analysis showed synergy at concentrations of gemcitabine and irinotecan > 1 µM but antagonism at concentrations < 1 µM.
Three phase I studies of three different schedules of the gemcitabine/irinotecan combination have been performed. Rocha Lima et al studied the administration of both drugs on days 1 and 8 of each 21-day cycle. Gemcitabine was administered first at a fixed dose of 1,000 mg/m² over 30 minutes followed by escalating doses of irinotecan given over 90 minutes. The initial irinotecan dose was 50 mg/m² with subsequent cohorts tested at 75, 100, and 115 mg/m². Nineteen patients with a variety of solid tumors were accrued. The maximum tolerated dose was determined to be 1,000 mg/m² of gemcitabine and 100 mg/m² of irinotecan, both given on days 1 and 8. The dose-limiting toxicity was grade 3 diarrhea in two of seven patients at the 115-mg/m² irinotecan dose.
O’Reilly and colleagues reported the results of a phase I trial of the gemcitabine/irinotecan combination, with both drugs administered on days 1, 8, and 15 in every 28-day cycle. The gemcitabine dose was fixed at 1,000 mg/m² given over 30 minutes. Irinotecan doses were escalated in four cohorts from a starting dose of 45 mg/m², to 60, 80, and 100 mg/m² over 90 minutes. When gemcitabine was given first immediately followed by irinotecan, the dose-limiting toxicities consisted of diarrhea, nausea and vomiting, neutropenia, and fatigue.
When irinotecan was given first immediately followed by gemcita-bine, the dose-limiting toxicities were neutropenic fever and diarrhea. The maximum tolerated dose with both sequences was gemcitabine at 1,000 mg/m² and irinotecan at 60 mg/m². Preliminary pharmacokinetic assessments demonstrated no differences between the two sequences in the levels of gemcitabine, the uridine metabolite of gemcitabine, irinotecan, and irinotecan metabolites SN-38 and SN-38G.
Alberts et al studied both drugs administered on days 1, 8, 15, and 22, with cycles repeated every 6 weeks in 26 patients with refractory solid tumors. The dose-limiting toxicity was hematologic toxicity in two of six patients receiving gemcitabine at 1,000 mg/m² and irinotecan at 125 mg/m², and the recommended phase II doses for the agents in combination were gemcitabine at 1,000 mg/m² and irinotecan at 100 mg/m². The dose intensity must be carefully analyzed in the follow-up phase II trials. One would anticipate treatment omissions on day 15 of therapy due to diarrhea and/or myelosuppression with this schedule at these doses.
Several phase II trials of the gemcitabine/irinotecan combination have been conducted in patients with non-small-cell lung cancer. A randomized phase II trial CALGB 39809 is assessing two nonplatinum combinationsirinotecan/gemcitabine and docetaxel(Drug information on docetaxel) (Taxotere)/gemcitabine (Figure 1). Efficacy results were presented at the 2002 annual meeting of the American Society of Clinical Oncology (ASCO). The efficacy results for gemcitabine and irinotecan included a response rate of 12.8%, with 48.7% stable disease, a 7.9-month median survival, and a 1-year survival rate of 16%. For the docetaxel/gemcitabine arm, the response rate was 23.1%, with 41% stable disease, a 12.8-month median survival, and a 1-year survival rate of 55%. Both doublets were well tolerated, which may reflect the administration schedule, ie, both agents given on days 1 and 8, every 21 days. Toxicity results are summarized in Tables 5 and 6.
Preclinical studies with human lung cancer cell lines H460 and H322 demonstrated an additive growth inhibition (and concentration- and time-dependent apoptotic effects) when another topoisomerase I inhibitor topotecan was combined with gemcitabine. Based on these preclinical data, two phase I studies of the gemcitabine/topotecan combination were conducted. Edelman et al determined the maximum tolerated dose of topotecan to be 1 mg/m²/d IV over 30 minutes daily for 5 days, and that of gemcitabine to be 1,000 mg/m² over 30 minutes on days 1 and 15, in 28-day cycles. After a dose-escalation study, Rainey and colleagues recommended phase II doses of topotecan at 0.75 mg/m²/d over 30 minutes for 5 days and gemcitabine at 400 mg/m² on days 1 and 5, every 21 days. Neutropenia and thrombocytopenia were the dose-limiting toxicities.
In a preliminary report from US Oncology, the combination of gemcitabine and topotecan resulted in a median survival time of 7.3 months in 53 advanced non-small-cell lung cancer patients with good performance status (0 or 1). Doses were topotecan at 1 mg/m²/d IV over 30 minutes for 5 consecutive days, and gemcitabine at 1,000 mg/m² days 1 and 15, on an every-28-day cycle. Grade 3/4 toxicities included neutropenia (49% of patients), anemia (15%), and thrombocytopenia (9%). The response rate was 17% (all partial responses), and 22% of patients had stable disease. Final results were presented at ASCO’s 2002 annual meeting.
At least one phase II study of second-line topotecan plus gemcitabine in non-small-cell lung cancer has been conducted. Cole and colleagues studied topotecan at 0.75 mg/m²/d IV days 1 to 5 and gemcitabine at 400 mg/m² days 1 and 5, given every 21 days to 32 patients with refractory non-small-cell lung cancer. A total of four patients (13%) had partial responses, and seven (22%) had stable disease for at least four cycles. Median survival time was 7 months. One year from the initiation of topotecan and gemcitabine treatment, 20% (5/25) of patients were still alive. Nonhematologic toxicity was mild. After the first treatment cycle, grade 4 neutropenia and thrombocytopenia was observed in 16% and 9% of patients, respectively. Hematologic toxicities for all cycles, to our knowledge, have not been reported.