Topoisomerase I-Based Nonplatinum Combinations in Non-Small-Cell Lung Cancer

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.[1] Similar results were recently reported for a European phase III trial.[2] 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.[3] 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.[4] 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.[5] 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.[6] 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.[7]

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.

Nonplatinum Combination Regimens With Topoisomerase I Inhibitors in Non-Small-Cell Lung Cancer

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.[22] 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[23] 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.[24] 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.[25] 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 combinations—irinotecan/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.[26] Based on these preclinical data, two phase I studies of the gemcitabine/topotecan combination were conducted. Edelman et al[27] 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[28] 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).[29] 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[30] 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.