Data supporting the potential for docetaxel(Drug information on docetaxel)/vinorelbine combination therapy in non-small-cell lung cancer come from single-agent trials as well as preclinical studies.
Docetaxel has demonstrated significant activity as a single agent in the treatment of patients with advanced non-small-cell lung cancer. Response rates for docetaxel administered intravenously 100 mg/m² over 60 minutes, once every 3 weeks, in patients with non-small-cell lung cancer have ranged from 33% to 38% in previously untreated patients, with projected median survival duration of 9 months and a 1-year survival rate of 40%. In previously treated patients, response rates have ranged from 21% to 27%, with projected median survival duration of 9 months and a 1-year survival rate of 34%.
As reported in a recent prospective multicenter trial in 216 previously untreated patients with stage IV non-small-cell lung cancer, 30 mg/m² of vinorelbine, infused over 5 to 10 minutes once weekly every 21 days, produced a partial response rate of 12%, with a median survival of 30 weeks and 1-year survival rate of 25%. This survival time was superior to the control regimen of 5-FU/leucovorin (16% at 1 year) and compares favorably with that achieved by previous combination regimens (28 weeks), as shown in Table 3.[16,18-25]
The potential for improving the survival time of vinorelbine was demonstrated by Le Chevalier and colleagues, who reported that survival times could be increased to 40 weeks when cisplatin(Drug information on cisplatin) was used in combination with vinorelbine in patients with non-small-cell lung cancer.
Preclinical/Phase I Combination Studies
Bissery and colleagues reported the in vitro synergistic effects of these agents when administered in mice bearing subcutaneous mammary adenocarcinoma MA 16/C. The study used a 3-arm dose-response design to assess the tolerance and efficacy of the combination when administered either simultaneously or 24 hours apart. The highest nontoxic dose of docetaxel (100 mg/m² IV every 21 days) and vinorelbine (21 mg/m² IV once a week) could be administered when given simultaneously. However, scheduling studies 24 hours apart necessitated a 20% reduction in the docetaxel dose, regardless of the order in which the agents were administered.
The results from this preclinical study proved to be predictive of the maximum tolerated dose in patients with breast cancer. The phase I clinical trial performed by the same authors evaluated patients' response to 20 mg/m² of vinorelbine administered intravenously on days 1 and 5 followed immediately by varying doses of docetaxel (60, 75, 85, and 100 mg/m²) on day 1, once every 3 weeks. Each dose level demonstrated significant clinical responses (31% to 34%), with the highest nontoxic dose being 85 mg/m² of docetaxel combined with 20 mg/m² of vinorelbine. These results suggest that the docetaxel/vinorelbine combination has activity in the breast cancer model.
The data published by Bissery and colleagues, as well as Fumoleau and co-workers, provided a basis for testing various schedules of docetaxel plus vinorelbine in patients with non-small-cell lung cancer. Monnier and colleagues reported the results of a French multicenter, phase II trial that evaluated the use of docetaxel/vinorelbine in 39 patients with locally advanced or metastatic non-small-cell lung cancer, 80% of whom had a performance status of 0 to 1. The initial dose was 75 mg/m²of docetaxel administered intravenously on day 1 followed by vinorelbine, 20 mg/m² administered intravenously on days 1 and 5, once every 3 weeks. Patients also received premedication with prednisone(Drug information on prednisone), diosmine, and antiemetics on an outpatient basis.
The dose-limiting toxicity was grade 4 neutropenia, which was seen in 77% of the patients (Table 4). Febrile neutropenia was experienced by 42% of patients. Grade 3 to 4 stomatitis and severe asthenia occurred in 11% of the patients. Partial responses were achieved in 23% of the patients.
The authors concluded that additional studies are needed to determine whether the efficacy documented in this study is similar to that of docetaxel alone. In addition, the regimen did not include colony-stimulating growth support, which may be appropriate for inclusion in future studies because of the 42% incidence of febrile neutropenia reported in this study.
A second trial, by Kourousis and colleagues, examined the combination regimen of 100 mg/m² of docetaxel (as a 3-hour infusion with premedication) and 25 mg/m² of vinorelbine, both administered intravenously once every 21 days, in 43 patients with non-small-cell lung cancer. Patients in this study also received growth factor support in the form of 5 mg/kg of granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim) [Neupogen]) beginning on days 4 through 15 to reduce the expected neutropenia. The majority (70%) of patients had stage IV disease, and 81% had a performance status of 0 to 1.
The addition of G-CSF minimized the magnitude of grade 3 or 4 neutropenia, which was noted in 19% of patients (Table 4). Further, only 6% of patients experienced febrile neutropenia. The incidence of grade 2 to 3 neurotoxicity was also low, at 8%. Partial response was documented in 47% of patients, with a median survival time of over 6 months (range, 2 to 10 months). The authors noted that the addition of G-CSF to docetaxel/vinorelbine resulted in an active, well-tolerated regimen with acceptable toxicity.
A third approach to the combination of docetaxel and vinorelbine in patients with non-small-cell lung cancer was reported by Viallet and colleagues. In this study, 45 patients with stage IIIB or IV non-small-cell lung cancer received 100 mg/m² of docetaxel on day 1, 100 mg/m² of cisplatin on day 21, and 30 mg/m² of vinorelbine on days 21, 28, and 35 of a 6-week cycle. A maximum of 3 cycles was given to patients with stable disease and a maximum of 2 cycles beyond maximal response to responding patients. Growth factor support was not administered in this study.
Febrile neutropenia was noted in 4 patients; 63 cycles were administered (Table 4). A response rate of 55% (15 of 27 patients) was documented, with stable disease being achieved in an additional 5 patients.
Recently, Early and colleagues reported preliminary results from a phase I/II trial in patients with stage IIIB and IV non-small-cell lung cancer who received escalating doses of vinorelbine (15 to 37.5 mg/m²) administered intravenously over 10 minutes followed by a 1-hour intravenous infusion of docetaxel, 50 mg/m². The cycle was repeated every 2 weeks. Patients also received prophylactic G-CSF support and dexamethasone(Drug information on dexamethasone) premedication.
Two episodes of febrile neutropenia were noted in the 83 cycles administered. Antitumor activity has been noted in 5 of the 17 patients enrolled to date in this ongoing study.
The optimal regimen for the combination of docetaxel and vinorelbine in patients with non-small-cell lung cancer remains to be determined. A number of preliminary studies of this combination have had encouraging results in terms of efficacy as well as tolerability. Future studies need to address the role of supportive therapy with G-CSF and whether dose intensification with a docetaxel/vinorelbine regimen can be achieved in patients with non-small-cell lung cancer.