Docetaxel/Vinorelbine: Preclinical and Clinical Studies
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.
Single-Agent Efficacy
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%.[17] 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%.[17]
As reported in a recent prospective multicenter trial[16] 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%.[16] 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[26], 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[27] 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.[27]
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[27] 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.[27]
The data published by Bissery and colleagues,[27] as well as Fumoleau and co-workers,[28] provided a basis for testing various schedules of docetaxel plus vinorelbine in patients with non-small-cell lung cancer. Monnier and colleagues[29] 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).[29] 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.[17] 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.[29]
Other Trials
A second trial, by Kourousis and colleagues[30], 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.[30]
The addition of G-CSF minimized the magnitude of grade 3 or 4 neutropenia, which was noted in 19% of patients (Table 4).[30] 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.[30]
A third approach to the combination of docetaxel and vinorelbine in patients with non-small-cell lung cancer was reported by Viallet and colleagues.[31] 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).[31] 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[32] 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.[32]
Conclusions
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.
