The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve.
Monotherapy with Docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy
Two randomized, controlled trials established that a docetaxel dose of 75 mg/m2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m2, however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5.3)].
One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m2. A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m2 or best supportive care.
In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤2 were randomized to docetaxel 75 mg/m2, docetaxel 100 mg/m2 and a treatment in which the investigator chose either vinorelbine 30 mg/m2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m2 days 1–3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the docetaxel 75 mg/m2 arm and the comparator arms are summarized in Table 15 and Figures 3 and 4 showing the survival curves for the two studies.
Table 15: Efficacy of Docetaxel in the Treatment of Non-small Cell Lung Cancer Patients Previously Treated with a Platinum-Based Chemotherapy Regimen (Intent-to-Treat Analysis) |
| TAX317 | TAX320 |
| Docetaxel 75 mg/m2 n=55 | Best Supportive Care n=49 | Docetaxel 75 mg/m2 n=125 | Control (V/I*) n=123 |
Overall Survival Log-rank Test | p=0.01 | p=0.13 |
Risk Ratio†, Mortality (Docetaxel: Control) 95% CI (Risk Ratio) | 0.56 (0.35, 0.88) | 0.82 (0.63, 1.06) |
Median Survival 95% CI | 7.5 months‡ (5.5, 12.8) | 4.6 months (3.7, 6.1) | 5.7 months (5.1, 7.1) | 5.6 months (4.4, 7.9) |
% 1-year Survival 95% CI | 37%‡§ (24, 50) | 12% (2, 23) | 30%‡§ (22, 39) | 20% (13, 27) |
Time to Progression 95% CI | 12.3 weeks‡ (9.0, 18.3) | 7.0 weeks (6.0, 9.3) | 8.3 weeks (7.0, 11.7) | 7.6 weeks (6.7, 10.1) |
Response Rate 95% CI | 5.5% (1.1, 15.1) | Not Applicable | 5.7% (2.3, 11.3) | 0.8% (0.0, 4.5) |
Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m2.
Patients treated with docetaxel at a dose of 75 mg/m2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.
Combination Therapy with Docetaxel for Chemotherapy-Naïve NSCLC
In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m2 administered over 6 - 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin.
The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 16.
Table 16: Survival Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC |
Comparison | Docetaxel + Cisplatin n=408 | Vinorelbine + Cisplatin n=405 |
Kaplan-Meier Estimate of Median Survival | 10.9 months | 10.0 months |
p-value* | 0.122 |
Estimated Hazard Ratio† | 0.88 |
Adjusted 95% CI‡ | (0.74, 1.06) |
The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 17).
Table 17: Response and TTP Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC |
Endpoint | Docetaxel + Cisplatin | Vinorelbine + Cisplatin | p-value |
Objective Response Rate (95% CI)* | 31.6% (26.5%, 36.8%) | 24.4% (19.8%, 29.2%) | Not Significant |
Median Time to Progression† (95% CI)* | 21.4 weeks (19.3, 24.6) | 22.1 weeks (18.1, 25.6) | Not Significant |