Prescription Drug Information: Docetaxel (Page 6 of 9)

14.2 Adjuvant Treatment of Breast Cancer

A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2 (FAC arm). Both regimens were administered every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC.

Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified log rank p=0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients (see Figure 1).

At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90) (see Figure 2). There will be further analysis at the time survival data mature.

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The following table describes the results of subgroup analyses for DFS and OS (see Table 14).

Table 14: Subset Analyses-Adjuvant Breast Cancer Study

Disease Free Survival Overall Survival
Patient subset Number of patients Hazard ratio* 95% CI Hazard ratio* 95% CI
No. of positive nodes
Overall7440.74(0.60, 0.92)0.69(0.53, 0.90)
1-34670.64(0.47, 0.87)0.45(0.29, 0.70)
4+2770.84(0.63, 1.12)0.93(0.66, 1.32)
Receptor status
Positive5660.76(0.59, 0.98)0.69(0.48, 0.99)
Negative1780.68(0.48, 0.97)0.66(0.44, 0.98)

* A hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC.

14.3 Non-small Cell Lung Cancer (NSCLC)

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 Testp=0.01p=0.13
Risk Ratio††, Mortality (Docetaxel: Control) 0.560.82
95% CI (Risk Ratio)(0.35,0.88)(0.63, 1.06)
Median Survival 95% CI7.5 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 Survival95% CI37%**†(24, 50)12%(2, 23)30%**†(22, 39)20%(13, 27)
Time to Progression 95% CI12.3 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% CI5.5%(1.1, 15.1)Not Applicable5.7%(2.3, 11.3)0.8%(0.0, 4.5)

* Vinorelbine/Ifosfamide

** p≤0.05

† uncorrected for multiple comparisons

†† a value less than 1.00 favors docetaxel

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.

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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 Survival10.9 months10.0 months
p-valuea 0.122
Estimated Hazard Ratiob 0.88
Adjusted 95% CIc (0.74,1.06)

a From the superiority test (stratified log rank) comparing docetaxel+cisplatin to vinorelbine+cisplatin

b Hazard ratio of docetaxel+cisplatin versus vinorelbine+cisplatin. A hazard ratio of less than 1 indicates that docetaxel+cisplatin is associated with a longer survival.

c Adjusted for interim analysis and multiple comparisons.

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)a 31.6%(26.5%, 36.8%)24.4%(19.8%, 29.2%)Not Significant
Median Time to Progressionb (95% CI)a 21.4 weeks(19.3, 24.6)22.1 weeks(18.1, 25.6)Not Significant

a Adjusted for multiple comparisons.

b Kaplan-Meier estimates.

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