DOCETAXEL (Page 16 of 20)

Single Arm Studies

Docetaxel at a dose of 100 mg/m 2 was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% CI: 31.0-44.8) and the complete response rate was 2.1%.

Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m 2 , in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% CI: 17.2-55.7), similar to the response rate in single arm studies of 100 mg/m 2.

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/m 2 administered 1-hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 (TAC arm), or doxorubicin 50 mg/m 2 followed by fluorouracil 500 mg/m 2 and cyclophosphamide 500 mg/m 2 (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.

Figure 1: TAX316 Disease Free Survival K-M curve

Docetaxel Injection
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Figure 2: TAX316 Overall Survival K-M curve

Docetaxel Injection
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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 SurvivalOverall Survival
Patient subsetNumber of patientsHazard ratio *95% CIHazard ratio *95% CI
a hazard ratio of less than 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC.
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)

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 naive.

Monotherapy with docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy

Two randomized, controlled trials established that a docetaxel dose of 75 mg/m 2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m 2 , 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/m 2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m 2. A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m 2 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/m 2 , docetaxel 100 mg/m 2 and a treatment in which the investigator chose either vinorelbine 30 mg/m 2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m 2 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/m 2 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)
Docetaxel 75 mg/m 2 n=55 Best Supportive Care n=49 Docetaxel 75 mg/m 2 n=125 Control (V/I *) n=123
a value less than 1.00 favors docetaxel
uncorrected for multiple comparisons
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 Survival7.5 months 4.6 months5.7 months5.6 months
95% CI(5.5, 12.8)(3.7, 6.1)(5.1, 7.1)(4.4, 7.9)
% 1-year Survival37% §12%30% §20%
95% CI(24, 50)(2, 23)(22, 39)(13, 27)
Time to Progression12.3 weeks 7.0 weeks8.3 weeks7.6 weeks
95% CI(9.0, 18.3)(6.0, 9.3)(7.0, 11.7)(6.7, 10.1)
Response Rate5.5%Not Applicable5.7%0.8%
95% CI(1.1, 15.1)(2.3, 11.3)(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/m 2.

Figure 3: TAX317 Survival K-M Curves — Docetaxel 75 mg/m 2 Versus Best Supportive Care

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Figure 4: TAX320 Survival K-M Curves — Docetaxel 75 mg/m 2 Versus Vinorelbine or Ifosfamide Control

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Patients treated with docetaxel at a dose of 75 mg/m 2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.

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