Docetaxel (Page 9 of 12)

14.2 Adjuvant Treatment of Breast Cancer

A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of another formulation 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 to 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 cyclosphosphamide 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
(click image for full-size original)

Figure 2 — TAX316 Overall Survival K-M curve

Docetaxel Injection
(click image for full-size original)

The following table describes the results of subgroup analyses for DFS and OS (See Table 15).

Table 15 — Subset Analyses-Adjuvant Breast Cancer Study
Disease Free Survival Overall Survival
Patient subset Number of patients Hazard ratio *95% CI Hazard ratio *95% CI
*
a hazard ratio of < 1 indicates that TAC is associated with a longer disease free survival or overall survival compared to FAC.

No. of positive nodes

Overall

744

0.74

(0.60, 0.92)

0.69

(0.53, 0.90)

1 to 3

467

0.64

(0.47, 0.87)

0.45

(0.29, 0.70)

4+

277

0.84

(0.63, 1.12)

0.93

(0.66, 1.32)

Receptor status

Positive

566

0.76

(0.59, 0.98)

0.69

(0.48, 0.99)

Negative

178

0.68

(0.48, 0.97)

0.66

(0.44, 0.98)

14.3 Non-Small Cell Lung Cancer (NSCLC)

The efficacy and safety of another formulation 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/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 to 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 16 and Figures 3 and 4 showing the survival curves for the two studies.

Table 16 — 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/m 2 n=55 Best Supportive Care n=49 Docetaxel 75 mg/m 2 n=125 Control (V/I *) n=123
*
Vinorelbine/Ifosfamide
a value < 1.00 favors docetaxel
p≤0.05
§
uncorrected for multiple comparisons

Overall Survival

Log-rank Test

p=0.01

p=0.13

Risk Ratio , Mortality

(Docetaxel: Control)

0.56

0.82

95% CI (Risk Ratio)

(0.35, 0.88)

(0.63, 1.06)

Median Survival

7.5 months

4.6 months

5.7 months

5.6 months

95% CI

(5.5, 12.8)

(3.7, 6.1)

(5.1, 7.1)

(4.4, 7.9)

% 1-year Survival

37% §

12%

30% *§

20%

95% CI

(24, 50)

(2, 23)

(22, 39)

(13, 27)

Time to Progression

12.3 weeks

7.0 weeks

8.3 weeks

7.6 weeks

95% CI

(9.0, 18.3)

(6.0, 9.3)

(7.0, 11.7)

(6.7, 10.1)

Response Rate

5.5%

Not Applicable

5.7%

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 vs. Best Supportive Care

Docetaxel
(click image for full-size original)

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

Docetaxel
(click image for full-size original)

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.

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/m 2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m 2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m 2 administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m 2 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 17.

Table 17 — Survival Analysis of Docetaxel in Combination Therapy for Chemotherapy Naïve NSCLC
Comparison Docetaxel + Cisplatin n=408 Vinorelbine + Cisplatin n=405
*
From the superiority test (stratified log rank) comparing docetaxel + cisplatin to vinorelbine+cisplatin
Hazard ratio of docetaxel + cisplatin vs. vinorelbine + cisplatin. A hazard ratio of < 1 indicates that docetaxel + cisplatin is associated with a longer survival.
Adjusted for interim analysis and multiple comparisons.

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 18).

Table 18 — Response and TTP Analysis of Docetaxel in Combination Therapy for Chemotherapy-Naïve NSCLC
Endpoint Docetaxel + Cisplatin Vinorelbine + Cisplatin p-value
*
Adjusted for multiple comparisons.
Kaplan-Meier estimates.

Objective Response Rate

31.6%

24.4%

Not Significant

(95% CI) *

(26.5%, 36.8%)

(19.8%, 29.2%)

Median Time to Progression

21.4 weeks (19.3, 24.6)

22.1 weeks (18.1, 25.6)

Not Significant

(95% CI) *

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