Paclitaxel (Page 4 of 15)

Subset Analyses

Subsets defined by variables of known prognostic importance in adjuvant breast carcinoma were examined, including number of positive lymph nodes, tumor size, hormone receptor status, and menopausal status. Such analyses must be interpreted with care, as the most secure finding is the overall study result. In general, a reduction in hazard similar to the overall reduction was seen with paclitaxel for both disease-free and overall survival in all of the larger subsets with one exception; patients with receptor-positive tumors had a smaller reduction in hazard (HR=0.92) for disease-free survival with paclitaxel than other groups. Results of subset analyses are shown in Table 4.

Table 4. Subset Analyses — Adjuvant Breast Carcinoma Study

a Positive for either estrogen or progesterone receptors.

b Negative or missing for both estrogen and progesterone receptors (both missing: n=15).

Patient Subset Disease-Free Survival Overall Survival
No. of Patients No. of Recurrences Hazard Ratio (95% CI) No. of Deaths Hazard Ratio (95% CI)
No. of Positive Nodes 1-34-910+ 14491310360 221274129 0.72(0.55-0.94)0.78(0.61-0.99)0.93(0.66-1.31) 10714887 0.76(0.52-1.12)0.66(0.47-0.91)0.90(0.59-1.36)
Tumor Size (cm) ≤2>2 and ≤5>5 10961611397 153358111 0.79(0.57-1.08)0.79(0.64-0.97)0.75(0.51-1.08) 6720172 0.73(0.45-1.18)0.74(0.56-0.98)0.73(0.46-1.16)
Menopausal Status PrePost 19291183 374250 0.83(0.67-1.01)0.73(0.57-0.93) 187155 0.72(0.54-0.97)0.77(0.56-1.06)
Receptor Status Positivea Negative/Unknownb 20661055 293331 0.92(0.73-1.16)0.68(0.55-0.85) 126216 0.83(0.59-1.18)0.71(0.54-0.93)

These retrospective subgroup analyses suggest that the beneficial effect of paclitaxel is clearly established in the receptor-negative subgroup, but the benefit in receptor-positive patients is not yet clear. With respect to menopausal status, the benefit of paclitaxel is consistent (see Table 4 and Figures 5 to 8).

Figure 5. Disease-Free Survival: Receptor Status Negative/Unknown AC Versus AC+T

Figure 5
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Figure 6. Disease-Free Survival: Receptor Status Positive AC Versus AC+T

Figure 6
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Figure 7. Disease-Free Survival: Premenopausal AC Versus AC+T

Figure 7
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Figure 8. Disease-Free Survival: Postmenopausal AC Versus AC+T

Figure 8
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The adverse event profile for the patients who received paclitaxel subsequent to AC was consistent with that seen in the pooled analysis of data from 812 patients (Table 10) treated with single-agent paclitaxel in 10 clinical studies. These adverse events are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 13) and narrative form.

After Failure of Initial Chemotherapy

Data from 83 patients accrued in three Phase 2 open label studies and from 471 patients enrolled in a Phase 3 randomized study were available to support the use of paclitaxel in patients with metastatic breast carcinoma.

Phase 2 Open Label Studies

Two studies were conducted in 53 patients previously treated with a maximum of one prior chemotherapeutic regimen. Paclitaxel was administered in these two trials as a 24-hour infusion at initial doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2. The response rates were 57% (95% CI: 37% to 75%) and 52% (95% CI: 32% to 72%), respectively. The third Phase 2 study was conducted in extensively pretreated patients who had failed anthracycline therapy and who had received a minimum of two chemotherapy regimens for the treatment of metastatic disease. The dose of paclitaxel was 200 mg/m2 as a 24-hour infusion with G-CSF support. Nine of 30 patients achieved a partial response, for a response rate of 30% (95% CI: 15% to 50%).

Phase 3 Randomized Study

This multicenter trial was conducted in patients previously treated with one or two regimens of chemotherapy. Patients were randomized to receive paclitaxel at a dose of either 175 mg/m2 or 135 mg/m2 given as a 3-hour infusion. In the 471 patients enrolled, 60% had symptomatic disease with impaired performance status at study entry, and 73% had visceral metastases. These patients had failed prior chemotherapy either in the adjuvant setting (30%), the metastatic setting (39%), or both (31%). Sixty-seven percent of the patients had been previously exposed to anthracyclines and 23% of them had disease considered resistant to this class of agents.

The overall response rate for the 454 evaluable patients was 26% (95% CI: 22% to 30%), with 17 complete and 99 partial responses. The median duration of response, measured from the first day of treatment, was 8.1 months (range: 3.4 to 18.1+ months). Overall for the 471 patients, the median time to progression was 3.5 months (range: 0.03 to 17.1 months). Median survival was 11.7 months (range: 0 to 18.9 months).

Response rates, median survival and median time to progression for the 2 arms are given in the following table.

Table 5. Efficacy in Breast Cancer after Failure of Initial Chemotherapy or Within 6 Months of Adjuvant Chemotherapy
175/3 (n=235) 135/3 (n=236)
• Response
— rate (percent) 28 22
— p-value 0.135
• Time to Progression
— median (months) 4.2 3.0
— p-value 0.027
• Survival
— median (months) 11.7 10.5
— p-value 0.321

The adverse event profile of the patients who received single-agent Paclitaxel Injection, USP, in the Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 breast carcinoma study are described in the ADVERSE REACTIONS section in tabular (Tables 10 and 14) and narrative form.

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