These retrospective subgroup analyses suggest that the beneficial effect of TAXOL (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 TAXOL is consistent (see TABLE 4 and FIGURES 5–8).

FIGURE 5: DISEASE-FREE SURVIVAL—RECEPTOR STATUS NEGATIVE/UNKNOWN AC VERSUS AC+T

FIGURE 6: DISEASE-FREE SURVIVAL—RECEPTOR STATUS POSITIVE AC VERSUS AC+T

FIGURE 7: DISEASE-FREE SURVIVAL—PREMENOPAUSAL AC VERSUS AC+T

FIGURE 8: DISEASE-FREE SURVIVAL—POSTMENOPAUSAL AC VERSUS AC+T

The adverse event profile for the patients who received TAXOL subsequent to AC was consistent with that seen in the pooled analysis of data from 812 patients (TABLE 10) treated with single-agent TAXOL 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 3, Phase 2 open-label studies and from 471 patients enrolled in a Phase 3 randomized study were available to support the use of TAXOL in patients with metastatic breast carcinoma.

Phase 2 open-label studies: Two studies were conducted in 53 patients previously treated with a maximum of 1 prior chemotherapeutic regimen. TAXOL was administered in these 2 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, 37–75%) and 52% (95% CI, 32– 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 2 chemotherapy regimens for the treatment of metastatic disease. The dose of TAXOL 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, 15–50%).

Phase 3 randomized study: This multicenter trial was conducted in patients previously treated with 1 or 2 regimens of chemotherapy. Patients were randomized to receive TAXOL (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, 22–30%), with 17 complete and 99 partial responses. The median duration of response, measured from the first day of treatment, was 8.1 months (range, 3.4–18.1+ months). Overall for the 471 patients, the median time to progression was 3.5 months (range, 0.03–17.1 months). Median survival was 11.7 months (range, 0–18.9 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

The adverse event profile of the patients who received single-agent TAXOL 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.

Non-Small Cell Lung Carcinoma (NSCLC)

In a Phase 3 open-label randomized study conducted by the ECOG, 599 patients were randomized to either TAXOL (T) 135 mg/m² as a 24-hour infusion in combination with cisplatin (c) 75 mg/m², TAXOL (T) 250 mg/m² as a 24-hour infusion in combination with cisplatin (c) 75 mg/m² with G-CSF support, or cisplatin (c) 75 mg/m² on day 1, followed by etoposide (VP) 100 mg/m² on days 1, 2, and 3 (control).

Response rates, median time to progression, median survival, and 1-year survival rates are given in the following table. The reported p-values have not been adjusted for multiple comparisons. There were statistically significant differences favoring each of the TAXOL plus cisplatin arms for response rate and time to tumor progression. There was no statistically significant difference in survival between either TAXOL plus cisplatin arm and the cisplatin plus etoposide arm.

TABLE 6: EFFICACY PARAMETERS IN THE PHASE 3 FIRST-LINE NSCLC STUDY

In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire had 7 subscales that measured subjective assessment of treatment. Of the 7, the Lung Cancer Specific Symptoms subscale favored the TAXOL 135 mg/m²/24 hour plus cisplatin arm compared to the cisplatin/etoposide arm. For all other factors, there was no difference in the treatment groups.

The adverse event profile for patients who received TAXOL in combination with cisplatin in this study was generally consistent with that seen for the pooled analysis of data from 812 patients treated with single-agent TAXOL in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line NSCLC study are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 15) and narrative form.

AIDS-Related Kaposi's Sarcoma

Data from 2, Phase 2 open-label studies support the use of TAXOL (paclitaxel) as second-line therapy in patients with AIDS-related Kaposi's sarcoma. Fifty-nine of the 85 patients enrolled in these studies had previously received systemic therapy, including interferon alpha (32%), DaunoXome® (31%), DOXIL® (2%), and doxorubicin containing chemotherapy (42%), with 64% having received prior anthracyclines.

Eighty-five percent of the pretreated patients had progressed on, or could not tolerate, prior systemic therapy.

In Study CA139-174, patients received TAXOL at 135 mg/m² as a 3-hour infusion every 3 weeks (intended dose intensity 45 mg/m²/week). If no dose-limiting toxicity was observed, patients were to receive 155 mg/m² and 175 mg/m² in subsequent courses. Hematopoietic growth factors were not to be used initially. In Study CA139-281, patients received TAXOL at 100 mg/m² as a 3-hour infusion every 2 weeks (intended dose intensity 50 mg/m²/week). In this study patients could be receiving hematopoietic growth factors before the start of TAXOL therapy, or this support was to be initiated as indicated; the dose of TAXOL was not increased. The dose intensity of TAXOL used in this patient population was lower than the dose intensity recommended for other solid tumors.

All patients had widespread and poor-risk disease. Applying the ACTG staging criteria to patients with prior systemic therapy, 93% were poor risk for extent of disease (T₁), 88% had a CD4 count < 200 cells/mm³ (I₁), and 97% had poor risk considering their systemic illness (S₁).

All patients in Study CA139-174 had a Karnofsky performance status of 80 or 90 at baseline; in Study CA139-281, there were 26 (46%) patients with a Karnofsky performance status of 70 or worse at baseline.

TABLE 7: EXTENT OF DISEASE AT STUDY ENTRY Percent of Patients

Although the planned dose intensity in the 2 studies was slightly different (45 mg/m²/week in Study CA139-174 and 50 mg/m²/week in Study CA139-281), delivered dose intensity was 38 to 39 mg/m²/week in both studies, with a similar range (20–24 to 51–61).

Efficacy: The efficacy of TAXOL was evaluated by assessing cutaneous tumor response according to the amended ACTG criteria and by seeking evidence of clinical benefit in patients in 6 domains of symptoms and/or conditions that are commonly related to AIDS- related Kaposi's sarcoma.

Cutaneous Tumor Response (Amended ACTG Criteria): The objective response rate was 59% (95% CI, 46–72%) (35 of 59 patients) in patients with prior systemic therapy. Cutaneous responses were primarily defined as flattening of more than 50% of previously raised lesions.

TABLE 8: OVERALL BEST RESPONSE (AMENDED ACTG CRITERIA) Percent of Patients

The median time to response was 8.1 weeks and the median duration of response measured from the first day of treatment was 10.4 months (95% CI, 7.0–11.0 months) for the patients who had previously received systemic therapy. The median time to progression was 6.2 months (95% CI, 4.6–8.7 months).

Additional Clinical Benefit: Most data on patient benefit were assessed retrospectively (plans for such analyses were not included in the study protocols). Nonetheless, clinical descriptions and photographs indicated clear benefit in some patients, including instances of improved pulmonary function in patients with pulmonary involvement, improved ambulation, resolution of ulcers, and decreased analgesic requirements in patients with Kaposi's sarcoma (KS) involving the feet and resolution of facial lesions and edema in patients with KS involving the face, extremities, and genitalia.

Safety: The adverse event profile of TAXOL administered to patients with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma was generally similar to that seen in the pooled analysis of data from 812 patients with solid tumors. These adverse events and adverse events from the Phase 2 second-line Kaposi's sarcoma studies are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 16) and narrative form. In this immunosuppressed patient population, however, a lower dose intensity of TAXOL and supportive therapy including hematopoietic growth factors in patients with severe neutropenia are recommended. Patients with AIDS-related Kaposi's sarcoma may have more severe hematologic toxicities than patients with solid tumors.

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