Xeloda (Page 10 of 11)

14.3 Breast Cancer

XELODA has been evaluated in clinical trials in combination with docetaxel (Taxotere®) and as monotherapy.

In Combination With Docetaxel

The dose of XELODA used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of XELODA (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m2 administered in 3-week cycles of docetaxel in combination with 1250 mg/m2 twice daily for 14 days of XELODA administered in 3-week cycles. The approved dose of 100 mg/m2 of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.

XELODA in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive XELODA 1250 mg/m2 twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.

Table 16 Baseline Demographics and Clinical Characteristics XELODA and Docetaxel Combination vs Docetaxel in Breast Cancer Trial
XELODA + Docetaxel(n=255)Docetaxel(n=256)
Age (median, years)5251
Karnofsky PS (median)9090
Site of Disease
Lymph nodes121 (47%)125 (49%)
Liver116 (45%)122 (48%)
Bone107 (42%)119 (46%)
Lung95 (37%)99 (39%)
Skin73 (29%)73 (29%)
Prior Chemotherapy
Anthracycline 255 (100%)256 (100%)
5-FU196 (77%)189 (74%)
Paclitaxel25 (10%)22 (9%)
Resistance to an Anthracycline
No resistance19 (7%)19 (7%)
Progression on anthracycline therapy65 (26%)73 (29%)
Stable disease after 4 cycles of anthracycline therapy41 (16%)40 (16%)
Relapsed within 2 years of completion of anthracycline-adjuvant therapy78 (31%)74 (29%)
Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose51 (20%)50 (20%)
No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease
089 (35%)80 (31%)
1123 (48%)135 (53%)
243 (17%)39 (15%)
30 (0%)2 (1%)

XELODA in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.

Table 17 Efficacy of XELODA and Docetaxel Combination vs Docetaxel Monotherapy
Efficacy ParameterCombination TherapyMonotherapyp-valueHazard Ratio
Time to Disease Progression
Median Days 1861280.00010.643
95% C.I. (165-198)(105-136)
Overall Survival
Median Days 4423520.01260.775
95% C.I. (375-497)(298-387)
Response Rate 32%22%0.009NA

Figure 4 Kaplan-Meier Estimates for Time to Disease Progression XELODA and Docetaxel vs Docetaxel

Figure 4
(click image for full-size original)

Figure 5 Kaplan-Meier Estimates of Survival XELODA and Docetaxel vs Docetaxel

Figure 5
(click image for full-size original)

Monotherapy

The antitumor activity of XELODA as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. XELODA was administered at a dose of 1255 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen.

Table 18 Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer Trial
Patients With Measurable Disease (n=135) All Patients(n=162)
*
Includes 2 patients treated with an anthracenedione
Age (median, years) 55 56
Karnofsky PS 90 90
No. Disease Sites
1-2 43 (32%) 60 (37%)
3-4 63 (46%) 69 (43%)
>5 29 (22%) 34 (21%)
Dominant Site of Disease
Visceral 101 (75%) 110 (68%)
Soft Tissue 30 (22%) 35 (22%)
Bone 4 (3%) 17 (10%)
Prior Chemotherapy
Paclitaxel 135 (100%) 162 (100%)
Anthracycline * 122 (90%) 147 (91%)
5-FU 110 (81%) 133 (82%)
Resistance to Paclitaxel 103 (76%) 124 (77%)
Resistance to an Anthracycline * 55 (41%) 67 (41%)
Resistance to both Paclitaxel and an Anthracycline * 43 (32%) 51 (31%)

Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.

Table 19 Response Rates in Doubly-Resistant Patients Single-Arm Breast Cancer Trial
Resistance to Both Paclitaxel and an Anthracycline(n=43)
*
Includes 2 patients treated with an anthracenedione
CR 0
PR * 11
CR + PR * 11
Response Rate * 25.6%
(95% C.I.) (13.5, 41.2)
Duration of Response,*
Median in days 154
(Range) (63-233)

For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18). The median time to progression was 90 days and the median survival was 306 days.

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