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.
XELODA + Docetaxel(n=255) | Docetaxel(n=256) | |
---|---|---|
Age (median, years) | 52 | 51 |
Karnofsky PS (median) | 90 | 90 |
Site of Disease | ||
Lymph nodes | 121 (47%) | 125 (49%) |
Liver | 116 (45%) | 122 (48%) |
Bone | 107 (42%) | 119 (46%) |
Lung | 95 (37%) | 99 (39%) |
Skin | 73 (29%) | 73 (29%) |
Prior Chemotherapy | ||
Anthracycline | 255 (100%) | 256 (100%) |
5-FU | 196 (77%) | 189 (74%) |
Paclitaxel | 25 (10%) | 22 (9%) |
Resistance to an Anthracycline | ||
No resistance | 19 (7%) | 19 (7%) |
Progression on anthracycline therapy | 65 (26%) | 73 (29%) |
Stable disease after 4 cycles of anthracycline therapy | 41 (16%) | 40 (16%) |
Relapsed within 2 years of completion of anthracycline-adjuvant therapy | 78 (31%) | 74 (29%) |
Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose | 51 (20%) | 50 (20%) |
No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease | ||
0 | 89 (35%) | 80 (31%) |
1 | 123 (48%) | 135 (53%) |
2 | 43 (17%) | 39 (15%) |
3 | 0 (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.
Efficacy Parameter | Combination Therapy | Monotherapy | p-value | Hazard Ratio |
---|---|---|---|---|
Time to Disease Progression | ||||
Median Days | 186 | 128 | 0.0001 | 0.643 |
95% C.I. | (165-198) | (105-136) | ||
Overall Survival | ||||
Median Days | 442 | 352 | 0.0126 | 0.775 |
95% C.I. | (375-497) | (298-387) | ||
Response Rate | 32% | 22% | 0.009 | NA |
Figure 4 Kaplan-Meier Estimates for Time to Disease Progression XELODA and Docetaxel vs Docetaxel
Figure 5 Kaplan-Meier Estimates of Survival XELODA and Docetaxel vs Docetaxel
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.
Patients With Measurable Disease (n=135) | All Patients(n=162) | |
---|---|---|
| ||
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.
Resistance to Both Paclitaxel and an Anthracycline(n=43) | |
---|---|
| |
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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