LETROZOLE (Page 7 of 9)
14.4 First-Line Treatment of Advanced Breast Cancer
A randomized, double-blind, multinational trial (P025) compared letrozole 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 11.
Table 11: Selected Study Population Demographics
Baseline Status | Letrozole | Tamoxifen |
N = 458 | N = 458 | |
Stage of Disease | ||
IIIB | 6% | 7% |
IV | 93% | 92% |
Receptor Status | ||
ER and PgR Positive | 38% | 41% |
ER or PgR Positive | 26% | 26% |
Both Unknown | 34% | 33% |
ER — or PgR -/Other Unknown | < 1% | 0 |
Previous Antiestrogen Therapy | ||
Adjuvant | 19% | 18% |
None | 81% | 82% |
Dominant Site of Disease | ||
Soft Tissue | 25% | 25% |
Bone | 32% | 29% |
Viscera | 43% | 46% |
Letrozole was superior to tamoxifen in TTP and rate of objective tumor response ( see Table 12).
Table 12 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P -values.)
Table 12: Results of First-Line Treatment of Advanced Breast Cancer
Letrozole | Tamoxifen | Hazard or Odds | |
2.5 mg | 20 mg | Ratio (95% CI) | |
N = 453 | N = 454 | P -Value (2-sided) | |
Median Time to Progression | 9.4 months | 6.0 months | 0.72 (0.62, 0.83) 1 |
P < 0.0001 | |||
Objective Response Rate | |||
(CR + PR) | 145 (32%) | 95 (21%) | 1.77 (1.31, 2.39) 2 |
P = 0.0002 | |||
(CR) | 42 (9%) | 15 (3%) | 2.99 (1.63, 5.47) 2 |
P = 0.0004 | |||
Duration of Objective Response | |||
Median | 18 months | 16 months | |
(N = 145) | (N = 95) | ||
Overall Survival | 35 months | 32 months | |
(N = 458) | (N = 458) | P = 0.5136 3 |
1 Hazard ratio
2 Odds ratio
3 Overall log-rank test
Figure 2 shows the Kaplan-Meier curves for TTP.
Figure 2 Kaplan-Meier Estimates of Time to Progression (Study P025)
Table 13 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 14, results by disease site and Table 15, the results by receptor status.
Table 13: Efficacy in Patients Who Received Prior Antiestrogen Therapy
Variable | Letrozole | Tamoxifen |
2.5 mg | 20 mg | |
N = 84 | N = 83 | |
Median Time to Progression (95% CI) | 8.9 months (6.2, 12.5) | 5.9 months (3.2, 6.2) |
Hazard Ratio for TTP (95% CI) | 0.60 (0.43, 0.84) | |
Objective Response Rate | ||
(CR + PR) | 22 (26%) | 7 (8%) |
Odds Ratio for Response (95% CI) | 3.85 (1.50, 9.60) |
Hazard ratio less than 1 or odds ratio greater than 1 favors letrozole; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.
Table 14: Efficacy by Disease Site
Letrozole | Tamoxifen | |
2.5 mg | 20 mg | |
Dominant Disease Site | ||
Soft Tissue: | N = 113 | N = 115 |
Median TTP | 12.1 months | 6.4 months |
Objective Response Rate | 50% | 34% |
Bone: | N = 145 | N = 131 |
Median TTP | 9.5 months | 6.3 months |
Objective Response Rate | 23% | 15% |
Viscera: | N = 195 | N = 208 |
Median TTP | 8.3 months | 4.6 months |
Objective Response Rate | 28% | 17% |
Table 15: Efficacy by Receptor Status
Variable | Letrozole | Tamoxifen |
2.5 mg | 20 mg | |
Receptor Positive | N = 294 | N = 305 |
Median Time to Progression (95% CI) | 9.4 months (8.9, 11.8) | 6.0 months (5.1, 8.5) |
Hazard Ratio for TTP (95% CI) | 0.69 (0.58, 0.83) | |
Objective Response Rate (CR+PR) | 97 (33%) | 66 (22%) |
Odds Ratio for Response 95% CI) | 1.78 (1.20, 2.60) | |
Receptor Unknown | N = 159 | N = 149 |
Median Time to Progression (95% CI) | 9.2 months (6.1, 12.3) | 6.0 months (4.1, 6.4) |
Hazard Ratio for TTP (95% CI) | 0.77 (0.60, 0.99) | |
Objective Response Rate (CR+PR) | 48 (30%) | 29 (20%) |
Odds Ratio for Response (95% CI) | 1.79 (1.10, 3.00) |
Hazard ratio less than 1 or odds ratio greater than 1 favors letrozole; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.
Figure 3 shows the Kaplan-Meier curves for survival.
Figure 3 Survival by Randomized Treatment Arm
Legend: Randomized letrozole: n = 458, events 57%, median overall survival 35 months (95% CI 32 to 38 months)
Randomized tamoxifen: n = 458, events 57%, median overall survival 32 months (95% CI 28 to 37 months)
Overall log-rank P = 0.5136 (i.e., there was no significant difference between treatment arms in overall survival).
The median overall survival was 35 months for the letrozole group and 32 months for the tamoxifen group, with a P -value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (letrozole to tamoxifen) and 13 months (tamoxifen to letrozole). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with letrozole (n = 219, 95% CI 29 to 43 months) vs 20 months with tamoxifen (n = 229, 95% CI 16 to 26 months).
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.