Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer

Abstract

Background: In patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months.

Methods: We randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis.

Results: The median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained.

Conclusions: In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. (Funded by F. Hoffmann-La Roche and Genentech; CLEOPATRA ClinicalTrials.gov number, NCT00567190.).

Figure 1. Enrollment and Outcomes

All patients who underwent randomization were included in the intention-to-treat population, and patients who received at least one dose of a study drug were included in the safety analysis. Reasons for withdrawals are shown. Included in the safety population are nine patients in the control group who received pertuzumab and one patient in the pertuzumab group who received placebo, as indicated.

Figure 2. Overall Survival

Panel A shows Kaplan–Meier estimates of overall survival in the intention-to-treat population, stratified according to adjuvant or neoadjuvant therapy and geographic region. The median overall survival among patients receiving pertuzumab, trastuzumab, and docetaxel (pertuzumab group) was 56.5 months, 15.7 months longer than survival among patients receiving placebo, trastuzumab, and docetaxel (control group). The tick marks indicate censoring events. Panel B shows hazard ratios and 95% confidence intervals for overall survival in all prespecified subgroups according to baseline characteristics, without stratification. Race or ethnic group was determined by the investigator. “Other” includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and other populations. A grade of 3+ on immunohistochemical (IHC) analysis indicates positivity for human epidermal growth factor receptor 2 (HER2). For the assessment of HER2 status, prespecified subgroup analyses were restricted to patients whose tumors had an IHC score of 3+ or fluorescence in situ hybridization (FISH) positive status, since these categories accounted for approximately 90% of patients. CI denotes confidence interval, ER estrogen receptor, and PgR progesterone receptor.

Figure 3. Progression-free Survival

Panel A shows Kaplan–Meier estimates of investigator-assessed progression-free survival in the intention-to-treat population, stratified according to adjuvant or neoadjuvant therapy and geographic region. The median progression-free survival was 18.7 months in the pertuzumab group as compared with 12.4 months in the control group, an improvement of 6.3 months. The tick marks indicate censoring events. Panel B shows hazard ratios and 95% confidence intervals for investigator-assessed progression-free survival in all prespecified subgroups according to baseline characteristics, without stratification.