Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer

Abstract

Background: The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer.

Methods: We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety.

Results: The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group.

Conclusions: The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.).

Figure 1. Progression-free Survival, as Assessed at an Independent Review Facility

Panel A shows Kaplan–Meier estimates of progression-free survival in the intention-to-treat population, stratified according to prior treatment and region. The median progression-free survival was longer by 6.1 months in the pertuzumab group (pertuzumab plus trastuzumab plus docetaxel) than in the control group (placebo plus trastuzumab plus docetaxel). The tick marks indicate the times at which events were recorded. Panel B shows hazard ratios and 95% confidence intervals for progression-free survival in all prespecified subgroups according to baseline characteristics, without stratification. The hazard ratio for the category of unknown status of estrogen receptor (ER) and progesterone receptor (PgR) was not quantifiable, owing to the small number of patients in the group. FISH denotes fluorescence in situ hybridization, and IHC immunohistochemistry.

Figure 2. Overall Survival

Kaplan–Meier estimates of overall survival in patients in the intention-to-treat population are shown. The tick marks indicate the times at which events were recorded. The interim overall survival analysis was performed after 165 events (43% of the prespecified total number for the final analysis) had occurred: 96 events in the control group (placebo plus trastuzumab plus docetaxel) and 69 events in the pertuzumab group (pertuzumab plus trastuzumab plus docetaxel). The interim analysis of overall survival did not cross the O’Brien–Fleming stopping boundary threshold; therefore, the interim result is not statistically significant and is deemed exploratory.