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.
—Sandra M. Swain, MD, and colleagues
As reported in The New England Journal of Medicine by Sandra M. Swain, MD, of Washington Cancer Institute, MedStar Washington Hospital Center, and colleagues, the final prespecified overall survival analysis in the phase III CLEOPATRA study showed a significant 15.7-month increase in median overall survival over 50 months of follow-up with the addition of pertuzumab (Perjeta) to trastuzumab (Herceptin) and docetaxel in the first-line treatment of women with HER2-positive metastatic breast cancer.1 An earlier report from CLEOPATRA showed significant improvement in the primary endpoint of progression-free survival with the pertuzumab-containing regimen.2
In the double-blind trial, 808 patients were randomly assigned between February 2008 and July 2010 to receive pertuzumab, trastuzumab, and docetaxel (n = 402) or placebo, trastuzumab, and docetaxel (n = 406) in 3-week cycles. Study drug doses were pertuzumab at 840 mg on day 1 of cycle 1 followed by 420 mg on day 1 of subsequent cycles, trastuzumab at 8 mg/kg on day 2 of cycle 1 followed by 6 mg/kg on day 1 of subsequent cycles, and docetaxel at 75 mg/m2 on day 2 of cycle 1 and day 1 of subsequent cycles.
Patients had to have left-ventricular ejection fraction ≥ 50% at baseline and could not have received more than one hormonal treatment for metastatic disease. Adjuvant or neoadjuvant chemotherapy with or without trastuzumab was permitted.
Overall Survival Improvement
Median follow-up was 49.5 months (range, 0–70 months) in the pertuzumab group and 50.6 months (range, 0–69 months) in the control group. Median overall survival was 56.5 months (95% confidence interval [CI] = 49.3 months to not reached) in the pertuzumab group vs 40.8 months (95% CI = 35.8–48.3 months) in the control group (difference = 15.7 months; hazard ratio [HR] = 0.68, P < .001) in an intent-to-treat analysis. Estimated survival rates were 94.4% vs 89.0% at 1 year, 80.5% vs 69.7% at 2 years, 68.2% vs 54.3% at 3 years, and 57.6% vs 45.4% at 4 years.
Subgroup and Sensitivity Analyses
Exploratory subgroup analyses generally showed a consistent benefit of the addition of pertuzumab according to prior neoadjuvant/adjuvant treatment, study region, age, race/ethnicity, and hormone receptor status. Hazard ratios were 0.59 among patients with visceral disease and 1.11 among those with nonvisceral disease (P = .03 for interaction). Among 47 patients in the pertuzumab group and 41 in the control group who had received previous trastuzumab treatment, the hazard ratio was 0.80 (95% CI = 0.44–1.47).
Sensitivity analyses were performed to adjust for outcomes in 48 patients (12%) without disease progression who crossed over from the control group to receive pertuzumab. All had been receiving study treatment for at least 2 years. Median overall survival was 56.5 vs 39.6 months (HR = 0.63, P < .001) when data from these patients were censored at the time of first pertuzumab dose and 56.5 vs 34.7 months (HR = 0.55, P < .001) when the data were excluded.
Overall, subsequent therapy was received by 77% of patients in the pertuzumab group and 79% in the control group after discontinuation of study treatment, including HER2-targeted treatment (usually trastuzumab) in 73% and 71% and capecitabine in 55% and 58% of those receiving subsequent treatment.
Investigator-assessed median progression-free survival was 18.7 vs 12.4 months (HR = 0.68, P < .001). Median duration of response among 275 patients in the pertuzumab group and 233 in the control group with response on independent assessment was 20.2 vs 12.5 months.
No New Safety Signals
Rates of adverse events were consistent with those reported in the primary progression-free survival analysis, with any-grade headache, upper respiratory tract infection, and muscle spasm occurring at an incidence ≥ 5% higher in the pertuzumab group. Most adverse events in both groups were grade 1 or 2 and were associated with docetaxel administration.
Overall, left-ventricular dysfunction was observed in 6.6% of patients in the pertuzumab group and 8.6% of patients in the control group. One new case of symptomatic left-ventricular dysfunction was observed in a patient in the pertuzumab group after 40 months, with the event resolving at 3 months after discontinuation of pertuzumab and trastuzumab. Reductions in left-ventricular ejection fraction of ≥ 10% from baseline to an absolute value of < 50% were observed in 6.1% and 7.4% of patients, with the reductions being reversed in 21 (87.5%) of 24 patients in the pertuzumab group and 22 (79%) of 28 in the control group.
Death due to febrile neutropenia or infection occurred in 1.7% of patients in the pertuzumab group and 1.5% of patients in the control group.
The investigators concluded: “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.” ■
Disclosure: The study was funded by F. Hoffmann-La Roche and Genentech. For full disclosures of the study authors, visit www.nejm.org.
1. Swain SM, Baselga J, Kim S-B, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-734, 2015.
2. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.
Javier Cortés, MD, of Vall d'Hebron Institute of Oncology in Barcelona, discusses the unexpectedly huge survival benefit with pertuzumab and trastuzumab in HER2-positive metastatic breast cancer.
In my opinion, the combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) is one of the most important advances in the field of metastatic breast cancer in the past 10 years. As recently reported by Swain, my other colleagues, and me and reviewed in this issue of The ASCO Post, the...