SAN ANTONIO—Addition of pertuzumab to a standard chemotherapy combination of trastuzumab (Herceptin) and docetaxel led to a 38% reduction in risk of disease worsening or death in patients with metastatic breast cancer positive for human epidermal growth factor receptor 2 (HER2), reported investigators from the randomized, double-blind, placebo-controlled phase III CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study. Median progression-free survival (PFS) was increased from 12.4 months in a control group treated with the standard combination to 18.5 months in the pertuzumab group, an improvement of more than 6 months (P < .0001).
This is the first randomized phase III trial of pertuzumab, a humanized monoclonal antibody being investigated for use in early and advanced stages of HER2-positive breast cancer and advanced HER2-positive gastric cancer. Findings support dual blockade of the HER2 growth factor, targeted by both pertuzumab and trastuzumab but in different locations. Results were published simultaneously online in the New England Journal of Medicine.
"Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting," said lead investigator Jos Baselga, MD, chief of hematology/oncology at Massachusetts General Hospital, Boston, who termed the improvement "huge."
"With the advent of trastuzumab and now pertuzumab," he added, “we have come a very long way in treating a type of breast cancer that once had a very poor prognosis."
The study evaluated the efficacy and safety of pertuzumab combined with trastuzumab and chemotherapy compared to trastuzumab and chemotherapy alone in 808 patients aged ≥ 18 years (median age, 54 years) and with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer.
Study medication consisted of an 840-mg loading dose of pertuzumab followed by 420 mg 3 times weekly; an 8-mg/kg loading dose of trastuzumab followed by 6 mg/kg 3 times weekly, and a 75-mg/m2 dose of docetaxel every 3 weeks with subsequent dose escalation to 100 mg/m2 if 75 mg/m2 was well tolerated. At least 6 cycles of docetaxel were recommended. The primary study endpoint was PFS as determined by independent review. Secondary endpoints were overall survival (OS), PFS by investigator assessment, safety profile, objective response rate, duration of response, time to symptom progression, and correlation of biomarkers with clinical outcome.
Survival data are not complete, the investigators said, "since the interim analysis of overall survival was performed after 165 events had occurred (43% of the prespecified total number of events for the final analysis). Although there is a strong trend toward prolonged survival with pertuzumab plus trastuzumab plus docetaxel, the result is exploratory.” Final analysis of OS is estimated to be performed in 2013.
The objective response rate was 69.3% in the control group vs 80.2% in the pertuzumab group. Nevertheless, the investigators said they consider the finding exploratory until the final analysis is conducted.
"It seems very likely that this will be a new standard for HER2-positive breast cancer and builds on handsome preclinical data and early stage clinical data," said Harold J. Burstein, MD, PhD, assistant professor of medicine at Harvard Medical School and a medical oncologist in the Breast Oncology Center at the Dana-Farber Cancer Institute, Boston.
No increased rates of symptomatic or asymptomatic cardiac dysfunction were observed in the pertuzumab group compared with the control group. However, diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported more frequently in the pertuzumab group. Although most of these effects were grade 1 or 2 and occurred during the period of concomitant docetaxel administration, grade 3 or higher febrile neutropenia and diarrhea were also increased in the pertuzumab group.
The CLEOPATRA investigators concluded that targeting HER2-positive tumors with two anti-HER2 monoclonal antibodies with complementary mechanisms of action “results in a more comprehensive blockade of HER2 and highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest extent possible."
1. Baselga J, Kim S-B, Im S-A, et al. A phase III, randomized, double-blind, placebo-controlled registration trial to evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel vs. placebo + trastuzumab + docetaxel in patients with previously untreated HER2-positive metastatic breast cancer (CLEOPATRA). San Antonio Breast Cancer Symposium 2011. Dec 6-11, 2011. San Antonio, TX. Abstract S5-5.
2. Baselga J, Corts J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2011 Dec 7. [Epub ahead of print]