Dual HER2 blockage significantly extends progression-free survival
Adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy extended progression-free survival by a median of 6.1 months in patients with metastatic HER2-positive breast cancer compared with patients who received the combination therapy with placebo. These exciting data from the international phase 3, double-blind, randomized CLEOPATRA trial were presented during the 2011 CTRC-AACR San Antonio Breast Cancer Symposium.
In CLEOPATRA, 808 patients with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomly assigned to receive trastuzumab and docetaxel chemotherapy in combination with pertuzumab (N=402) or placebo (N=406). Patients who received pertuzumab in combination with trastuzumab and docetaxel experienced a 38% reduction in the risk of disease progression. The median progression-free survival improved from 12.4 months in the trastuzumab plus docetaxel arm to 18.5 months in patients receiving pertuzumab, trastuzumab and docetaxel.
“This is huge. It is very uncommon to have a clinical trial showing this level of improvement in progression-free survival” says senior investigator José Baselga, MD, PhD (Massachusetts General Hospital cancer center, Boston, USA). “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 the current treatment in order to delay progression is very exciting.”
Pertuzumab is designed to work in combination with trastuzumab as a dual blockade of HER2 signaling, which fuels about one third of all breast tumors. Both drugs are monoclonal antibodies that bind to the HER2 receptor protein in different locations. Pertuzumab’s role is to prevent the receptor from linking to HER3, forming a “dimer” that further signals tumor growth. “These two agents offer a dual HER2 blockade, shutting down different mechanisms responsible for HER2 signaling,” Baselga said. The addition of pertuzumab to trastuzumab and docetaxel also resulted in a significant increase in the overall response rate from 69.3% to 80.2% (P=0.0011). Although overall survival data are not yet mature, Baselga reported 69 deaths among the 402 patients treated with the three-drug combination and 96 deaths among the 406 patients who only received trastuzumab and docetaxel.
Interestingly, this impressive clinical benefit for the three-drug combination did not come at the cost of excessive toxicity. No new safety signals were observed and the adverse events were consistent with what has been reported in previous studies of pertuzumab and trastuzumab. Only minimal side effects were seen with the addition of pertuzumab. Some of those effects were grade 1 and 2 diarrhoea and neutropenia, but no additional cardiac toxicity was seen.
Enrollment is already underway in a new double-blind, randomized clinical trial, APHINITY, to test the use of pertuzumab as adjuvant treatment for early-stage HER2-positive breast cancer. “It is in that setting that patients can really be cured,” Baselga concluded.
