The CLEOPATRA trial marks the first time that dual inhibitors have demonstrated value in the treatment of HER2-positive metastatic breast cancer.
José Baselga, MD, PhD
The CLEOPATRA trial marks the first time that dual inhibitors have demonstrated value in the treatment of HER2-positive metastatic breast cancer, and the dramatic findings likely will result in a “sea change” in the way the disease is treated, according to the lead investigator.
The study found that combining pertuzumab with trastuzumab (Herceptin) and docetaxel chemotherapy reduced the risk of progression by 38% in women with metastatic HER2-positive disease. The combination is now under study in patients with early-stage disease.
José Baselga, MD, PhD, a professor in the Department of Medicine at Harvard Medical School and chief of Hematology/Oncology at Massachusetts General Hospital in Boston, said the study “is perhaps the formal demonstration that dual tumor blockade is superior to single blockade.”
“This is likely to become the new standard of therapy for this patient population,” Baselga said in an interview. “It’s a sea change in that way. It’s a new concept. I think this will gain strength as we move along with other studies.
“This is, I think, the key proof that we were looking for in support of dual blockade as a better approach to targeting HER2-positive tumors,” he added.
As a result of the positive findings, Genentech, the San Francisco-based company developing the drug, said an application has been submitted with the FDA for pertuzumab to be used for patients with previously untreated HER2-positive metastatic breast cancer.
Both pertuzumab and trastuzumab are monoclonal antibodies. Trastuzumab targets HER2, while pertuzumab is the first in a new class of HER2 dimerization inhibitors that prevents HER2 receptor proteins from linking to other HER receptors, according to Genentech.
Baselga detailed the results of the international phase III study during a press briefing at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium in Texas on Thursday. The study enrolled 808 women with confirmed HER2-positive, locally recurrent, unresectable, or metastatic disease who had not undergone >1 hormonal regimen.
At median follow-up of 19.3 months, the findings show that patients who received pertuzumab (402 patients) experienced a median progression-free survival (PFS) of 18.5 months. By comparison, patients who received trastuzumab, docetaxel, and a placebo (406 patients) demonstrated a median PFS of 12.4 months. (Hazard ratio = 0.62; confidence interval, 0.51-0.75; P = <0.0001).
In addition, the objective response rate (tumor shrinkage ≥30%) was 80.2% in the pertuzumab group as opposed to 69.3% in the placebo arm.
Based on a 3-week cycle, patients in the pertuzumab arm received an 840-mg loading dose followed by a 420-mg maintenance dose. Patients in both arms received an 8-mg/kg loading dose of trastuzumab followed by a 6-mg/kg maintenance dose and 75 mg/m2 of docetaxel, escalating to 100 mg/m2 if tolerated.
Baselga said more time is needed before survival data are determined, but he said early indications are quite positive.
Lisa A. Carey, MD
Concerning adverse events, the results indicate that patients taking the pertuzumab combination experienced higher rates of diarrhea, rash, mucosal inflammation, and febrile neutropenia than those in the placebo arm but that most of the effects were grades 1-2. Significantly, Basegla said, patients in the pertuzumab arm did not experience cardiac dysfunction.
Commenting on the data, Lisa A. Carey, MD, a professor in breast cancer research at the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill, said during the press briefing that the study explored the dual blockade strategy explored in earlier, less definitive trials to demonstrate a “marked advance” in the concept.
She said the challenges for researchers going forward include identifying which patients benefit from the targeted therapies and chemotherapy.