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Pertuzumab/trastuzumab/docetaxel combination linked to prolonged PFS
Baselga J. N Engl J Med. 2012;366:109-119.
The addition of pertuzumab to trastuzumab and docetaxel was linked to increased PFS in a cohort of patients with HER-2–positive breast cancer, according to study results.
Researchers from the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study group aimed to determine the extent to which the mechanism of action of pertuzumab (Genentech) could be complementary to that of trastuzumab (Herceptin, Genentech) in patients with HER-2–positive metastatic disease. The researchers aimed to evaluate this combination for PFS (as assessed by the investigator), OS, the objective response rate and safety.
The analysis involved 808 participants. There were 406 participants in the control group who were assigned placebo plus trastuzumab plus docetaxel, and 402 participants in the study group who were assigned pertuzumab plus trastuzumab plus docetaxel. These first-line regimens were administered until progression or the development of unmanageable toxic effects.
The control group experienced a median PFS of 12.4 months, and the pertuzumab group had a PFS of 18.5 months (HR for progression or death=0.62; 95% CI, 0.51-0.75).
Interim analysis results indicated a strong trend toward OS in the pertuzumab group. The two groups had similar safety profiles. There was no increase in left ventricular systolic dysfunction, but febrile neutropenia and at least grade-3 diarrhea were higher in the study group than in the control group.
“Our findings suggest that targeting HER-2–positive tumors with two anti-HER-2 monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of HER-2 and highlights the clinical importance of preventing the ligand-dependent formation of HER-2 dimers in order to silence HER-2 signaling to the greatest extent possible,” the researchers wrote.
Earn CME this spring at the HemOnc Today Breast Cancer Review & Perspective meeting to be held March 23-24, 2012 at the Hilton San Diego Bayfront. See details at HemOncTodayBreastCancer.com.
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There have been significant data coming out of large clinical trials that validate the notion that blockade of a cancer-driving pathway at multiple points can improve the clinical benefit compared to a single targeted approach. This has long been supported by results of cell line and animal studies, but in many past examples, such findings are not always replicated in the clinic. The ultimate proof of this concept is the improvement in survival which while not formally demonstrated in the CLEOPATRA trial with the additional of pertuzumab to trastuzumab and docetaxel, is already showing a large benefit in progression-free survival and will almost certainly over follow meet the survival endpoint.
Pertuzumab is a HER2 antibody that blocks dimerization of HER2 with its partners, HER3 and HER4, thus inhibiting ligand-dependent activation of these dimmers. Trastuzumab is felt to inhibit ligand-independent activity of HER2, and possibly also work through the immune effector system. Dual blockade effectiveness has also been shown convincingly in the neoadjuvant setting. The era of combination blockade is now upon us – the challenge will be to further personalize these combinations based on individual tumor and host characteristics.
Debasish "Debu" Tripathy, MD
HemOnc Today Editorial Board member
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