Dual HER2 Blockade with Pertuzumab Substantially Delays Disease Progression

VBCC - December 2011, Volume 2, No 7 - CTRC-AACR SABCS Annual Meeting
Caroline Helwick

San Antonio, TX—It is becoming increasingly clear that 2 agents are better than 1 in treating HER2-positive advanced breast cancer.

The latest evidence comes from the results of the phase 3 clinical trial CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), which were presented at the 2011 CTRC-AACR/San Antonio Breast Cancer Symposium by Jose Baselga, MD, PhD, Professor of Medicine, Harvard Medical School and Associate Director of the Massachusetts General Hospital Cancer Center, Boston.

Adding pertuzumab to a combination of trastuzumab and docetaxel chemotherapy as first-line treatment for metastatic disease extended progression- free survival (PFS) by a median of 6.1 months compared with patients who received only trastuzu - mab-docetaxel, Dr Baselga reported.

“This is huge. It is very uncommon to have a clinical trial show this level of improvement in PFS,” Dr Baselga emphasized.

Pertuzumab is designed to work in combination with trastuzumab as a dual blockade of the HER2 growth factor. Both drugs are monoclonal antibodies that bind to the HER2 receptor protein in different regions. Pertuzumab prevents the receptor from linking to HER3, which stops the formation of a “dimer” that could enhance tumor growth.

“Pertuzumab is the first in a new class of drugs called ‘dimerization inhibitors,’ and its combination with trastuzumab produces dual HER2 blockade, shutting down different mechanisms responsible for HER2 signaling,” Dr Baselga said.

CLEOPATRA randomly assigned 808 postmenopausal women with metastatic breast cancer—without previous treatment for metastatic disease— to trastuzumab and docetaxel chemotherapy, with the addition of either pertuzumab or placebo. The PFS was 18.5 months for patients receiving pertuzumab on top of chemotherapy compared with 12.4 months for trastuzumab-docetaxel alone, a 38% reduction in the risk of progression.

Adding pertuzumab to the combination also raised the objective response rate to 80.2% compared with 69.3% for the chemotherapy combination alone.

Although survival outcomes are not mature, 69 deaths were reported in the 402 patients who were treated with the 3-drug regimen versus 96 among the 406 patients receiving the 2 drugs alone; this amounts to a 36% reduction in mortality.

The 3-drug combination was “remarkably safe and well tolerated,” Dr Baselga noted, reporting that pertuzumab added only minimal toxicity.

Enrollment is already under way in a new double-blind, randomized clinical trial, APHINITY, which will test the use of pertuzumab as adjuvant treatment for early-stage HER2- positive breast cancer: “the setting in which you can really cure patients,” Dr Baselga noted.

“We are looking forward to getting pertuzumab approved as soon as possible. The sooner the better,” Dr Baselga commented.

Genentech recently submitted a biologic license application for pertuzumab in HER2-positive metastatic breast cancer.

Lisa Carey, MD, Medical Director, the University of North Carolina Breast Cancer, Chapel Hill, who moderated a press conference, commented that the findings from the CLEOPATRA study extend the findings from neoadjuvant studies and smaller, less definitive trials “that dual HER2 blockade has a marked advantage of single blockade of HER2. The challenge will be figuring out which patients need both these drugs.”

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