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Nature Reviews Drug Discovery 10, 648 (September 2011) | doi:10.1038/nrd3538

Trial watch: ERBB2 dimerization inhibitor meets end point in breast cancer trial

Preliminary results from a Phase III clinical trial of pertuzumab, an antibody that prevents dimerization of the ERBB2 (also known as HER2) receptor with other ligand-activated ERBB receptors, have shown that the drug significantly extended the progression-free survival of patients with ERBB2-positive metastatic breast cancer.

In the CLEOPATRA clinical trial, 808 patients with previously untreated metastatic breast cancer were treated either with pertuzumab plus trastuzumab (Herceptin, Roche/Genentech) and docetaxel chemotherapy or with trastuzumab and docetaxel. Although no comprehensive data have been released yet, Roche has announced that it intends to seek regulatory approval for pertuzumab based on the results of this trial.

“Pertuzumab is very likely to be a milestone in the treatment of ERBB2-positive breast cancer for a number of reasons,” says José Baselga, Associate Director of the Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA, and principal investigator of the CLEOPATRA trial. “To begin with, it is likely that pertuzumab in combination with trastuzumab and docetaxel will be the new standard of care as a first-line treatment in patients with metastatic breast cancer. This combination is superior to the standard trastuzumab and docetaxel, with very minimal — if any — additional side effects. In addition, a clinical trial of pertuzumab as adjuvant therapy (postoperative) is just starting (ClinicalTrials.gov identifier: NCT01358877), so pertuzumab could also change the way we treat breast cancer in the early disease setting.”

Pertuzumab is very likely to be a milestone in the treatment of ERBB2-positive breast cancer for a number of reasons

Although both pertuzumab and trastuzumab bind to the same receptor tyrosine kinase — ERBB2, which has aberrant expression or function in breast cancer and is associated with poor prognosis — the antibodies function through different mechanisms.

“The ERBB family of receptors have four extracellular domains. Trastuzumab binds to domain IV of the ERBB2 receptor, whereas pertuzumab binds to domain II — the so-called dimerization arm,” explains Nancy Hynes, who studies the molecular basis of breast cancer at the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. “Domain II is the domain that interacts with the other ERBB family members — epidermal growth factor receptor (EGFR), ERBB3 and ERBB4 — when they are ligand-activated.”

Importantly, pertuzumab blocks interactions between ERBB2 and ERBB3, which together form the most potent dimer of the ERBB family in initiating oncogenic signalling. Moreover, unlike trastuzumab, pertuzumab has the potential to function in tumours with normal levels of ERBB2. However, Hynes notes that the antibody might be less effective in tumours with active EGFR, given that EGFR homodimers can signal without the help of ERBB2. Another advantage of pertuzumab lies in the fact that it interferes with ligand-activated ERBB2-containing complexes, which means that the drug could work in ERBB2-positive tumours in which trastuzumab alone is ineffective. “In ERBB2-overexpressing tumours, one mechanism that could contribute to trastuzumab resistance is co-expression of heregulin or any of the other ERBB ligands. Based on the promising results of combining trastuzumab and pertuzumab in ERBB2-overexpressing breast cancer, we can hypothesize that the ability of pertuzumab to disrupt ligand-activated ERBB2-containing complexes contributes to its activity.”

Given the success of this trial, which investigated a combination of two antibodies, it is possible that combination therapies that target more than one component of a signalling pathway could become more widespread. Indeed, as Baselga points out, “The demonstration that combined ERBB2 blockade with two antibodies may be superior to therapy with just one antibody has implications that extend far beyond ERBB2, as the concept could also be applied to the targeting of other receptor tyrosine kinases.”