ERBB2 Dimerization Inhibitor Meets End Point in Breast Cancer Trial

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TRIAL WATCH ERBB2 dimerization inhibitor meets end point in breast cancer trial

Preliminary results from a Phase III clinical domain IV of the ERBB2 receptor, whereas trial of pertuzumab, an antibody that prevents pertuzumab binds to domain II — the so-called Pertuzumab is dimerization of the ERBB2 (also known as dimerization arm,” explains Nancy Hynes, who very likely to be HER2) receptor with other ligand-activated studies the molecular basis of breast cancer at a milestone in ERBB receptors, have shown that the drug the Friedrich Miescher Institute for Biomedical significantly extended the progression-free Research, Basel, Switzerland. “Domain II is the treatment of survival of patients with ERBB2‑positive the domain that interacts with the other ERBB ERBB2‑positive metastatic breast cancer. family members — epidermal growth factor breast cancer In the CLEOPATRA clinical trial, receptor (EGFR), ERBB3 and ERBB4 — when for a number of 808 patients with previously untreated they are ligand-activated.” reasons metastatic breast cancer were treated Importantly, pertuzumab blocks either with pertuzumab plus trastuzumab interactions between ERBB2 and ERBB3, (Herceptin, Roche/Genentech) and docetaxel which together form the most potent dimer chemotherapy or with trastuzumab and of the ERBB family in initiating oncogenic docetaxel. Although no comprehensive data signalling. Moreover, unlike trastuzumab, have been released yet, Roche has announced pertuzumab has the potential to function that it intends to seek regulatory approval for in tumours with normal levels of ERBB2. pertuzumab based on the results of this trial. However, Hynes notes that the antibody “Pertuzumab is very likely to be a might be less effective in tumours with active milestone in the treatment of ERBB2‑positive EGFR, given that EGFR homodimers can breast cancer for a number of reasons,” signal without the help of ERBB2. Another says José Baselga, Associate Director advantage of pertuzumab lies in the fact of the Massachusetts General Hospital that it interferes with ligand-activated Cancer Center, Boston, Massachusetts, ERBB2‑containing complexes, which means USA, and principal investigator of the that the drug could work in ERBB2‑positive CLEOPATRA trial. “To begin with, it is tumours in which trastuzumab alone is likely that pertuzumab in combination with ineffective. “In ERBB2‑overexpressing trastuzumab and docetaxel will be the new tumours, one mechanism that could standard of care as a first-line treatment in contribute to trastuzumab resistance is patients with metastatic breast cancer. This co-expression of heregulin or any of the other combination is superior to the standard ERBB ligands. Based on the promising results trastuzumab and docetaxel, with very of combining trastuzumab and pertuzumab in minimal — if any — additional side effects. ERBB2‑overexpressing breast cancer, we can In addition, a clinical trial of pertuzumab hypothesize that the ability of pertuzumab to as adjuvant therapy (postoperative) is disrupt ligand-activated ERBB2‑containing just starting (ClinicalTrials.gov identifier: complexes contributes to its activity.” NCT01358877), so pertuzumab could Given the success of this trial, which also change the way we treat breast cancer investigated a combination of two antibodies, in the early disease setting.” it is possible that combination therapies Although both pertuzumab and that target more than one component of trastuzumab bind to the same receptor a signalling pathway could become more tyrosine kinase — ERBB2, which has aberrant widespread. Indeed, as Baselga points out, expression or function in breast cancer and “The demonstration that combined ERBB2 is associated with poor prognosis — the blockade with two antibodies may be antibodies function through different superior to therapy with just one antibody has mechanisms. implications that extend far beyond ERBB2, “The ERBB family of receptors have four as the concept could also be applied to the extracellular domains. Trastuzumab binds to targeting of other receptor tyrosine kinases.”