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Rationale for a Phase II Trial of Pertuzumab, a HER-2 Dimerization Inhibitor, in Patients with Non–Small Cell Lung Cancer

Authors' Affiliation: Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Bruce E. Johnson, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-4790; Fax: 617-632-5786; E-mail: bejohnson{at}partners.org.

Background and Rationale: In non–small cell lung cancer (NSCLC) HER-2 gene amplification and 3+ staining by immunohistochemistry are present in only 2% to 5% of the tumors. Therefore, relatively few patients with lung cancer are likely to benefit from treatment with trastuzumab, the humanized monoclonal antibody that is effective in the 20% of patients with breast cancer and HER-2 gene amplification and/or 3+ staining by immunohistochemistry. Pertuzumab (rhuMAb 2C4), a humanized HER2 antibody, represents a new class of targeted therapeutics that inhibit dimerization of HER2 with ligand-activated EGFR (HER1), HER3, and HER-4. Pertuzumab can have antitumor activity in patients with HER-2 present on the tumor without gene amplification or 3+ staining by immunohistochemistry. Preclinical xenograft studies have shown efficacy of pertuzumab in treating NSCLC. Therefore, a trial was undertaken for patients with relapsed NSCLC.

Materials and Methods: Subjects with advanced or recurrent NSCLC treated previously with chemotherapy were treated with pertuzumab (840 mg i.v. loading dose then 420 mg every 3 weeks). Mandatory fresh tumor biopsies before treatment were obtained for biomarker analysis including HER-2 phosphorylation. Computed tomography scans were obtained every two cycles to assess tumor response. Tumor response (response evaluation criteria in solid tumors criteria) was the primary end point.

Results: As reported in a previous abstract, none of the 33 patients with NSCLC and evaluable disease had a response to the treatment.

Conclusions: Pertuzumab has an appropriate rationale for therapeutic use in patients with NSCLC. A phase II trial in patients with NSCLC has completed enrollment, and the details of the trial will be presented in a future publication. This article will review the preclinical rationale for undertaking a study of pertuzumab for patients with relapsed NSCLC.