Originally published as JCO Early Release 10.1200/JCO.2005.03.184 on February 7 2005

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Phase I Clinical Study of Pertuzumab, a Novel HER Dimerization Inhibitor, in Patients With Advanced Cancer

David B. Agus, Michael S. Gordon, Charles Taylor, Ronald B. Natale, Beth Karlan, David S. Mendelson, Michael F. Press, David E. Allison, Mark X. Sliwkowski, Gracie Lieberman, Stephen M. Kelsey, Gwen Fyfe

From the Cedars-Sinai Prostate Cancer Center and Medical Center; University of Southern California, Los Angeles; Genentech Inc, South San Francisco, CA; and Arizona Cancer Center, Scottsdale and Tucson, AZ

Address reprint requests to David B. Agus, MD, Cedars-Sinai Prostate Cancer Center and Medical Center, Los Angeles, CA 90048; e-mail: david.agus{at}cshs.org.

PURPOSE: Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy.

PATIENTS AND METHODS: Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks.

RESULTS: Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients.

CONCLUSION: These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.

Supported by Genentech Inc, South San Francisco, CA.

Previously presented in abstract form at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

M.F.P. was supported by a grant from the National Cancer Institute (RO1-CA48780).

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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