Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy

帕妥珠单抗 曲妥珠单抗 拉帕蒂尼 曲妥珠单抗 医学 转移性乳腺癌 药理学 癌症 乳腺癌 癌症研究 肿瘤科 内科学
作者
Gail D. Lewis Phillips,Carter T. Fields,Guangmin Li,Donald Dowbenko,Gabriele Schaefer,Kathy D. Miller,Fabrice André,Howard A. Burris,Kathy S. Albain,Nadia Harbeck,Véronique Dièras,Diana Crivellari,Fang Ting Liang,Ellie Guardino,Steven R. Olsen,Lisa Crocker,Mark X. Sliwkowski
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:20 (2): 456-468 被引量:173
标识
DOI:10.1158/1078-0432.ccr-13-0358
摘要

Abstract Purpose: Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the HER2-directed antibody–drug conjugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta). Experimental Design: Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2-positive locally advanced or metastatic breast cancer (mBC), T-DM1 was dose-escalated with a fixed standard pertuzumab dose in a 3+3 phase Ib/II study design. Results: Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1β), reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addition of pertuzumab. Results from mouse xenograft models showed enhanced antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent. In patients with mBC previously treated with trastuzumab, lapatinib, and chemotherapy, T-DM1 could be dosed at the maximum tolerated dose (MTD; 3.6 mg/kg every 3 weeks) with standard dose pertuzumab. Adverse events were mostly grade 1 and 2, with indications of clinical activity. Conclusions: Dual targeting of HER2 with the combination of T-DM1 and pertuzumab in cell culture and mouse xenograft models resulted in enhanced antitumor activity. In patients, this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy. Clin Cancer Res; 20(2); 456–68. ©2013 AACR.
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