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

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Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy Published OnlineFirst October 4, 2013; DOI: 10.1158/1078-0432.CCR-13-0358 Clinical Cancer Cancer Therapy: Clinical Research See related article by Gwin and Spector, p. 278 Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy Gail D. Lewis Phillips1, Carter T. Fields1, Guangmin Li1, Donald Dowbenko1, Gabriele Schaefer1, Kathy Miller5, Fabrice Andre6, Howard A. Burris III8, Kathy S. Albain9, Nadia Harbeck10, Veronique Dieras7, Diana Crivellari11, Liang Fang2, Ellie Guardino3, Steven R. Olsen3, Lisa M. Crocker4, and Mark X. Sliwkowski1 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 con- jugate 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 3þ3 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-1b), 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. Ó2013 AACR. Introduction ErbB2, HER3/ErbB3, and HER4/ErbB4. Numerous ligands The ErbB/HER family of receptor tyrosine kinases (RTK) have been identified that interact with all HER family plays critical roles in both development and cancer (1). receptors, with the exception of HER2. Ligand binding These receptors include EGF receptor (EGFR)/ErbB1, HER2/ activates multiple downstream signal transduction path- ways. HER2 is the common coreceptor for the other HER family members. Association of HER2 with HER3 is the most potent signaling complex formed in this receptor 1 2 Authors' Affiliations: Research Oncology, Departments of Biostatistics, family (2, 3). HER3 is considered a pseudo-kinase (4, 5), 3Product Development Oncology, and 4Translational Oncology, Genen- tech, Inc., South San Francisco, California; 5Indiana University Simon but can potently activate phosphoinositide 3-kinase (PI3K) Cancer Center, Indianapolis, Indiana; 6Institute Gustave Roussy, Villejuif; signaling upon dimerization with other HER family mem- 7 8 Department of Medical Oncology, Institut Curie, Paris, France; Sarah bers (6). In addition to growth factor regulation of cell Cannon Research Institute, Nashville, Tennessee; 9Loyola University Med- ical Center, Maywood, Illinois; 10University of Munich, Munich, Germany; proliferation and differentiation, recent reports show an and 11Division of Medical Oncology, Centro di Riferimento Oncologico, important role for multiple RTK ligands in resistance to Instituto Nazionale Tumori Aviano, Italy kinase inhibitors (7–9). The HER3 ligand, neuregulin 1 Note: Supplementary data for this article are available at Clinical Cancer (NRG-1), was recently shown to mediate resistance to Research Online (http://clincancerres.aacrjournals.org/). chemotherapeutic agents as well (10). Moreover, HER3 was G.D.L. Phillips and C.T. Fields contributed equally to this work. reported to mediate resistance to EGFR, HER2, and PI3K Corresponding Author: Gail D. Lewis Phillips, Genentech, Inc., 1 DNA inhibitors. Treatment resulted in HER3 activation, leading Way, South San Francisco, CA 94080. Phone 650-225-2201; Fax: 650- to attenuation of the response to kinase inhibition (11, 12). 225-1411; E-mail: [email protected] Trastuzumab (Herceptin), a humanized HER2 antibody doi: 10.1158/1078-0432.CCR-13-0358 that binds domain IV of the HER2 extracellular domain Ó2013 American Association for Cancer Research. (ECD), is used in combination with chemotherapy for 456 Clin Cancer Res; 20(2) January 15, 2014 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst October 4, 2013; DOI: 10.1158/1078-0432.CCR-13-0358 Enhanced Antitumor Activity with Trastuzumab Emtansine plus Pertuzumab HER2 with other HER family members (24) and demon- Translational Relevance strated clinical activity as a single agent and in combination The antibody–drug conjugate ado-trastuzumab with chemotherapy in ovarian, non–small cell lung and emtansine (T-DM1; Kadcyla) increases progression-free prostate cancer (25–29). Pertuzumab combined with tras- and overall survival versus lapatinib plus capecitabine in tuzumab has antitumor activity in cell culture (30) and patients with HER2-positive metastatic breast cancer animal models of HER2-amplified cancer (23, 31) and in (mBC) who have received prior treatment with trastu- patients with HER2-positive mBC (32, 33). Combining zumab (Herceptin) and a taxane chemotherapy, with a pertuzumab, trastuzumab, and docetaxel significantly better safety profile than the comparator treatments. improves the pathologic complete response rate in the Dual antibody blockade of HER2 with pertuzumab, neoadjuvant setting compared with treatment without per- trastuzumab plus docetaxel showed increased progres- tuzumab (33). In June 2012, the U.S. Food and Drug sion-free and overall survival with the addition of per- Administration (FDA) approved Pertuzumab (Perjeta) in tuzumab to trastuzumab plus docetaxel. Neoadjuvant combination with Herceptin and chemotherapy for treat- treatment with trastuzumab plus pertuzumab (Neo- ment of patients with HER2-positive mBC who have not Sphere trial) or trastuzumab plus lapatinib (NeoALTTO received prior anti-HER2 therapy or chemotherapy for trial) in conjunction with taxane-based therapy resulted metastatic disease (34). We therefore explored the potential in better clinical activity than with single-agent HER2- of combining T-DM1 with pertuzumab in models of HER2- directed therapy. The studies described here show amplified breast and lung cancer. Our data underscore the enhanced antitumor activity with T-DM1 plus pertuzu- feasibility of using multiple strategies to target HER2-pos- mab in preclinical models, with an encouraging safety itive cancer. profile and preliminary evidence of efficacy in a phase Ib study. Moreover, our data show suppression of T-DM1 activity upon ligand activation of HER2/HER3, support- Materials and Methods ing the rationale for combining pertuzumab with Cell lines and reagents T-DM1. Human breast tumor lines BT-474, SK-BR-3, UACC-812, ZR-75-30, HCC1954, and MDA-MB-175-VII (MDA-175), and the non–small cell lung carcinoma line Calu-3 were obtained from the American Type Culture Collection. treatment of HER2-positive breast cancer. Proposed KPL-4 breast cancer cells were provided by Prof. Junichi mechanisms of trastuzumab action include inhibition of Kurebayashi, Kawasaki Medical Hospital, Kurashiki, ECD shedding, disruption of downstream signal-transduc- Okayama, Japan (35). Cells were maintained as previously tion pathways, induction of cell-cycle arrest, inhibition of described (16). T-DM1, pertuzumab, N297A-pertuzumab DNA repair, decreased angiogenesis, and mediation of (36), and E. coli-derived NRG-1b (EGF domain) were antibody-dependent cell-mediated cytotoxicity (ADCC; produced at Genentech, Inc. Unconjugated DM1 was ref. 13). Clinical benefit from trastuzumab-containing ther- obtained from ImmunoGen, Inc. and chemotherapeutic apy, however, can be limited, especially in the metastatic drugs from Sigma-Aldrich. Western blot antibodies were setting, necessitating development of alternate forms of from R&D Systems (cleaved PARP), Cell Signaling Tech- treatment (14, 15). We developed a cytotoxic drug-conju- nology (phospho-HER3, phospho-Akt, Akt), and Santa gate of trastuzumab by covalently linking the antimitotic Cruz Biotechnology, Inc. (HER3). agent DM1 to trastuzumab through a stable MCC linker. Trastuzumab emtansine (T-DM1) potently inhibits growth Cell viability and apoptosis assays of trastuzumab-sensitive and -insensitive HER2-amplified Cell viability and apoptosis assays were performed as cancer cells and shows a favorable safety profile in preclin- described in ref. (16). T-DM1, pertuzumab, or the combi- ical toxicity studies (16). T-DM1 activity has been evaluated nation was added to cells; treatments were in duplicate to fit in phase II and III clinical trials in patients with HER2- all groups onto one plate and experiments were repeated 5 positive locally advanced or mBC (17, 18). T-DM1 (ado- times. Studies performed without
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