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Phase II Study of the Dual EGFR/HER3 Inhibitor Published OnlineFirst March 5, 2018; DOI: 10.1158/1078-0432.CCR-17-0646 Cancer Therapy: Clinical Clinical Cancer Research Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer Andrew G. Hill1, Michael P. Findlay2, Matthew E. Burge3, Christopher Jackson4, Pilar Garcia Alfonso5, Leslie Samuel6, Vinod Ganju7, Meinolf Karthaus8, Alessio Amatu9, Mark Jeffery10, Maria Di Bartolomeo11, John Bridgewater12, Andrew L. Coveler13, Manuel Hidalgo14, Amy V. Kapp15, Roxana I. Sufan15, Bruce B. McCall15, William D. Hanley15, Elicia M. Penuel15, Andrea Pirzkall15, and Josep Tabernero16 Abstract Purpose: Duligotuzumab is a dual-action antibody directed cetuximab, although there was a trend for a lower objective against EGFR and HER3. response rate (ORR) in the duligotuzumab arm. No relation- Experimental Design: Metastatic colorectal cancer (mCRC) ship was seen between PFS or ORR and ERBB3, NRG1, or AREG patients with KRAS ex2 wild-type received duligotuzumab or expression. There were fewer skin rash events for duligotuzu- cetuximab and FOLFIRI until progression or intolerable toxicity. mab but more diarrhea. Although the incidence of grade 3 Mandatory tumor samples underwent mutation and biomarker AEs was similar, the frequency of serious AEs was higher for analysis. Efficacy analysis was conducted in patients with RAS duligotuzumab. exon 2/3 wild-type tumors. Conclusions: Duligotuzumab plus FOLFIRI did not appear Results: Of 134 randomly assigned patients, 98 had RAS ex2/ to improve the outcomes in patients with RAS exon 2/3 wild- 3 wild-type. Duligotuzumab provided no progression-free sur- type mCRC compared with cetuximab þ FOLFIRI. Clin Cancer vival (PFS) or overall survival (OS) benefit compared with Res; 24(10); 2276–84. Ó2018 AACR. Introduction sion, and its overexpression (found in 65% to 70% of human colorectal cancer) has been associated with advanced disease (1). EGFR is a growth factor receptor with tyrosine kinase activity Anti-EGFR monoclonal antibodies (mAb) are established in the implicated in both colorectal tumorigenesis and tumor progres- treatment of metastatic colorectal cancer (mCRC), either as single agent or in combination with chemotherapy (2–4). Although the benefit was initially thought to be restricted to patients lacking 1Tasman Oncology Research, Southport, Australia. 2Discipline of Oncology, hotspot mutations in KRAS exon 2, codons 12 and 13, a more University of Auckland, Auckland, New Zealand. 3Royal Brisbane and Women's recent retrospective analysis of phase III studies with anti-EGFR Hospital, Herston, Australia; University of Queensland, Queensland, Australia. mAbs either in first-line or second-line mCRC identified addi- 4 Department of Medicine, Dunedin School of Medicine, University of Otago, tional mutations in KRAS or NRAS exons 2, 3, and 4 as negative 5 ~ 6 Dunedin, New Zealand. Gregorio Maranon Hospital, Madrid, Spain. Aberdeen predictive biomarkers for EGFR inhibition (5–9). Consequently, Royal Infirmary, Aberdeen, United Kingdom. 7Peninsula Oncology Centre, Frankston, Australia. 8Staedtisches Klinikum Muenchen GmbH—Klinikum Neu- the European Society for Medical Oncology clinical practice perlach, Munich, Germany. 9Niguarda Cancer Center, Grande Ospedale Metro- guidelines for the treatment of mCRC were updated to recom- politano Niguarda, Milan, Italy. 10Canterbury Regional Cancer and Haematology mend additional testing for KRAS mutations in exons 3 and 4, and Service, Christchurch, New Zealand. 11Fondazione IRCCS Istituto Nazionale dei NRAS mutations in exons 2 to 4 as a prerequisite for anti-EGFR 12 Tumori, Milan, Italy. University College London Cancer Institute, London, UK. antibody therapy (10). Similarly, National Comprehensive Can- 13University of Washington, Seattle, Washington. 14Centro Integral Oncologico 15 cer Network guidelines now recommend against treating patients Clara Campal (CIOCC), Madrid, Spain. Genentech, Inc., South San Francisco, KRAS NRAS California. 16Vall d'Hebron University Hospital and Institute of Oncology (VHIO), with known (exon 2 or non-exon 2) or mutation with Universitat Autonoma de Barcelona, CIBERONC, Barcelona, Spain. either cetuximab or panitumumab (11). Nonclinical and preliminary clinical data suggest a role Note: Supplementary data for this article are available at Clinical Cancer – Research Online (http://clincancerres.aacrjournals.org/). for HER3 in acquired resistance to EGFR inhibitors (12 14). Yonesaka and colleagues (15) reported amplification of the HER2 ClinicalTrials.gov identifier: NCT01652482 gene and/or increased concentrations of neuregulin (NRG1) the Corresponding Author: Andrew G. Hill, Tasman Oncology Research, Suite 1, ligand for HER3 in cetuximab-resistant clones of colorectal Level 3, 123 Nerang Street, Southport, Queensland 4215, Australia. Phone: and lung cancers. Further analysis suggested that aberrant 614-0014-2592; Fax: 617-551-34815; E-mail: [email protected] HER2 signaling, through either HER2/HER2 dimers associated doi: 10.1158/1078-0432.CCR-17-0646 with gene amplification or HER2/HER3 dimer activation through Ó2018 American Association for Cancer Research. autocrine expression of neuregulin, led to persistent ERK signaling 2276 Clin Cancer Res; 24(10) May 15, 2018 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst March 5, 2018; DOI: 10.1158/1078-0432.CCR-17-0646 DAF Inhibition in Metastatic Colorectal Cancer and is additive in combination with chemotherapy (19). In Translational Relevance colorectal cancer cell lines, standard chemotherapy may modulate Duligotuzumab, a dual-action antibody to EGFR and HER3, the HER3/NRG network. These properties provided the rationale shows preclinical efficacy in EGFR-dependent colorectal can- for investigating duligotuzumab for the treatment of patients with cer cell lines refractory to EGFR inhibition. We evaluated mCRC. duligotuzumab compared with cetuximab in combination with FOLFIRI as second-line therapy in patients with RAS exon 2/3 wild-type metastatic colorectal cancer and found no Materials and Methods advantage to duligotuzumab. Study design This open-label, randomized phase II study enrolled patients with KRAS exon 2 wild-type mCRC who progressed on/after oxaliplatin-containing chemotherapy. The primary objectives of and consequently to cetuximab resistance. Interestingly, a retro- this study were to (i) evaluate the efficacy of duligotuzumab þ spective review of data from mCRC patients treated with cetux- FOLFIRI versus cetuximab þ FOLFIRI in KRAS wild-type mCRC imab as a single agent or in combination with irinotecan (also patients, and (ii) evaluate the efficacy of duligotuzumab þ FOL- reported in ref. 15) found that those patients with a partial FIRI versus cetuximab þ FOLFIRI in KRAS wild-type mCRC response had significantly lower baseline expression of NRG1 in patients whose tumors express low levels of HER3. The secondary plasma or tumor samples than patients with a best response of objectives included evaluating the safety and tolerability of duli- stable or progressive disease. Furthermore, patients with lower gotuzumab versus cetuximab in combination with FOLFIRI in baseline plasma NRG1 levels had significantly longer progres- KRAS exon 2 wild-type mCRC patients, assessing the effect of sion-free survival (PFS) and overall survival (OS) when compared concomitant FOLFIRI on the pharmacokinetics (PK) of duligo- with those with higher levels. tuzumab and vice versa, and evaluating the incidence and impact Clinical trial reports on the evaluation of therapeutics that of anti-duligotuzumab antibodies. inhibit HER3-dependent signaling are relatively rare, as are Eligible patients were randomly assigned in a 1:1 ratio and HER3-related biomarker studies that aim to identify clinically received duligotuzumab at a fixed dose of 1,100 mg i.v. every 2 meaningful patient subsets. This is in part due to the attenuated weeks (q2w; arm A). Patients in arm B received cetuximab enzymatic activity of HER3 that renders HER3 activity dependent administered according to the prescribing label, with a loading on critical protein–protein interactions. Innovative methods for dose of 400 mg/m2 i.v. on day 1 of cycle 1, followed by weekly inhibiting activity often focus on these interactions, and, more- doses of 250 mg/m2 i.v. (2 Â per cycle). No dose reductions were over, biomarkers of HER3 activity often include these interaction allowed for duligotuzumab, and for cetuximab doses were limited partners independent of HER3 expression. HER3 activity can be to reductions for rash in accordance with its prescribing informa- enhanced by elevated ligand or heterodimer expression or, in tion. FOLFIRI chemotherapy was administered q2w (every cycle) some cases, activity is driven by multiple binding sites for sig- starting on day 1 of cycle 1. FOLFIRI consisted of irinotecan (180 naling partners (i.e., PI3K). In addition, there is evidence for mg/m2), 5-FU (bolus and 46-hour infusional doses of 400 mg/m2 controlled HER3 feedback including altered transcription of and 2,400 mg/m2, respectively), and leucovorin (racemic, 400 HER3 itself. This was most clearly shown in a randomized phase mg/m2 or L-isomer form, 200 mg/m2). Recommendations for II trial of pertuzumab (an mAb that targets HER2 and therefore chemotherapy dose reductions were in accordance with standard inhibits heterodimerization of HER2
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