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Phase Ib Study of Lumretuzumab Plus Cetuximab Or Erlotinib in Solid

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Phase Ib Study of Lumretuzumab Plus Cetuximab Or Erlotinib in Solid Published OnlineFirst June 9, 2017; DOI: 10.1158/1078-0432.CCR-17-0812 Cancer Therapy: Clinical Clinical Cancer Research Phase Ib Study of Lumretuzumab Plus Cetuximab or Erlotinib in Solid Tumor Patients and Evaluation of HER3 and Heregulin as Potential Biomarkers of Clinical Activity Didier Meulendijks1, Wolfgang Jacob2, Emile E. Voest1, Morten Mau-Sorensen3, Maria Martinez-Garcia4, Alvaro Taus4, Tania Fleitas5, Andres Cervantes5, Martijn P. Lolkema6,7, Marlies H.G. Langenberg6, Maja J. De Jonge7, Stefan Sleijfer7, Ji-Youn Han8, Antonio Calles9, Enriqueta Felip10, Sang-We Kim11, Jan H.M. Schellens1,12, Sabine Wilson2, Marlene Thomas2, Maurizio Ceppi2, Georgina Meneses-Lorente13, Ian James14, Suzana Vega-Harring2, Rajiv Dua15, Maitram Nguyen15, Lori Steiner15, Celine Adessi16, Francesca Michielin16, Birgit Bossenmaier2, Martin Weisser2, and Ulrik N. Lassen3 Abstract Purpose: This study investigated the safety, clinical activity, and Results: Altogether, 120 patients were treated. One dose-lim- target-associated biomarkers of lumretuzumab, a humanized, iting toxicity (DLT) in the cetuximab part and two DLTs in the glycoengineered, anti-HER3 monoclonal antibody (mAb), in erlotinib part were reported. The most frequent adverse events combination with the EGFR-blocking agents erlotinib or cetux- were gastrointestinal and skin toxicities, which were manageable. imab in patients with advanced HER3-positive carcinomas. The objective response rate (ORR) was 6.1% in the cetuximab part Experimental Design: The study included two parts: dose and 4.2% in the erlotinib part. In the sqNSCLC extension cohort escalation and dose extension phases with lumretuzumab in of the erlotinib part, higher tumor HRG and HER3 mRNA levels combination with either cetuximab or erlotinib, respectively. were associated with a numerically higher disease control rate but In both parts, patients received lumretuzumab doses from not ORR. 400 to 2,000 mg plus cetuximab or erlotinib according to stan- Conclusions: The toxicity profile of lumretuzumab in combi- dard posology, respectively. The effect of HRG mRNA and nation with cetuximab and erlotinib was manageable, but only HER3 mRNA and protein expression were investigated in a modest clinical activity was observed across tumor types. In the dedicated extension cohort of squamous non–small cell lung sqNSCLC cohort, there was no evidence of meaningful clinical cancer (sqNSCLC) patients treated with lumretuzumab and benefit despite enriching for tumors with higher HRG mRNA erlotinib. expression levels. Clin Cancer Res; 1–10. Ó2017 AACR. Introduction particularly the PI3K/Akt pathway (1). Recent studies indicate HER3 is a key dimerization partner of HER family members that HER3 pathway activation is important in the development of that activates several oncogenic signal transduction pathways, resistance to EGFR- and HER2-targeting treatments (2–6). The 1Department of Clinical Pharmacology, Division of Medical Oncology, The Research and Early Development, Roche Innovation Center, Basel, Basel, Netherlands Cancer Institute, Amsterdam, the Netherlands. 2Pharma Research Switzerland. and Early Development, Roche Innovation Center Munich, Penzberg, Germany. 3Department of Oncology, Rigshospitalet, Copenhagen, Denmark. 4Department Note: Supplementary data for this article are available at Clinical Cancer of Medical Oncology, Hospital del Mar, Barcelona, Spain. 5Department of Medical Research Online (http://clincancerres.aacrjournals.org/). Oncology, CIBERONC, Institute of Health Research INCLIVA, University of D. Meulendijks and W. Jacob contributed equally to this article. Valencia, Valencia, Spain. 6Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands. 7Department of Medical Oncology, Current address for A. Calles: Department of Oncology, Hospital General Erasmus Medical Center Cancer Institute and Cancer Genomics, Rotterdam, the Universitario Gregorio Maran~on, Madrid, Spain. Netherlands. 8Center for Lung Cancer, National Cancer Center, Goyang, South Korea. 9START-Madrid, Centro Integral Oncologico Clara Campal, Madrid, Spain. Prior presentation: This work was presented as a poster abstract in Annals of 10Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Heb- Oncology 25 (Supplement 4): iv147, 2014. ron Institute of Oncology, Barcelona, Spain. 11Department of Oncology, Asan Corresponding Author: Wolfgang Jacob, Roche Innovation Center Munich, Medical Center, Seoul, South Korea. 12Utrecht Institute for Pharmaceutical Nonnenwald 2, Penzberg 82377, Germany. Phone: 4988-5660-2736; Fax: Sciences (UIPS), University Utrecht, Utrecht, the Netherlands. 13Pharma 4988-56607-92736; E-mail: [email protected] Research and Early Development, Roche Innovation Center Welwyn, Welwyn, doi: 10.1158/1078-0432.CCR-17-0812 United Kingdom. 14A4P Consulting Ltd, Discovery Park, Sandwich, United Kingdom. 15Roche Molecular Systems Inc., Pleasanton, California. 16Pharma Ó2017 American Association for Cancer Research. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst June 9, 2017; DOI: 10.1158/1078-0432.CCR-17-0812 Meulendijks et al. clinical data from early studies with anti-HER3 antibodies are Translational Relevance consistent with these reports (22, 27, 28). We therefore hypoth- Preclinical models have demonstrated superior antitumor esized that (i) the combination of lumretuzumab with EGFR activity when HER3- and EGFR-targeting therapies are com- inhibitors could improve clinical activity versus EGFR inhibitors bined as compared with single-agent activity. Furthermore, alone, and (ii) higher tumor expression levels of HRG mRNA preclinical and clinical data suggest that response to HER3- could indicate improved clinical outcome and could ultimately targeting therapy is positively correlated to expression of the serve as a predictive biomarker for HER3-targeting therapy. HER3 ligand heregulin (HRG). The current study evaluated the safety and clinical activity, and Across tumor types, the clinical activity of the anti-HER3 potential biomarkers of lumretuzumab treatment when com- antibody lumretuzumab when given in combination with the bined with the EGFR-targeting agents cetuximab or erlotinib. To EGFR-blocking agents cetuximab or erlotinib was modest, evaluate the clinical activity of lumretuzumab plus erlotinib in a with a manageable safety profile. To enrich for tumors with biomarker-enriched population, we recruited an extension cohort higher HRG mRNA levels, we evaluated the combination of of sqNSCLC patients, as sqNSCLC has been shown to express lumretuzumab and erlotinib in a dedicated cohort of squa- higher HRG mRNA levels compared with non-sqNSCLC (data on mous non–small cell lung cancer patients. Here, neither HRG file; refs. 29, 30). nor HER3 mRNA expression levels were associated with an increased response rate, questioning (i) the relevance of HER3 Materials and Methods blockade in combination with EGFR-targeting therapy per se Study design and (ii) the relevance of HRG and HER3 as response prediction This was a multicenter, phase Ib, open-label, nonrandomized, biomarkers for this therapy. dose escalation and extension study (ClinicalTrials.gov Identifier: NCT01482377) investigating the safety (including the MTD and/ or optimal biological dose), pharmacokinetics, pharmacodynam- ics, and clinical activity of lumretuzumab in combination with role of HER3 as a prognostic marker remains controversial. cetuximab or erlotinib in patients with metastatic or advanced Increased HER3 protein expression as measured by immunohis- HER3-positive carcinomas. The study consisted of a dose escala- tochemistry (IHC) has been described as an adverse prognostic tion phase following a standard "3 þ 3" study design and an factor in many solid tumor types, including breast, gastric, lung, extension phase conducted for the cetuximab plus lumretuzumab ovarian, and colon cancers (7–11), and targeting HER3 can as well as the erlotinib plus lumretuzumab combination. sensitize refractory tumor models to EGFR inhibitors (12). In For lumretuzumab monotherapy, pharmacokinetics was linear contrast, higher expression levels of HER3 mRNA were associated at dosages 400 mg, indicative of target-mediated drug disposi- with increased progression-free survival (PFS) in HER2-positive tion saturation, and clinical pharmacodynamic activity was dem- metastatic breast cancer treated with pertuzumab plus trastuzu- onstrated (22). Therefore, the dose of 400 mg was used as the mab plus docetaxel (13) and in patients with platinum-resistant starting dose for the combination treatments with cetuximab and ovarian cancer treated with gemcitabine plus pertuzumab (14). erlotinib. Two administration schedules were applied: every 2 However, adding pertuzumab to chemotherapy in platinum- weeks and every 3 weeks; the latter only applied for a subset of resistant ovarian cancer patients selected on low HER3 mRNA patients in the lumretuzumab plus erlotinib part. expression did not increase PFS significantly (15). Autocrine loops Standard doses of cetuximab (400 mg/m2 for the first infusion involving the HER3 ligand HRG and leading to HER3 activation followed by 250 mg/m2 weekly infusions) and erlotinib (daily have been described in squamous cell carcinoma of the head and dose of 150 mg orally) were used. neck (SCCHN), non–small cell lung cancer (NSCLC), and ovarian Patients continued treatment until disease progression,
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