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Clin Cancer Res. 2017 Sep 15;23(18):5406-5415. doi: 10.1158/1078-0432.CCR-17-0812. Epub 2017 Jun 9.

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.

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Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
Department of Medical Oncology, Hospital del Mar, Barcelona, Spain.
Department of Medical Oncology, CIBERONC, Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain.
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Medical Oncology, Erasmus Medical Center Cancer Institute and Cancer Genomics, Rotterdam, the Netherlands.
Center for Lung Cancer, National Cancer Center, Goyang, South Korea.
START-Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain.
Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Department of Oncology, Asan Medical Center, Seoul, South Korea.
Utrecht Institute for Pharmaceutical Sciences (UIPS), University Utrecht, Utrecht, the Netherlands.
Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.
Pharma Research and Early Development, Roche Innovation Center Welwyn, Welwyn, United Kingdom.
A4P Consulting Ltd, Discovery Park, Sandwich, United Kingdom.
Roche Molecular Systems Inc., Pleasanton, California.
Pharma Research and Early Development, Roche Innovation Center, Basel, Basel, Switzerland.


Purpose: This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas.Experimental Design: The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of squamous non-small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib.Results: Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with a numerically higher disease control rate but not ORR.Conclusions: The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels. Clin Cancer Res; 23(18); 5406-15. ©2017 AACR.

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