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

Abstract

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. 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 mRNA and 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. 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 and mRNA levels were associated with a numerically higher disease control rate but not ORR. 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 mRNA expression levels..

Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer

“…HRG mRNA expression was determined in a small cohort of patients and compared to expression in patients with squamous NSCLC treated with lumretuzumab and erlotinib in a previous study, where HRG was investigated as a potential predictive marker of lumretuzumab activity [ 19 ]. In the present study, HRG mRNA was lower for MBC patients than that observed in squamous NSCLC patients (median delta Ct [range]): MBC -3.35 [−6.78 to −1.4], n = 8; squamous NSCLC -0.72 [−5.12 to 1.64], n = 15).…”

HER3 signaling and targeted therapy in cancer

“…102 A phase Ib study of RG7116 plus cetuximab/erlotinib identified NRG as potential biomarker in patients with solid tumors. 103 …”

Understanding the biology of HER3 receptor as a therapeutic target in human cancer

“…Although lumretuzumab was well tolerated and showed evidence of clinical activity in a phase I trial 110 , two recent phase Ib studies suggest otherwise. The toxicity profile of lumretuzumab in combination with the EGFR-targeted therapies cetuximab and erlotinib was managable, but it exerted little clinical benefit in various cancers 111 . The therapeutic window of lumretuzumab in combination with the anti-HER2 Ab pertuzumab and chemotherapeutic drug paclitaxel for HER3-positive metastatic breast cancer was too narrow to warrant further clinical development 112 .…”