First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors

Abstract

Purpose: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.Experimental Design: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3þ3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.Results: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (C max ) and area under the concentration-time curve up to the last measurable concentration (AUC last ) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses !400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in ontreatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80-225 days).Conclusions: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards.

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

“…As the liver is a key organ in antibody clearance and attracting the immune system for ADCC, it might explain the relatively higher tracer uptake in healthy liver tissue compared to liver metastases. This, however, did not result in specific liver toxicity or higher efficacy in liver metastases (11). On the other hand, the target receptor density, which is generally lower in HER3-positive tumor lesions compared to HER2-positive lesions, might also explain the PET-negative liver lesions.…”

“…Results of first trials with these HER3 antibodies indicate that further application of these drugs will focus on biomarker-enriched populations, as well as on combination with other treatments targeting other HER family members (11). This makes insight in biodistribution, information on intraand interpatient target heterogeneity and target accessibility, as well as target occupation or (30,37).…”

“…During the second series (on-treatment), 89 Zr-lumretuzumab was dosed with increasing PD-active doses of unlabeled lumretuzumab (400, 800 or 1600 mg) in subsequent patient cohorts. These lumretuzumab doses had been cleared for safety in the phase I study and all resulted in a downregulation of membranous HER3 protein measured by IHC in 35/38 tumor and skin biopsies 14 days after the first lumretuzumab administration compared to baseline (11).…”

“…Furthermore, the antibody can cause direct cell death through antibody-dependent cellular cytotoxicity (10). A phase I study in patients with HER3-positive solid tumors of epithelial origin showed that lumretuzumab monotherapy was well tolerated and signs of clinical activity were reported (11).…”

Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti‐cancer antibodies: IUPHAR Review 18

“…HER3 involvement in acquirement of resistance to trastuzumab and other cancer drugs has been amply supported (Ritter et al , ; Narayan et al , ; Campbell et al , ; Schoeberl et al , ), and although several anti‐HER3 mAbs entered clinical trials, currently no mAb has progressed to clinical approval. For example, lumretuzumab, a glycoengineered anti‐HER3 monoclonal antibody (Meulendijks et al , ), failed to show added benefit when combined with the EGFR inhibitor erlotinib in a phase I/II NSCLC trial. In addition, it is still unclear whether homo‐combinations of anti‐HER3 antibodies are endowed with synergistic anti‐tumour effects (D'Souza et al , ; Gaborit et al , ).…”