Background
NRG1 fusions are rare oncogenic drivers of PDAC and other solid tumours. These chimeric proteins bind HER3, leading to HER2/HER3 heterodimerization and oncogenic transformation. Zenocutuzumab (MCLA-128; Zeno) is a bispecific antibody that overcomes HER3 mediated NRG1 signalling in NRG1+ cancer. Zeno is being evaluated in the ongoing pivotal phase II eNRGy study and early access program (EAP). Updated NRG1+ PDAC data are presented.
Methods
Patients (pts) with advanced NRG1+ PDAC determined by NGS, previously treated with or not candidate for standard therapy, age ≥ 18 y, ECOG PS ≤ 2, and measurable (RECIST v1.1) or evaluable disease were enrolled. Zeno (750 mg IV Q2W) was administered until disease progression or unacceptable toxicity. Tumour imaging was conducted Q8W. The primary endpoint is investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include duration of response (DOR) and safety.
Results
As of 01 Feb 2023, 38 pts with NRG1+ PDAC (33 eNRGy/5 EAP) were enrolled. Efficacy was assessed in 27 pts who received ≥ 1 dose of Zeno and were enrolled by 01 Aug 2022 to allow for the opportunity for ≥ 6 months (mo) follow-up and met the criteria for the primary efficacy population. The median age was 49 y (range 21–72), 52% were male, 44%/52%/4% pts had ECOG PS 0/1/3. Pts had a median of 2 prior systemic therapies (range 0-5), 93% with FOLFIRINOX and/or gemcitabine-based therapy. All had liver metastases and measurable disease. Common fusion partners were ATP1B1 (52%) and SLC4A4 (11%). The confirmed ORR was 44% (95% CI 26-65), with 1 CR and 11 PRs. Most (22/27; 81%) pts had target lesion reduction and 16/19 (84%) pts had CA 19-9 decline ≥ 50% from baseline. Median DOR was 9.1 mo with responses ongoing in 4/12 (33%) pts. Kaplan Meier estimate of 6-mo DOR rate was 64%. Among 38 pts treated with Zeno, Grade ≥ 3 individual AEs irrespective of causality occurred in < 5% pts. No pt discontinued Zeno for a treatment related AE.
Conclusions
In this updated analysis, Zeno continues to demonstrate unprecedented efficacy in pts with previously treated advanced/metastatic NRG1+ PDAC with robust and durable responses and a well-tolerated safety profile.
Clinical trial identification
NCT02912949.
Editorial acknowledgement
Medical writing support was provided by Sarah Mackenzie of Merus, N.V.
Legal entity responsible for the study
Merus N.V.
Funding
Merus N.V.
Disclosure
A. Schram: Financial Interests, Personal, Advisory Board: Mersana, Relay Therapeutics, Blueprint Medicines; Financial Interests, Institutional, Local PI, Funds to the institution as part of trial participation: AstraZeneca, ArQule, BeiGene/Springworks, Black Diamond Therapeutics, Elevation Oncology, Kura Oncology, Lilly, Pfizer, Northern Biologics, PMV Pharma, Repare, Surface Oncology, Revolution Medicine; Financial Interests, Institutional, Coordinating PI, Funds to the institution as part of trial participation: Merus; Financial Interests, Institutional, Other, Funds to the institution as part of trial participation: Relay Therapeutics; Non-Financial Interests, Advisory Role: Pfizer, Relay Therapeutics, PMV Pharma, Merus. T. Macarulla: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Batxer, BioLineRX Ltd, Celgene SLU, Eisai, Ipsen Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, MSD, Novocure, QED Therapeutics Inc, Roche, Sanofi-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences, Basilea, Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, VCN Biosciences, AbbVie Pharma, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZeneca, Bayer, BeiGene, Biolinerx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-la Roche, FibroGen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, MedImmune, Merrimack, Millennium, Nelum, Novartis, Novocure, Pfizer, Pharmacyclics, Roche, Zymeworks; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” – SEOM, Sociedad Europea de Oncología Médica - ESMO. J. Cleary: Financial Interests, Personal, Ownership Interest, Grants or Contracts: Merck, Tesaro; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Incyte; Financial Interests, Personal, Advisory Board: Incyte Pharma, Blueprint, Syros; Financial Interests, Personal, Other, Receipt of equipment, materials, drugs, medical writing, gifts or other services: Bayer, AstraZeneca, Esperas pharma, Arcus, Apexigen, Merus, Roche, Servier, BMS. D. 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S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, durg supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clinical trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: Zymeworks; Financial Interests, Institutional, Local PI, drug supply for clinical trial: BeiGene; Financial Interests, Coordinating PI, Drug supply for clinical trial: Incyte. M. 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Drilon: Financial Interests, Personal, Advisory Board: 14ner/Elevation Oncology, AbbVie, Amgen, ArcherDX, AstraZeneca, BeiGene, Bergenbio, Blueprint Medicines, EcoR1, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Liberum, Loxo/Bayer/Lilly, Melendi, Monopteros, Monte Rosa, Novartis, Pfizer, Remedica Ltd., TP Therapeutics, Takeda/Ariad/Millennium, Tyra Biosciences, Verastem Oncology; Financial Interests, Personal, Other, CME: AiCME, Clinical Care Options, MJH Life Sciences, Med Learning, Medscape, Medscape, Onclive, Paradigm Medical Communications, PeerView Institute, PeerVoice, Physicians Education Resources, Targeted Oncology, WebMD; Financial Interests, Personal, Other, Consulting: Applied Pharmaceutical Science, Inc, EPG Health, Entos, Harborside Nexus, Merus, Nuvalent, Ology, Prelude, TouchIME, Treeline Bio, mBrace; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, RV More, Remedica Ltd; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, PharmaMar, GSK, Teva, Taiho; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Member: ASCO, AACR, IASLC; Other, Other, Food/Beverage: Merck, PUMA, Merus; Other, Other, Other: Boehringer Ingelheim. E.M. 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All other authors have declared no conflicts of interest.
