1315MO - Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC)

Background

NRG1 fusions are rare oncogenic drivers of NSCLC and other solid tumors. 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 signaling in NRG1+ cancer. Zeno is being evaluated in the ongoing pivotal phase 2 eNRGy study and early access program (EAP). Updated NRG1+ NSCLC data are presented.

Methods

Patients (pts) with advanced NRG1+ NSCLC 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. Tumor 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, 85 pts with NRG1+ NSCLC (78 eNRGy/7 EAP) were enrolled. Efficacy was assessed in 65 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 64 y (range 32-86), 65% were female, 29%/63%/5% pts had ECOG PS 0/1/2 (missing 2 pts). Most were Asian (52%) or White (37%), 77% had visceral metastases, 98% had adenocarcinoma histology, and 1 pt had non-measurable disease. Common fusion partners were CD74 (52%) and SLC3A2 (23%). Pts received a median of 2 prior systemic therapies (range 0-6), 78% with platinum-based chemotherapy; 12% were treatment naïve. In the 64 pts with measurable disease, the confirmed ORR was 34% (22/64; 95% CI 23-47). 50/64 (78%) pts had target lesion reduction. Median DOR was 12.9 mo with responses ongoing in 11/22 (50%) pts. Kaplan-Meier estimate of 6-mo DOR rate was 79%. Among 85 pts treated with Zeno, Grade ≥ 3 individual AEs irrespective of causality occurred in < 4% pts. No pt discontinued Zeno for a treatment related AE.

Conclusions

In this updated analysis, Zeno provides robust and durable efficacy in advanced NRG1+ NSCLC, with 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, Institutional, Writing Engagement, & funding to institution as part of participation in the clinical study: Merus ; Financial Interests, Institutional, Research Funding: AstraZeneca, ArQule, BeiGene/Springworks, Black Diamond Therapeutics, Elevation Oncology, Kura, Lilly, Merus, Northern Biologics, Pfizer, PMV Pharma, Relay Therapeutics, Repare Therapeutics, Revolution Medicine, Surface Oncology; Financial Interests, Institutional, Advisory Board: Relay Therapeutics, Mersana, Blueprint Bio; Financial Interests, Institutional, Advisory Board, Payment to me for participation including travel to event: Merus. K. Goto: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Amgen K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Amoy Diagnostics Co., Ltd., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb K.K., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Guardant Health Inc., Merck Biopharma Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K., Medpace Japan K.K.; Financial Interests, Personal and Institutional, Funding: Amgen Inc., Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta,Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical ＆ Biological Laboratories Co., LTD., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics,Inc., Amgen Astellas BioPharma K.K., Bayer Yakuhin, Ltd., Blueprint Medicines Corporation., Life Technologies Japan Ltd., NEC Corporation., Novartis Pharma K.K.; Non-Financial Interests, Member: American Society of Clinical Oncology, The Japan Lung Cancer Society, Japanese Society of Medical Oncology, The Japanese Cancer Association. D. Kim: Financial Interests, Personal, Invited Speaker: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Taiwan Lung Cancer Society, Japan Cancer Association; Financial Interests, Personal, Other, Scientific Advisor: Health Insurance Review & Assessment Service, Korea; Financial Interests, Personal, Writing Engagement, Medical writing assistance: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, Daiichi Sankyo, GSK, Pfizer, MSD, Merck, Novartis, Roche, Takeda, Yuhan; Financial Interests, Institutional, Local PI, Clinical Trial Funding: Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer Ingelheim, Daiich-Sankyo, Hanmi, Janssen, Merus, MIrati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Bridge BioTherapeutics, GSK; Financial Interests, Institutional, Coordinating PI, Clinical Trial Funding: Chong Keun Dang; Financial Interests, Institutional, Research Grant, Laboratory research funding to my institution: InnoN; Non-Financial Interests, Advisory Role: Amgen, BMS / ONO Pharmaceuticals, Daiich-Sankyo, Janssen, GSK, Pfizer, AstraZeneca, SK Biopharm, Takeda, Yuhan; Non-Financial Interests, Member of Board of Directors: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Asian Thoracic Oncology Research Group; Other, Travel support for advisory board meeting attendance: Amgen, Daiichi Sankyo; Other, Clinical trial research funding to my institution: Asian Thoracic Oncology Research Group. A. Hollebecque: Financial Interests, Personal, Invited Speaker: Servier, Incyte, Eisai; Financial Interests, Personal, Advisory Board: Basilea, Tahio, Relay Theraeutics, QED Therapeutics, Debiopharm, MSD, Boehringer Ingelheim; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Principal Investigator, M19-345: AbbVie; Non-Financial Interests, Principal Investigator, CO42216 ; WP42627 ; CO40939: Roche; Non-Financial Interests, Principal Investigator, MCLA-158: Merus; Non-Financial Interests, Principal Investigator, SGNB6A: Seatle Genetics; Non-Financial Interests, Principal Investigator, TAS-120-202: Tahio; Non-Financial Interests, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Principal Investigator, ACT16902: Sanofi; Non-Financial Interests, Principal Investigator, C4201002: Pfizer; Non-Financial Interests, Principal Investigator, RLY-4008: Relay Therapeutics; Non-Financial Interests, Principal Investigator, CC-90011: Celgene/BMS; Non-Financial Interests, Principal Investigator, Loxo-IDH: Loxo/Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator, SN-201 study: Sotio; Non-Financial Interests, Principal Investigator, Tropics-03: Gilead; Non-Financial Interests, Principal Investigator, BI1403: Boehringer Ingelheim. 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 clincal trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: zy,meworks; Financial Interests, Institutional, Local PI, drug supply for clinical trial: BeiGene; Financial Interests, Coordinating PI, Drug supply for clinical trial: Incyte. K. Nishino: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., NSD, Amgen, Janssen Pharmaceutical K.K., Novartis Pharmaceuticals, Eli Lilly Japan, Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Nippon Kayaku; Financial Interests, Institutional, Other, Research grant: Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD, AbbVie, Daiichi Sankyo Company, Limited, Amgen, Sanofi K.K., Janssen Pharmaceutical K.K., Novartis Pharmaceuticals, Pfizer, Eli Lilly, Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical, Merus, AstraZeneca; Financial Interests, Institutional, Other, Research grant: Eisai Co., Ltd.; Financial Interests, Personal, Invited Speaker, Advisary Board: Pfizer; Financial Interests, Personal, Invited Speaker, Advisory Board: Merck Biopharma Co., Ltd., AstraZeneca. M. Duruisseaux: Financial Interests, Institutional, Advisory Role: BMS, GSK, Sanofi, MSD, AstraZeneca, AbbVie, Takeda, Boehringer Ingelheim, Amgen, Guardant, Pfizer, Mirati; Financial Interests, Institutional, Speaker, Consultant, Advisor: Roche; Financial Interests, Institutional, Advisory Board: BMS, MSD, AstraZeneca, AbbVie, Takeda, Boehringer Ingelheim, Gamamabs Pharma, Pfizer, NanoString, Lilly, Blueprint, Merus; Financial Interests, Institutional, Research Grant: Takeda. J.O. Park: Financial Interests, Personal, Advisory Board: MedPacto, BMS (Celgene), Servier, MediRama, Adicet Bio, AstraZeneca, Merck Sereno; Financial Interests, Personal, Other, Travel support for a poster presentation at ASCO GI 2023 : Minneamrita Therapeutics LLC; Financial Interests, Personal, Research Grant, Clinical research grant: MedPacto, Servier, BMS (Celgene); Financial Interests, Personal, Research Grant: Eutilex, ABL Bio. N. Leighl: Financial Interests, Personal, Other, CME/independent lectures: MSD, BMS, Hoffmann LaRoche, EMD Serono; Financial Interests, Personal, Invited Speaker, independent lectures: Novartis, Takeda; Financial Interests, Personal, Advisory Board: Puma Biotechnology; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Array, Bayer, EMD Serono, Guardant Health, Lilly, MSD, Pfizer, Roche, Takeda, Janssen. 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, Merck, Sharp and Dhome, 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 Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZecena, 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, Merimarck, Millenim, Nelum, Novartis, Novocure, Zymeworks, Pfizer, Pharmacyclics, Roche; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” – SEOM, Sociedad Europea de Oncología Médica - ESMO. S.V. Liu: Financial Interests, Personal, Advisory Board, Consultant: AstraZeneca, Elevation Oncology, Genentech / Roche, Janssen, Jazz Pharmaceuticals, Novartis, Regeneron, Sanofi, Turning Point Therapeutics; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Catalyst, Eisai, Gilead, Guardant Health, Merus, Takeda; Financial Interests, Personal, Other, Consultant: Daiichi Sankyo, Merck; Financial Interests, Institutional, Local PI: Alkermes, Elevation Oncology, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics; Financial Interests, Institutional, Steering Committee Member, Local PI: Genentech; Non-Financial Interests, Member: ASCO, IASLC. M.N. Al-Hallak: Financial Interests, Personal, Speaker’s Bureau: Ipsen, AstraZeneca, Guardant Health; Non-Financial Interests, Personal, Advisory Board: Karmanos Cancer Institute DSMB; Non-Financial Interests, Personal, Member of Board of Directors: Michigan Society of Hematology-Oncology (MSHO); Foundation Board Member. J. Cleary: Financial Interests, Personal, Research Grant: Merck, Tesaro; Financial Interests, Personal, Other, 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. C. Neuzillet: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, AstraZeneca, Baxter, Bristol Myers Squibb, Fresenius Kabi, Incyte Biosciences, Merck, MSD, MundiPharma, Mylan, Novartis, Nutricia, OSE Immunotherapeutics, Pierre Fabre, Roche, Sanofi, Servier, Viatris; Financial Interests, Personal, Research Funding: AstraZeneca, Bristol Myers Squibb, Fresenius Kabi, Nutricia, OSE Immunotherapeutics, Roche, Servier, Viatris. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fisher; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Preferred Network; Financial Interests, Personal and Institutional, Coordinating PI: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network; Financial Interests, Institutional, Coordinating PI: Guardant Health. A.K. Joe: Financial Interests, Institutional, Other, Employee: Merus. S. Adeyemi: Financial Interests, Institutional, Other, Employee: Merus . S. Jauhari: Financial Interests, Institutional, Other, Employee: Merus. A. Drilon: Financial Interests, Personal, Advisory Board: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem Oncology, More Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Amgen, Janssen, EcoR1, Monte Rosa; Financial Interests, Personal, Other, CME: Medscape, Onclive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, PeerView Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Options, AiCME; Financial Interests, Personal, Other, CME, Consulting: Axis; Financial Interests, Personal, Other, Consulting: Nuvalent, Merus, EPG Health, mBrace, Harborside Nexus, Ology, TouchIME, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Remedica Ltd, RV More; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, GSK, Teva, Taiho, PharmaMar; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Member: ASCO, AACR, IASLC; Other, Food/Beverage: Merck, Puma, Merus; Other: Boehringer Ingelheim. All other authors have declared no conflicts of interest.