Bizengri (zenocutuzumab-zbco) / Merus, Partner Therap - LARVOL DELTA

Neuregulin-1(NRG1)-directed therapies induce alkaline phosphatase placental (ALPP) expression in NRG1-fusion positive cancers: Preclinical data and therapeutic perspective (AACR 2026) - "NRG1+ cancers targeting relies on bispecific anti-ERBB2/ERBB3 antibodies such as zenocutuzumab (zeno) or ERBB2 inhibitors such as afatinib (afa). Afa induced early ALPP expression in NRG1+ MDA-MB-175 cells, and afa-resistance was associated with high ALPP expression and a decrease of ERBB3 and ERK phosphorylation. Validation of ALPP as a relevant target is ongoing using ALPP KO and overexpressing NRG1+ models, including NRG1+ engineered preclinical models and NRG1+ patient-derived models from patients exposed to NRG1-directed therapies. Zeno and zongertinib impact on ALPP expression in preclinical models as well as ALPP expression in a cohort of NRG1+ non-small cell lung cancer and pancreatic ductal adenocarcinoma is ongoing."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ALPP • ERBB3 • NRG1 • TENM4

Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer. (PubMed, N Engl J Med) - P2 | "Zenocutuzumab showed efficacy in patients with advanced NRG1 fusion-positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events. (Funded by Merus; eNRGy ClinicalTrials.gov number, NCT02912949.)."

Journal • Fatigue • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ERBB3 • HER-2 • NRG1

Integrative Whole Genome and Transcriptome Characterization of Neuregulin 1 (NRG1) Alterations Across a Pan Cancer Cohort (USCAP 2026) - "Although the reported frequency of NRG1 fusions across solid tumors is <1%, by targeted sequencing assays, they are established oncogenic drivers and underlie FDA approval of zenocutuzumab, a bispecific HER2/HER3 antibody for NRG1 fusion positive non-small cell lung and pancreatic cancers... Our findings expand the spectrum of NRG1 molecular alterations across diverse cancers. Future functional studies are needed to determine the role of these molecular alterations in dysregulation of the HER2/HER3 signaling axis and whether a larger spectrum of patients than those with an NRG1 fusion alone may benefit from approved targeted therapies."

Pan tumor • Colorectal Cancer • Esophageal Adenocarcinoma • Gastric Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Small Intestinal Carcinoma • Solid Tumor • KRAS • NRG1 • TNFRSF10D

The Neuregulin 1 (NRG1)-HER2-HER3 Axis as a Therapeutic Target in Metastatic Castration-Resistant Prostate Cancer (USCAP 2026) - "This is especially relevant given the approval of zenocutuzumab, a bispecific antibody against HER2 and HER3, in patients with NRG1 fusion–positive lung and pancreatic cancers... The NRG1-HER2-HER3 axis is a viable target in a subset of advanced CRPC, including NEPC. In addition to gene fusions, other NRG1 genomic alterations are observed in CRPC. Furthermore, NRG1 is specifically overexpressed in NEPC relative to PRAD."

Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Pancreatic Cancer • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • ERBB3 • HER-2 • NRG1

Integrative Whole Genome and Transcriptome Characterization of Neuregulin 1 (NRG1) Alterations Across a Pan Cancer Cohort (USCAP 2026) - "Although the reported frequency of NRG1 fusions across solid tumors is <1%, by targeted sequencing assays, they are established oncogenic drivers and underlie FDA approval of zenocutuzumab, a bispecific HER2/HER3 antibody for NRG1 fusion positive non-small cell lung and pancreatic cancers... Our findings expand the spectrum of NRG1 molecular alterations across diverse cancers. Future functional studies are needed to determine the role of these molecular alterations in dysregulation of the HER2/HER3 signaling axis and whether a larger spectrum of patients than those with an NRG1 fusion alone may benefit from approved targeted therapies."

Pan tumor • Colorectal Cancer • Esophageal Adenocarcinoma • Gastric Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Small Intestinal Carcinoma • Solid Tumor • KRAS • NRG1 • TNFRSF10D

A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy) (clinicaltrials.gov) - P2 | N=250 | Active, not recruiting | Sponsor: Merus N.V. | Recruiting ➔ Active, not recruiting

Enrollment closed • First-in-human • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • NRG1

A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy) (clinicaltrials.gov) - P2 | N=250 | Recruiting | Sponsor: Merus N.V. | Trial completion date: Dec 2024 ➔ Dec 2026 | Trial primary completion date: Dec 2022 ➔ Dec 2026

First-in-human • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • NRG1

A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy) (clinicaltrials.gov) - P2 | N=250 | Recruiting | Sponsor: Merus N.V. | Phase classification: P1/2 ➔ P2 | Trial completion date: Sep 2022 ➔ Dec 2024 | Trial primary completion date: Sep 2021 ➔ Dec 2022

First-in-human • Phase classification • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • NRG1

A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy) (clinicaltrials.gov) - P1/2 | N=130 | Recruiting | Sponsor: Merus N.V. | Trial primary completion date: Dec 2017 ➔ Dec 2018

First-in-human • Trial primary completion date • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer • NRG1

A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy) (clinicaltrials.gov) - P1/2 | N=250 | Recruiting | Sponsor: Merus N.V. | N=130 ➔ 250 | Trial completion date: Dec 2018 ➔ Sep 2022 | Trial primary completion date: Dec 2018 ➔ Sep 2021

Enrollment change • First-in-human • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer • NRG1

Acquired NRG1 Fusion as a Mechanism of Secondary Resistance to EGFR Therapy in EGFR-Mutated Lung Cancer (IASLC-TTLC 2026) - "Since NRG1 fusions are known to act through HER3-HER2 complexes, the patient was treated with afatinib monotherapy, which resulted in a partial response lasting almost 12 months. Further preclinical studies exploring combination therapies, including zenocutuzumab with osimertinib are currently being investigated. Zenocutuzumab has recently been FDA-approved for lung, pancreatic, and cholangiocarcinoma with NRG1 rearrangements."

IO biomarker • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • ERBB3 • FGFR • HER-2 • KRAS • MET • NRG1 • PIK3CA • TNFRSF10B

Continued Treatment Beyond Progression with Zenocutuzumab, A HER2/HER3 Bispecific Antibody, in Patients with NRG1+ NSCLC: Analysis from the Ongoing Phase 2 eNRGy Trial (IASLC-TTLC 2026) - P2 | "Some patients benefited from local therapy for progressing lesions, permitting continuation of zenocutuzumab. These findings support continued zenocutuzumab treatment beyond progression as a potential viable option"

Clinical • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • HER-2 • NRG1

Zenocutuzumab Treatment Beyond Progression Demonstrates Continued Benefit in Patients with NRG1+ Non-Small Cell Lung Cancer: New Results from the eNRGy Trial (PRNewswire) - "Results were presented at the 2026 International Association for the Study of Lung Cancer (IASLC) Targeted Therapies of Lung Cancer (TTLC) meeting...Oligoprogression occurred in 81% of patients, while 19% experienced diffuse progression. Median total zenocutuzumab exposure increased to nearly 10 months, compared with approximately 7 months before progression. Eight patients continued treatment for more than six months beyond progression, including one patient remaining on zenocutuzumab for more than 23 months after progression, with treatment still ongoing as of December 2025....Additionally, 22% of patients were able to continue zenocutuzumab following local management of progressing lesions including radiotherapy, gamma knife surgery, and surgical resection."

P2 data • Non Small Cell Lung Cancer

Zenocutuzumab‑zbco Receives FDA Orphan Drug Designation for Treatment of Cholangiocarcinoma (PRNewswire)

Orphan drug • Cholangiocarcinoma

Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. (ASCO 2022) - P1/2 | "Zeno demonstrated robust and durable efficacy in pts with advanced NRG1+ cancer regardless of tumor histology. A well tolerated safety profile of Zeno was observed."

Clinical • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ATP1B1 • CD74 • ERBB3 • HER-2 • NRG1 • SLC3A2

Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC) (ESMO 2023) - P2 | "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 • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD74 • ERBB3 • HER-2 • NRG1 • SLC3A2

COLEC12high TAMs Orchestrate Lenvatinib Resistance and Cancer Stemness in HCC via Paracrine NRG1-HER2/HER3 Signaling. (PubMed, Clin Mol Hepatol) - "Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models. Our work establishes the COLEC12high TAM / NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • ERBB3 • HER-2 • NRG1 • STAT1 • STAT3

Characterizing the molecular and clinical implications of NRG1 fusions in NSCLC through integrated RNA and DNA sequencing analysis. (PubMed, Eur J Med Res) - "NRG1 fusions are oncogenic drivers in non-small cell lung cancer (NSCLC), with therapeutic relevance highlighted by the FDA's designation of Zenocutuzumab for NRG1 fusion-positive cases...No significant difference in progression-free survival was seen following first-line EGFR TKI therapy between uncommon and wild-type groups. Our findings highlight the heterogeneity of NRG1 fusions in NSCLC, revealing novel fusions, unique pathway enrichments, and expression profiles that may inform future personalized treatment strategies."

Journal • Tumor mutational burden • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD74 • DNAJB1 • FANCI • KRAS • LMNA • MSH2 • NRG1 • SLC3A2 • TMB

Continued zenocutuzumab treatment beyond progression in patients with NRG1+ pancreatic cancer and cholangiocarcinoma: Analysis from the phase 2 eNRGy trial. (ASCO-GI 2026) - P2 | "Continued treatment with zenocutuzumab beyond progression in select cases of NRG1+ PDAC and CCA was well tolerated and provided a clinically meaningful benefit, especially adjunct to local therapy for progressing lesions. This meaningful extension of therapy is important for patients with limited treatment options."

Clinical • P2 data • Biliary Cancer • Cholangiocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • HER-2 • NRG1

Continued Zenocutuzumab Treatment Beyond Progression Shows Benefit in Patients with NRG1+ Pancreatic Cancer and Cholangiocarcinoma: New Results from the eNRGy Trial Presented at ASCO GI (PRNewswire) - "The new analysis examined efficacy and safety of zenocutuzumab in 17 patients with NRG1+ gastrointestinal tumors (12 PDAC, 5 CCA) who received at least three doses of therapy after experiencing progressive disease, including oligoprogressive, mixed, or otherwise indolent progression patterns. Across the subset zenocutuzumab showed an overall response rate (ORR) of 35%, with one complete response, five partial responses, and eight patients achieving stable disease; the clinical benefit rate, defined as complete/partial response or stable disease for at least 24 weeks, was 65%. Treatment was generally well tolerated, and no patients discontinued therapy due to adverse events...Median total therapy duration was 11 months with a median of two months on therapy after progression, and an upper range exceeding 35 months."

P2 data • Cholangiocarcinoma • Pancreatic Ductal Adenocarcinoma

Advances in the clinical application of bispecific antibodies in cancer therapy. (PubMed, iScience) - "Several BsAbs, such as blinatumomab, mosunetuzumab, teclistamab, glofitamab, epcoritamab, talquetamab, ivonescimab, cadonilimab, tarlatamab, zenocutuzumab, and catumaxomab, have achieved notable success in clinical trials. This review highlights clinically approved BsAbs and provides a comprehensive summary of their therapeutic applications in cancer treatment."

Journal • Review • Oncology

Targeting Tumor Microenvironment-Derived NRG1-HER2/3 Signaling with Zenocutuzumab Restores Sensitivity to AR Inhibition in PTEN Wild-type Prostate Cancer. (PubMed, Mol Cancer Ther) - "In the context of PTEN loss and AR inhibitor resistance, Zeno did not restore sensitivity. These findings highlight the critical molecular context in which tumor microenvironment-derived NRG1 affects responsiveness to AR inhibition and suggest that targeting NRG1 is a promising strategy for overcoming resistance to androgen blockade in PTEN wild-type prostate cancers."

Biomarker • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ERBB3 • HER-2 • NRG1 • PTEN

NRG1 fusion-positive solid tumors: clinical detection, genomic landscape, and real-world data in pancreatic cancer. (PubMed, J Natl Cancer Inst) - "NRG1 fusions are a newly described clinically actionable target in solid tumors. We report the landscape of NRG1+ cancers and highlight the importance of RNA testing. NRG1+ PDAC is enriched in younger patients with KRAS wild-type disease and has a unique biology."

Journal • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ATP1B1 • CD74 • KRAS • NRG1

Zenocutuzumab-zbco (BIZENGRI) Shows Durable Efficacy in Patients with Treatment-Naïve NRG1+NSCLC: Updated eNRGy Trial Results Presented at IASLC-ASCO NACLC (PRNewswire) - "The new analysis evaluated the efficacy and safety of zenocutuzumab-zbco in treatment-naïve and previously treated NRG1+ NSCLC. Among 20 treatment-naïve and 121 previously treated patients, zenocutuzumab demonstrated an overall response rate (ORR) of 35% and 31%, respectively. The clinical benefit rate, defined as partial/complete response or stable disease for ≥24 weeks, was 65% in treatment-naïve and 58% in previously treated patients. Median duration of response was 17.1 months in treatment naïve patients, notably longer than in previously treated patients, 7.4 months."

P2 data • Non Small Cell Lung Cancer

Actionable mutations in pancreatic cancer: where targeted therapies are making a difference. (PubMed, BMJ Open Gastroenterol) - "It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the..."

Journal • Review • Gene Therapies • Microsatellite Instability • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2 • HER-2 • KRAS • MSI • MTAP • NRG1 • NTRK