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

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, zenocutuzumab did not restore sensitivity. These findings highlight the critical molecular context in which tumor microenvironment (TME)-derived NRG1 impacts responsiveness to AR inhibition and suggest that targeting NRG1 is a promising strategy for overcoming resistance to androgen blockade in PTEN-wildtype prostate cancers."

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

Continued zenocutuzumab treatment beyond progression in patients with NRG1+ pancreatic cancer and cholangiocarcinoma: Analysis from the phase 2 eNRGy trial. (ASCO-GI 2026) - P2 | "Funded by Partner Therapeutics, Inc. Clinical Trial Registration Number: NCT02912949 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Clinical • P2 data • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • NRG1

KRAS-Wild Pancreatic Cancer-More Targets than Treatment Possibilities? (PubMed, Cancers (Basel)) - "Currently, selpercatinib, larotrectinib, and repotrectinib are approved by the FDA for the treatment of certain solid tumors harboring specific gene fusions. Recent studies on zenocutuzumab resulted in the FDA-accelerated approval for NGR1 fusion-positive NSCLC and PDAC. Germline mutations may specifically increase responsiveness to poly(ADP-ribose) polymerase (PARP) inhibitors or platinum-based treatments. Comprehensive genomic profiling, incorporating fusion detection and germline testing, is essential to identify patients who may benefit from precision-based approaches."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ALK • FGFR • KRAS • NRG1 • NTRK • RET • ROS1

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

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

Zenocutuzumab-zbco Granted FDA Breakthrough Therapy Designation for NRG1+ Cholangiocarcinoma (PRNewswire) - "The designation was supported by new interim data presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics meeting which evaluated zenocutuzumab-zbco in patients with advanced NRG1+ cholangiocarcinoma in the eNRGy trial."

Breakthrough therapy • Cholangiocarcinoma

Zenocutuzumab efficacy and safety in advanced NRG1+ cholangiocarcinoma: Analysis from the phase 2 eNRGy trial* (AACR-NCI-EORTC 2025) - No abstract available

Clinical • Metastases • P2 data • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • NRG1

Zenocutuzumab efficacy and safety in advanced NRG1+ cholangiocarcinoma: Analysis from the phase 2 eNRGy Trial (AACR-NCI-EORTC 2025) - "Most adverse events (AEs) were Grade 1/2. Grade 3+ AEs in ≥2 patients included anemia (14%), hypomagnesemia (9%), and GGT increase (9%).ConclusionZenocutuzumab demonstrated clinically meaningful and durable efficacy with a favorable safety profile in patients with advanced NRG1+ cholangiocarcinoma, an aggressive disease with few treatment options."

Clinical • Metastases • P2 data • Biliary Cancer • Cholangiocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • HER-2 • NRG1

Landscape of neuregulin1 (NRG1) gene fusions using circulating tumor DNA (ctDNA) next-generation sequencing (NGS) in patients with advanced solid tumors (AC) (ESMO 2025) - "Zenocutuzumab, a bispecific antibody directed against HER2 and HER3, has recently received FDA approval to treat NRG1 fusion–positive malignancies...Ltd. Singapore."

Biomarker • Circulating tumor DNA • Clinical • Metastases • Next-generation sequencing • Tumor mutational burden • Biliary Cancer • Biliary Tract Cancer • Bladder Cancer • Breast Cancer • Colorectal Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CCNE1 • CD74 • CDKN2A • EGFR • ERBB3 • FGFR1 • HER-2 • MSI • MTAP • NRG1 • PIK3CA • RBPMS • TMB • TP53

Data Highlighting Potential of Zenocutuzumab-zbco in NRG1+ Cholangiocarcinoma to be Presented at AACR-NCI-EORTC (PRNewswire) - "These findings will...serve as the basis for a supplemental Biologics License Application (sBLA) that will be submitted to FDA in 2026...In 19 evaluable patients, the results demonstrated an investigator-assessed overall response rate of 37%, a median duration of response of 7.4 months, and a median time to response of 1.9 months. Progression-free survival was 9.2 months and clinical benefit rate, defined as partial/complete response or stable disease for ≥24 weeks, was 58%. Among patients with evaluable CA 19-9 data, all experienced a decline in serum levels, including a >50% reduction in 69% of patients. The safety profile was consistent with the overall eNRGy trial population, with most adverse events grade 1 or 2."

FDA filing • P2 data • Cholangiocarcinoma

Study Evaluating Zenocutuzumab in Patients With or Without Molecularly Defined Cancers (clinicaltrials.gov) - P2 | N=13 | Terminated | Sponsor: Merus N.V. | N=90 ➔ 13 | Trial completion date: Mar 2026 ➔ Jul 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Oct 2025 ➔ Jul 2025; Merus terminated the study early due to changes in organizational priorities.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • NRG1

Unveiling the Potential of Zenocutuzumab: A Breakthrough in NSCLC and Pancreatic Adenocarcinoma Treatment. (PubMed, Oncology (Williston Park)) - "Its safety profile remains favorable, with most adverse effects being mild to moderate. This editorial explores the clinical potential of zenocutuzumab in reshaping treatment strategies for NSCLC and pancreatic adenocarcinoma."

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

Bispecific Antibodies in Solid Tumors: Advances and Challenges. (PubMed, Int J Mol Sci) - "There are currently five BsAbs approved by the FDA in the United States for solid tumors-amivantamab, tarlatamab, tebentafusp, zanidatamab and zenocutuzumab-and two BsAbs approved in China-cadonilimab and ivonescimab. Currently, several BsAbs are under clinical development for solid tumors, but are mostly in early phase I and II trials. This review provides an overview of the basic mechanism of action of BsAbs, current FDA-approved BsAbs, and current BsAbs under clinical development, their challenges in clinical use, the management of toxicities, and future directions."

Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

Therapy for Stage IV Non–Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2025.1 (ASCO.org) - "EGFR Exon 19 Deletion, Exon 21 L858R Substitution...First-Line Treatment Options Update: Recommendation 1.1.1 - Clinicians may offer osimertinib with platinum doublet chemotherapy or amivantamab plus lazertinib (Evidence quality: Moderate; Strength of recommendation: Weak); NRG1 Fusion...Second-Line Treatment Options Update: Recommendation 2.20 - Clinicians may offer zenocutuzumab (Evidence quality: Low; Strength of recommendation: Strong)"

Clinical guideline • Non Small Cell Lung Cancer

Bispecific Antibodies in Non-Small Cell Lung Cancer: From Targeted Innovation to Real-World Integration. (PubMed, Am Soc Clin Oncol Educ Book) - "Recent US Food and Drug Administration approvals-including amivantamab, an epidermal growth factor receptor (EGFR)/mesenchymal-epithelial transition factor-targeting monoclonal antibody for EGFR exon 20 insertions and frontline EGFR-mutant (Exon 19 and 21) NSCLC, and zenocutuzumab for tumors harboring neuregulin 1 fusions-highlight their expanding therapeutic footprint. Furthermore, we highlight an emerging PD-1/vascular endothelial growth factor-A bispecific antibody (ivonescimab) and its potential to reshape frontline therapy paradigms in NSCLC. By integrating clinical trial evidence with real-world considerations, this review aims to equip oncologists with the tools to optimize the use of bispecific antibodies in NSCLC and guide future therapeutic integration."

IO biomarker • Journal • Real-world evidence • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • NRG1 • PD-1

Targeting mechanisms of adaptive resistance to the PI3Kαmutant selective inhibitor RLY-2608 in HR+/PIK3CA mutant breast cancer (AACR 2025) - "Alpelisib and inavolisib are currently FDA approved for treatment of PIK3CA-mutant breast cancers, although neither is selective for mutant PIK3CA...To identify the ERBB RTKs causing this adaptation, we tested the TKIs erlotinib, neratinib, and tucatinib, and the HER3 antibodies patritumab and zenocutuzumab, each in combination with RLY-2608...Other upregulated Hallmark pathways in both cell lines included Myogenesis, Hypoxia, and KRAS signaling down. These findings suggest that, in addition to RTK activation, adaptive resistance to RLY-2608 may involve metabolic reprogramming, increased oxidative stress, and hypoxia signaling, highlighting the need for combination strategies to overcome resistance and enhance treatment efficacy."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • ERBB4 • KRAS • PIK3CA

Characterizing the molecular and clinical implications ofNRG1fusions in NSCLC through integrated RNA and DNA sequencing analyses (AACR 2025) - "Background: NRG1 fusions are oncogenic drivers in NSCLC, with therapeutic implications underscored by FDA's designation of Zenocutuzumab for NRG1 fusion-positive cases... This study revealed the diversity of NRG1 fusions in NSCLC, identifying novel fusion partners and distinct molecular and clinical features across novel NRG1+ groups, especially the enriched DNA repair/oncogenic signaling pathways and uniquely upregulated transcription profile. Our study highlights the need of subtyping different NRG+ tumors to better understand their tumorigenesis and facilitates more personalized and targeted treatment of NRG1+ NSCLC patients."

Clinical • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD74 • DNAJB1 • FANCI • KRAS • LMNA • MSH2 • MSH6 • NRG1 • SLC3A2 • TMB

eNRGy: Making progress toward a future for NRG1 fusion-positive cancer. (PubMed, Med) - "The eNRGy trial demonstrated zenocutuzumab's efficacy in advanced cancer with NRG1 fusion, mainly non-small cell lung and pancreatic cancers.1 Responses were observed across multiple tumor types identified through RNA-based next-generation sequencing, with low-grade adverse events. This suggests a potentially agnostic role of NRG1 fusions in solid tumors and underscores the need for comprehensive gene fusion testing in patients with cancer."

Journal • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • NRG1

Emerging importance of HER3 in tumorigenesis and cancer therapy. (PubMed, Nat Rev Clin Oncol) - "In December 2024, the HER3 × HER2 bispecific antibody zenocutuzumab was granted FDA Accelerated Approval for the treatment of non-small-cell lung cancers or pancreatic cancers harbouring fusions involving NRG1, the gene encoding the high-affinity HER3 ligand neuregulin 1. In this Review, we provide an essential guide to HER3 signalling and oncogenesis, HER3 expression in cancer and its prognostic implications, oncogenic HER3 somatic mutations as well as rare NRG1 fusions that might depend on HER3 signalling, and the roles of HER3 in resistance to cancer therapies. We also highlight efforts to target HER3 with diverse therapeutic strategies and the potential interplay between HER3 and the antitumour immune response."

Journal • Review • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • EGFR • ERBB3 • ERBB4 • NRG1

Novel drugs approved by the EMA, the FDA and the MHRA in 2024: A year in review. (PubMed, Br J Pharmacol) - "Some notable examples are the first drug successfully using a 'dock-and-block' mechanism of inhibition (zenocutuzumab), the first approved drug for schizophrenia designed as an agonist of M1/M4 muscarinic receptors (xanomeline), the first biparatopic antibody (zanidatamab), binding two distinct epitopes of the same molecule, the first haemophilia therapy that instead of relying on external supplementation of clotting factors, restores Factor Xa activity by inhibiting TFPI (marstacimab), or the first ever authorised direct telomerase inhibitor (imetelstat) that reprogrammes the oncogenic drive of tumour cells. In addition, an impressive percentage of novel drugs were first in class (28 out of 53 or 53% of the total) and a substantial number can be considered disease agnostic, indicating the possibility of future approved extensions of their use for additional indications. The 2024 harvest demonstrates the therapeutic potential of innovative pharmacological design,..."

European regulatory • FDA event • Journal • Review • CNS Disorders • Hematological Disorders • Hemophilia • Oncology • Psychiatry • Rare Diseases • Schizophrenia

Zenocutuzumab: First Approval. (PubMed, Drugs) - "On 4 December 2024, zenocutuzumab received its first approval in the USA for the treatment of adults with advanced, unresectable or metastatic pancreatic adenocarcinoma or non-small cell lung cancer (NSCLC) harbouring an NRG1 gene fusion with disease progression on or after prior systemic therapy. This article summarizes the milestones in the development of zenocutuzumab leading to this first approval for the second-line treatment of NRG1+ pancreatic adenocarcinoma or NSCLC."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • HER-2 • NRG1

Zenocutuzumab shows efficacy in NRG1 fusion-positive solid tumours. (PubMed, Nat Rev Clin Oncol) - No abstract available

Journal • Oncology • Solid Tumor • NRG1

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

New England Journal of Medicine Publishes Results of Global, Multicenter eNRGy Study Evaluating Zenocutuzumab-zbco (BIZENGRI) in NRG1+ cancer (PRNewswire) - "Partner Therapeutics...announced today that the New England Journal of Medicine (NEJM) published results of the 204-patient, global, multicenter, single-arm, Phase 2 clinical trial of zenocutuzumab-zbco (BIZENGRI) (eNRGy trial; NCT02912949). The eNRGy trial evaluated overall response rate to zenocutuzumab-zbco in patients with NRG1 gene fusions across multiple tumor types....'The overall response rate and durability of responses we observed in the eNRGy trial are noteworthy'....A subset of data from the eNRGy trial reported in the NEJM publication supported the recent FDA approval of BIZENGRI in adult patients with pancreatic adenocarcinoma or NSCLC that are advanced unresectable or metastatic and harbor a neuregulin 1 (NRG1) gene fusion who have disease progression on or after prior systemic therapy."

P2 data • Non Small Cell Lung Cancer • Pancreatic Adenocarcinoma

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) and the NCCN Drugs & Biologics Compendium (NCCN Compendium) for Pancreatic Adenocarcinoma, Version 2.2025. (NCCN)

NCCN guideline • Pancreatic Adenocarcinoma