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

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

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

NRG1 Fusions: The New Kid on the Block. (PubMed, Curr Oncol Rep) - "Zenocutuzumab, a bispecific antibody targeting HER2 and HER3, is the first FDA approved treatment for previously treated NRG1 fusion-positive NSCLC and pancreatic cancer...NRG1 fusions are rare molecular drivers of NSCLC that can be effectively treated with targeted therapies. Here, we summarize the biology and detection of NRG1 fusions, the currently approved bispecific antibody used to treat NRG1 fusion-positive NSCLC, and new agents under investigation."

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

Exploring the role of bispecific and CAR-T cell therapies in gastric cancer: A systematic review and meta-analysis. (ASCO-GI 2025) - "Bispecific antibodies were MCLA-128 (25/138), catumaxomab (15/138), AK104 PD-1/CTLA-4 (16/138), ABL 001 DLL4VEGFA (19/138), and KN026 (25/138) while CART therapy was CT041 (38/138)... This analysis shows promising results in GC patients using bi-specific antibodies and CAR-T cell therapy. However, further clinical trials are needed to fully explore their potential."

CAR T-Cell Therapy • Retrospective data • Review • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CTLA4 • PD-1

Antibodies to watch in 2025. (PubMed, MAbs) - "In particular, we report on 21 antibody therapeutics granted a first approval in at least one country or region during 2024, including bispecific antibodies tarlatamab (IMDELLTRA®), zanidatamab (Ziihera®), zenocutuzumab (BIZENGRI®), odronextamab (Ordspono®), ivonescimab (®), and antibody-drug conjugate (ADC) sacituzumab tirumotecan (®). We also discuss 30 investigational antibody therapeutics for which marketing applications were undergoing review by at least one regulatory agency, as of our last update on December 9, 2024, including ADCs datopotamab deruxtecan, telisotuzumab vedotin, patritumab deruxtecan, trastuzumab botidotin, becotatug vedotin, and trastuzumab rezetecan. Of 178 antibody therapeutics we include in the late-stage pipeline, we summarize key data for 18 for which marketing applications may be submitted by the end of 2025, such as bi- or multispecific antibodies denecimig, sonelokimab, erfonrilimab, and anbenitamab. Key..."

Journal • Review • Oncology

Zenocutuzumab (Bizengri) for NSCLC and pancreatic adenocarcinoma. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

MODULE 4: Future Directions for HER2-Targeted Therapy for HER2-Low Breast Cancer (SABCS 2024) - "This CME symposium is sponsored by Research To Practice, and supported by educational grants from AstraZeneca Pharmaceuticals LP and Daiichi Sankyo Inc. Rationale for combining T-DXd with other systemic therapies for HER2-low breast cancer Early research findings and ongoing efforts attempting to define the future role of various combination approaches for HER2-low mBC Available clinical research findings with and ongoing evaluation of T-DXd for localized HER2-low breast cancer Mechanisms of action and structural components of other novel antibody-drug conjugates (ADCs) under development for HER2-low breast cancer; similarities with and differences from T-DXd Available efficacy and safety data with and ongoing evaluation of investigational HER2-targeted ADCs for HER2-low breast cancer Mechanisms of action of, early data with and ongoing assessment of the HER2 targeted bispecific antibodies zanidatamab and zenocutuzumab for HER2-low breast cancer"

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

The @OncoAlert Newsletter is out. REGISTER AT http://OncoAlert360.com OR http://buff.ly/48Xpgz0 This week covering several updates, including: ✅FDA Approves Duvalumab in #SCLC in ✅FDA ACCELERATED APPROVAL TO ZENOCUTUZUMAB-ZBCO IN #NSCLC ✅Lung adenocarcinomas with mucinous histology by our own @DiFedericoMD But also: ✅Exercising and immuno-oncology tx …

Finally, our lung cancer patients and pancreas cancer with NRG1 fusion protein (genomic alteration) have a new treatment. Zenocutuzumab. Remember to test all your patients with NSCLC using next generation sequencing (NGS), which includes DNA and RNA analyses. @IASLC @OncologyInst

Merus Announces FDA Approval of BIZENGRI (zenocutuzumab-zbco) for NRG1+ Pancreatic Adenocarcinoma and NRG1+ Non–Small Cell Lung Cancer (NSCLC) Based on Safety and Efficacy Data From the eNRGy Study (GlobeNewswire) - "Merus...announced today that the U.S. Food and Drug Administration (FDA) approved BIZENGRI (zenocutuzumab-zbco), the first and only treatment indicated for adults with pancreatic adenocarcinoma or non–small cell lung cancer (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. These indications are approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR)....The approval of BIZENGRI is based on data from the eNRGy trial, a multicenter, open-label clinical trial that enrolled patients with NRG1+ pancreatic adenocarcinoma or NRG1+ NSCLC that is advanced unresectable or metastatic and had disease progression on or after prior systemic therapy."

Accelerated approval • Evidence highlight • FDA approval • Non Small Cell Lung Cancer • Pancreatic Adenocarcinoma • NRG1

Merus and Partner Therapeutics Announce License Agreement for the U.S. Commercialization of Zenocutuzumab in NRG1 Fusion-Positive Cancer (GlobeNewswire) - "Merus N.V....and Partner Therapeutics...announced they have entered into an agreement in which Merus has exclusively licensed to PTx the right to commercialize zenocutuzumab (Zeno) for the treatment of NRG1 fusion-positive (NRG1+) cancer in the United States (U.S.)....Under the terms of the agreement, following a specified transition period, PTx will assume full rights to U.S. commercialization of Zeno for the treatment of NRG1+ cancer. In exchange for the rights granted under the license agreement, Merus will receive an upfront payment and is eligible to receive milestones and high single-digit to low double-digit royalty payments based on the annual net sales of Zeno in NRG1+ cancer in the U.S. for any potential future sales."

Licensing / partnership • Non Small Cell Lung Cancer • Pancreatic Ductal Adenocarcinoma

Merus Receives FDA extension of PDUFA for zenocutuzumab (GlobeNewswire) - "Merus N.V...announced that the United States Food and Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) goal date for zenocutuzumab (Zeno) Biologics License Application (BLA) currently under priority review. The US FDA has extended the PDUFA goal date to February 4, 2025 to enable sufficient time to review information recently submitted by the Company in response to a CMC information request. No additional clinical data have been requested."

PDUFA • Non Small Cell Lung Cancer • Pancreatic Cancer

Study Evaluating Zenocutuzumab in Patients with or Without Molecularly Defined Cancers (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: Merus N.V. | Recruiting ➔ Active, not recruiting

Enrollment closed • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • NRG1

Antibodies to watch in 2024. (PubMed, MAbs) - "In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi))...These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa)...Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates..."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Foundation Medicine Collaborates With Merus to Advance Treatment Options in NRG1 Fusion-Driven Tumors Using Foundation Medicine’s RNA Platform (Businesswire) - "Foundation Medicine...announced a collaboration to develop Foundation Medicine’s RNA platform as a companion diagnostic for Merus N.V.’s...bispecific antibody zenocutuzumab (Zeno) to treat patients with neuregulin 1 fusion (NRG1+) cancer. Zeno is a Biclonics that utilizes the Merus Dock & Block mechanism to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors with NRG1 fusions (NRG1+ cancer)....'We anticipate this innovative molecular information will help detect more NRG1 fusions and provide healthcare providers with important information to inform their care decisions for patients'."

Diagnostic • Licensing / partnership • Oncology • Solid Tumor