Bizengri (zenocutuzumab-zbco)

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 necessity of comprehensive next-generation sequencing for every patient with advanced disease, enabling identification of rare, yet clinically meaningful, targets and moving PDAC management towards a precision-oncology paradigm.

P2, N=13, Terminated, 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.

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.

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.

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.

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.

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.

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.).

P2, N=250, Active, not recruiting, Merus N.V. | Recruiting --> Active, not recruiting

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.

P2, N=90, Active, not recruiting, Merus N.V. | Recruiting --> Active, not recruiting