Zenocutuzumab NRG1 Fusion Data Show Continued Benefit After Disease Progression in Lung Cancer

Partner Therapeutics (PTx), a Massachusetts-based biotechnology company, announced new findings from a post hoc analysis of the eNRGy trial evaluating zenocutuzumab treatment beyond progression in patients with NRG1 fusion-positive non-small cell lung cancer. Zenocutuzumab-zbco (marketed as BIZENGRI), a HER2/HER3 bispecific antibody that blocks the receptor signaling driven by NRG1 gene fusions, was granted US FDA accelerated approval in late 2024 for NRG1+ NSCLC and NRG1+ pancreatic adenocarcinoma — making it the first therapy specifically approved for tumors defined by this genomic alteration. The new analysis, presented at the 2026 IASLC Targeted Therapies of Lung Cancer meeting, addresses a question that frequently arises in oncology practice: whether patients derive continued benefit from remaining on a targeted agent after radiographic progression.

Trial specifics

The eNRGy trial (NCT02912949) is an ongoing, open-label, single-arm Phase II basket study enrolling patients with advanced solid tumors harboring NRG1 gene fusions. The post hoc analysis reported by PTx focused on 27 patients with NRG1+ non-small cell lung cancer who received at least three doses of zenocutuzumab after RECIST-defined radiographic progression. Among these patients, 81% experienced oligoprogression — disease advancement at a limited number of sites — while 19% had diffuse progression. Median total zenocutuzumab exposure increased to approximately 10 months, compared with roughly 7 months before the point of initial progression. Eight patients continued treatment for more than six months beyond progression, and one patient remained on zenocutuzumab for more than 23 months after progression, with treatment still ongoing as of the December 2025 data cutoff. Another patient had received zenocutuzumab for nearly four years in total. Notably, 22% of patients were able to continue zenocutuzumab following local management of progressing lesions, including radiotherapy, gamma knife surgery, and surgical resection. No patients in the treatment-beyond-progression cohort discontinued therapy due to adverse events, and no new safety signals were identified.

The eNRGy trial results that supported the original accelerated approval were based on overall response rate and duration of response. The current post hoc analysis does not carry the same evidentiary weight as a pre-specified endpoint analysis, and no formal statistical testing was reported. The company did not disclose specific numerical response rates or survival data for the treatment-beyond-progression subset.

PTx said it continues to work with physicians to generate additional data on the use of zenocutuzumab beyond progression. "These data underscore the potential heterogeneity of disease at progression and provide evidence that continued use of a targeted therapy, like zenocutuzumab, may offer meaningful clinical benefit without introducing new safety concerns," said Pritesh J. Gandhi, Chief Development Officer at Partner Therapeutics. The company has not disclosed a timeline for a confirmatory trial, which will be required to convert the accelerated approval into full approval. PTx holds exclusive US rights to develop, manufacture, and commercialize zenocutuzumab-zbco for NRG1+ cancer under an agreement with Netherlands-based Merus N.V., which discovered the molecule using its proprietary Biclonics bispecific antibody platform.

Zenocutuzumab NRG1 mechanism and disease context

NRG1 gene fusions are rare oncogenic drivers found across multiple tumor types, including NSCLC and pancreatic adenocarcinoma. Unlike the more commonly described chimeric receptor fusions such as those involving ALK, ROS1, RET, NTRK, and FGFR, NRG1 fusions produce chimeric ligands. These aberrant ligands bind to HER3, triggering HER2/HER3 heterodimerization and activating downstream proliferative and survival signaling pathways. Zenocutuzumab was engineered to sit at this interface: it binds both HER2 and HER3 simultaneously, blocking their dimerization and preventing NRG1 fusion proteins from engaging HER3. This dual-targeting approach is designed to shut down the specific signaling axis on which NRG1 fusion-driven tumors depend.

The clinical challenge with NRG1 fusion lung cancer is twofold. First, the alteration is rare — estimates suggest NRG1 fusions occur in fewer than 1% of NSCLC cases — which makes identification dependent on comprehensive molecular profiling using the combination of tissue-based DNA and RNA next-generation sequencing. Second, patients with NRG1+ tumors have historically had low response rates to standard chemotherapy and immunotherapy regimens, leaving a population with few options before zenocutuzumab's approval.

Zenocutuzumab received Breakthrough Therapy designation, Fast Track designation, and Priority Review from the US FDA, along with Orphan Drug designation for pancreatic cancer. The accelerated approval in late 2024 covered adult patients with unresectable or metastatic NRG1+ NSCLC and NRG1+ pancreatic adenocarcinoma who had progressed on or after prior systemic therapy. Continued approval remains contingent on verification of clinical benefit in confirmatory studies. Outside the United States, zenocutuzumab has not received marketing authorization in any other jurisdiction.

Competitive landscape for zenocutuzumab NRG1 fusion therapies

The competitive landscape for targeted therapies in NRG1 fusion-positive cancers is thin. Zenocutuzumab is currently the only approved agent with a specific indication for NRG1 fusion-driven tumors. No other HER2/HER3 bispecific antibody or NRG1-directed therapy has reached late-stage clinical development for this genomic subset. This reflects both the rarity of the target population and the relatively recent recognition of NRG1 fusions as actionable drivers.

The only other therapeutic approach with published clinical evidence in NRG1 fusion-positive tumors is the use of pan-ERBB tyrosine kinase inhibitors, principally afatinib, which targets the broader ERBB receptor family including HER2. Evidence for afatinib in this setting is limited to case reports and real-world single-patient protocols rather than prospective clinical trials:

• Afatinib (Boehringer Ingelheim) has been reported in case series and individual patient reports to produce responses in NRG1 fusion-positive lung adenocarcinoma, including some durable responses. However, there is no dedicated prospective trial program for afatinib in NRG1+ tumors, and the evidence base remains anecdotal. A real-world outcomes analysis has also described afatinib use via single-patient protocols in NRG1 fusion-positive disease.

Beyond these, no other molecules with specific NRG1 fusion-directed development programs were identified in available clinical trial registries or published literature. Broader HER2-directed agents such as trastuzumab deruxtecan (Daiichi Sankyo/AstraZeneca) and tucatinib (Seagen/Pfizer) are approved for HER2-positive or HER2-mutant cancers, but none carry indications for NRG1 fusion-positive disease, and no prospective data in this specific population have been reported for these agents.

The treatment-beyond-progression data from the eNRGy trial, while exploratory, address a practical clinical question for physicians managing patients on zenocutuzumab who develop radiographic progression. The predominance of oligoprogression in this cohort — and the ability of some patients to undergo local therapy while continuing systemic treatment — mirrors patterns observed with other targeted agents in oncogene-driven lung cancers, such as ALK and EGFR inhibitors, where treatment beyond progression has become part of routine practice. Whether this approach will be incorporated into formal treatment guidelines for NRG1+ NSCLC will depend on accumulation of larger datasets and, ultimately, the results of the confirmatory trials that PTx is required to conduct under the terms of its accelerated approval.

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