Zenocutuzumab Yields Durable Responses in Treatment-Naïve NRG1+ NSCLC

Across 20 patients with treatment-naive NSCLC enrolled in the eNRGy trial who received zenocutuzumab, the ORR was 35%, with a median DOR of 17.1 months.

Zenocutuzumab-zbco (Bizengri) showed potential in patients with treatment-naïve non–small cell lung cancer (NSCLC) harboring an NRG1 gene fusion in results from a post hoc analysis of the phase 2 eNRGy trial (NCT02912949). These results were shared at the IASLC-ASCO North American Conference on Lung Cancer, and announced in a press release from the developer, Partner Therapeutics.1,2

Among 20 treatment-naive patients, zenocutuzumab elicited an overall response rate (ORR) of 35% (95% CI, 15.4%-59.2%), and in 121 previously treated patients, the ORR was 31% (95% CI, 22.5%-39.6%). The clinical benefit rate, defined as maintaining a partial or complete response or stable disease for at least 24 weeks, was 65% and 58% in each respective group.

The median duration of response (DOR) was 17.1 months (95% CI, 3.7-not evaluable) in treatment-naïve patients and 7.4 months (95% CI, 7.4-12.7) in previously treated patients, and the median time to response was 1.8 months (range, 1.7-3.6) and 1.9 months (range, 1.5-18.3), respectively. The median progression-free survival (PFS) in each respective group was 7.5 months (95% CI, 3.9-13.2) and 6.8 months (95% CI, 5.5-7.4).

The data were shared in a late-breaking oral presentation delivered by Stephen Liu, MD, the division chief of Hematology Oncology at MedStar of Georgetown University Hospital, titled, “Efficacy and safety of zenocutuzumab, a HER2/HER3 bispecific antibody, in treatment-naive, advanced NRG1+ NSCLC: Updated analysis from the ongoing phase 2 eNRGy trial”.

"These data underscore the potential of zenocutuzumab as a first-line option for patients with NRG1-positive NSCLC, a patient population that typically responds poorly to standard first-line therapy," stated Liu, in the press release.2 "Early and durable responses, coupled with a favorable safety profile are encouraging and highlight the importance of targeted therapy in this rare molecular subset."

The eNRGy trial had an estimated enrollment of 250 patients.3 For patients with NSCLC harboring NRG1 fusion, treatment was intravenous zenocutuzumab at 750 mg every 2 weeks. Eligible patients were 18 years or older with locally advanced unresectable or metastatic solid tumor malignancy with documented NRG1 gene fusion, identified via molecular assays, and receipt of prior standard therapy, or an unlikelihood to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy in the opinion of the investigator. Additional enrollment criteria include at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status from 0 to 2, and at least 12 weeks of estimated life expectancy.

Exclusion criteria included presence of a previous or concurrent malignancy unless it was treated with curative intent more than 2 years prior to study entry, known or symptomatic brain metastases, leptomeningeal metastases, and any other medical or psychological condition deemed likely to interfere with study operations.

The primary end points of the trial were ORR and DOR per local investigator assessment. Secondary end points included clinical benefit rate, time to response, PFS, overall survival, and safety and tolerability.

Regarding safety, all treatment-related adverse effects (TRAEs) were grade 1 or 2, and the safety profile of zenocutuzumab was consistent with prior data. TRAEs led to discontinuation in 1 treatment-naïve patient and 1 previously treated patient, with them being pneumonitis and dyspnea, vomiting, and tachycardia, respectively.

“For patients and families facing NRG1-positive lung cancer, these results mark meaningful progress,” said Danielle Hicks, chief patient officer of GO2 for Lung Cancer.2 “The durable responses and manageable safety profile of zenocutuzumab offer renewed hope and reinforce the need for continued innovation in biomarker-driven lung cancer care.”

Previously, in December 2024, the FDA granted accelerated approval to zenocutuzumab as a treatment for patients with NSCLC and pancreatic adenocarcinoma harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy.4

References

1. Liu SV, A M, Goto K, et al. Efficacy and safety of zenocutuzumab, a HER2/HER3 bispecific antibody, in treatment-naive, advanced NRG1+ NSCLC: updated analysis from the ongoing phase 2 eNRGy trial. Presented at the 2025 IASLC-ASCO NACLC; December 5-7, 2025; Chicago, IL. Abstract OA01.01.
2. Zenocutuzumab-zbco (BIZENGRI®) shows durable efficacy in patients with treatment-naïve NRG1+NSCLC: updated eNRGy trial results presented at IASLC-ASCO NACLC. Press release. Partner Therapeutics. December 6, 2025. Accessed December 8, 2025. https://tinyurl.com/2t2uwahv
3. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy). ClinicalTrials.gov. Updated April 29, 2025. Accessed December 8, 2025. https://tinyurl.com/3wcnzehr
4. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. News release. FDA. December 4, 2024. Accessed December 8, 2025. https://shorturl.at/E3HBS