Background: NRG1 fusions are rare oncogenic drivers that have been identified in a variety of solid tumors. These proteins bind HER3, leading to HER2/HER3 heterodimerization and oncogenic transformation. Zenocutuzumab (MCLA-128; Zeno) is a Biclonics antibody that overcomes HER3 mediated NRG1 (or NRG1 fusion) signaling in tumor cells. Zeno docks on HER2, then binds to and blocks the NRG1 fusion-HER3 interaction and HER3 heterodimerization with HER2. Zeno is being evaluated in patients (pts) with NRG1+ cancer in the ongoing pivotal phase 2 part of the eNRGy study and early access program (EAP). Methods: Pts with NRG1+ solid tumors previously treated with or not candidates for standard therapy, aged ≥ 18 years, with ECOG PS ≤ 2, and measurable (RECIST 1.1) or evaluable disease, were enrolled. NRG1 fusions were determined by next generation sequencing (NGS) before enrollment. Zeno (750 mg IV Q2W) was administered until disease progression or unacceptable toxicity. Tumor imaging was conducted every 8 weeks. The primary endpoint is investigator (INV)-assessed objective response rate (ORR) and secondary endpoints include duration of response (DOR) and safety. Results: As of 12 Jan 2022, 99 pts with NRG1+ cancer (85 eNRGy, 14 EAP) were enrolled. Efficacy was assessed in 73 pts who received ≥ 1 dose of Zeno and who were enrolled as of 12 Jul 2021 to allow for the opportunity to have ≥ 6 months (mo) follow-up and met the criteria for the primary efficacy population. Median age was 59 y (range 22–84), 58% were female, 47%/53% pts had ECOG PS 0/1. Tumor types were non-small cell lung cancer (NSCLC; 41 pts), pancreas cancer (18 pts), breast cancer (5 pts), cholangiocarcinoma (3 pts), colorectal cancer (2 pts), and 4 other tumor types (1 pt each), with a median 2 prior systemic therapies (range 0-9). The most frequent fusion partners were CD74 (27%), SLC3A2 (18%), and ATP1B1 (15%). Among the 71 pts with measurable disease, the INV-assessed confirmed ORR was 34% (90% CI, 25;44), including responses in NSCLC (35%; 14/40 pts), pancreas cancer (39%; 7/18 pts), breast cancer (2/4 pts), and cholangiocarcinoma (1/3 pts). Responses occurred at the first tumor assessment in 20/24 responders, and are ongoing in 13 pts. Treatment is ongoing in 22 pts (13 NSCLC, 6 pancreas, 3 other solid tumors). Median DOR was 9.1 mo (95% CI, 5.2-12.0). Kaplan-Meier estimate of DOR rate at 6 mo was 70%. Among the 208 pts treated with Zeno monotherapy across all dosing schedules in the phase 2 setting, for individual adverse events irrespective of causality, grade ≥ 3 events were reported in <5% of pts. Conclusions: Zeno demonstrated robust and durable efficacy in pts with advanced NRG1+ cancer regardless of tumor histology. A well tolerated safety profile of Zeno was observed. Clinical trial information: NCT02912949.