Background: NRG1 fusion proteins are oncogenic drivers in pancreas cancer and other solid tumors. They bind HER3, leading to HER2/HER3 heterodimerization and oncogenic transformation. The activity of zenocutuzumab (MCLA-128; zeno), a bispecific antibody targeting NRG1 fusion signaling in NRG1 fusion positive (NRG1+) cancers, is being evaluated in the ongoing global multicenter phase 2 part of the eNRGy study and a global early access program (EAP). Methods: Enrolled patients (pts) have advanced NRG1+ pancreas cancer, non-small cell lung cancer (NSCLC), and other solid tumors previously treated with standard therapy, are ≥ 18 years-old, have ECOG ≤1, adequate organ function, and measurable disease (RECIST v1.1). Zeno dosing: 750 mg IV every 2 weeks until progression or unacceptable toxicity. Primary endpoint: investigator (INV)-assessed objective response rate (ORR). Secondary endpoints: ORR per central independent radiologist review, duration of response (DOR), and safety. Tumor imaging is conducted every 8 weeks. Results: 51 pts with NRG1+ cancer have received zeno, 37 in the eNRGy study and 14 pts in the EAP. As of 12 Jan 2021, treatment is ongoing in 27/51 pts (8/13 pancreas, 10/25 NSCLC, 9/13 other solid tumors). Among the 51 pts, 10 pts with pancreas cancer, 18 pts with NSCLC, and 5 pts with other solid tumors had measurable disease and had the opportunity for ≥1 tumor assessment (TA) and are included in this analysis. Among the 10 pts with pancreas cancer, median age was 49 y (range 34-72), 50% were male, 6/4 pts had ECOG 0/1, and all had metastatic disease and were KRAS wild-type. The median number of prior therapies was 3 (range 1-6). The INV-assessed confirmed ORR was 40% (4/10; 90% CI, 15;70), and for this cohort of pts, responses occurred at the first TA. Tumor regression was seen in 7/10 pts, and the disease control rate was 90% (90% CI, 61-100). A CA 19-9 decline of ≥ 50% was observed in 9/9 (100%) pts. DOR is pending. In the overall NRG1+ population, tumor regression was observed in 25 of 33 pts and confirmed INV-assessed responses were seen in 9 of 33 pts (ORR 27%; 90% CI, 15;43), including in pts who previously received afatinib. Zeno was well tolerated with no pts requiring dose reduction for toxicity. Across all cohorts, for individual AEs, grade 3 events were reported in ≤5% of pts, and there was a notable lack of cardiotoxicity and severe gastrointestinal or skin toxicity. Updated data from all cohorts (pancreas, NSCLC, other solid tumors) will be presented. Conclusions: Zeno induces rapid and major radiologic tumor regression and biomarker responses in heavily-pretreated metastatic KRAS wild-type NRG1+ pancreas cancer, with minimal toxicity. Zeno is a promising novel targeted therapeutic option for pts with NRG1+ cancers. Clinical trial information: NCT02912949