Background: NRG1 fusions are oncogenic drivers across various cancers. NRG1 fusion proteins bind to HER3, leading to HER2/HER3 heterodimerization, increased downstream signaling, and tumor growth. Clinical responses to anti-HER3 antibodies or HER2 tyrosine kinase inhibitors have been reported. In contrast to these agents, MCLA-128 is a HER2/HER3 bispecific antibody that blocks both NRG1 binding and HER2/3 dimerization. Two patients with chemotherapy-resistant ATP1B1-NRG1-positive pancreatic KRAS-wild-type adenocarcinomas who received MCLA-128 through FDA-approved single-patient Investigational New Drug (IND) applications showed significant tumor shrinkage and durable tumor marker (CA-19-9) response. These data support the evaluation of MCLA-128 in NRG1 fusion-positive tumors using a basket approach. Methods: This is a global, open-label, multicenter phase 2 basket trial of MCLA-128 in patients with solid tumors harboring NRG1 gene fusions. Main eligibility criteria are locally advanced unresectable or metastatic cancers harboring an NRG1 fusion, and failure under prior standard therapy appropriate for the tumor type and disease stage. Genomic screening of tumor tissue is done at a local laboratory (with post-hoc central confirmation) or central laboratory (RNA sequencing). Three NRG1 fusion-positive tumor cohorts are being evaluated: pancreatic cancer, NSCLC, and other solid tumors. The sample size for the first two cohorts is up to 25 patients; the basket group may enroll up to 40 patients. The primary endpoint for all cohorts is investigator-assessed objective response rate (RECIST v1.1). The key secondary endpoint is duration of response. Other secondary endpoints include progression-free and overall survival. Eligible patients receive a bi-weekly dosing regimen of 750 mg of MCLA-128 (2-hour infusion), every 2 weeks, in 4-week cycles. The study is actively accruing patients in North America, Europe, and Asia. Previously presented at ESMO 2019, 685TiP, Schram et al.-Reused with permission. Clinical trial information: NCT02912949.