1315MO Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC)

NRG1 fusions are rare oncogenic drivers of NSCLC and other solid tumors. These chimeric proteins bind HER3, leading to HER2/HER3 heterodimerization and oncogenic transformation. Zenocutuzumab (MCLA-128; Zeno) is a bispecific antibody that overcomes HER3-mediated NRG1 signaling in NRG1+ cancer. Zeno is being evaluated in the ongoing pivotal phase 2 eNRGy study and early access program (EAP). Updated NRG1+ NSCLC data are presented. Patients (pts) with advanced NRG1+ NSCLC determined by NGS, previously treated with or not candidate for standard therapy, age ≥ 18 y, ECOG PS ≤ 2, and measurable (RECIST v1.1) or evaluable disease were enrolled. Zeno (750 mg IV Q2W) was administered until disease progression or unacceptable toxicity. Tumor imaging was conducted Q8W. The primary endpoint is investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include duration of response (DOR) and safety. As of 01 Feb 2023, 85 pts with NRG1+ NSCLC (78 eNRGy/7 EAP) were enrolled. Efficacy was assessed in 65 pts who received ≥ 1 dose of Zeno and were enrolled by 01 Aug 2022 to allow for the opportunity for ≥ 6 months (mo) follow-up and met the criteria for the primary efficacy population. The median age was 64 y (range 32-86), 65% were female, 29%/63%/5% pts had ECOG PS 0/1/2 (missing 2 pts). Most were Asian (52%) or White (37%), 77% had visceral metastases, 98% had adenocarcinoma histology, and 1 pt had non-measurable disease. Common fusion partners were CD74 (52%) and SLC3A2 (23%). Pts received a median of 2 prior systemic therapies (range 0-6), 78% with platinum-based chemotherapy; 12% were treatment naïve. In the 64 pts with measurable disease, the confirmed ORR was 34% (22/64; 95% CI 23-47). 50/64 (78%) pts had target lesion reduction. Median DOR was 12.9 mo with responses ongoing in 11/22 (50%) pts. Kaplan-Meier estimate of 6-mo DOR rate was 79%. Among 85 pts treated with Zeno, Grade ≥ 3 individual AEs irrespective of causality occurred in < 4% pts. No pt discontinued Zeno for a treatment related AE. In this updated analysis, Zeno provides robust and durable efficacy in advanced NRG1+ NSCLC, with a well-tolerated safety profile.