Abstract Background: NRG1 fusions represent a rare and potentially actionable oncogenic alteration found in ~0.2% of solid tumors. Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that blocks aberrant NRG1 fusion protein binding to HER3 thereby preventing ligand-dependent activation and dimerization resulting in complete inhibition of the PI3K/AKT and MAPK downstream signaling pathways. Seribantumab has shown significant anti-tumor activity in PDX models and in patients (pts) with solid tumors harboring NRG1 fusions. Methods: CRESTONE (NCT04383210) is a phase 2 study of seribantumab in adult pts with solid tumors harboring NRG1 fusions who received at least one prior therapy and were naïve to ERBB-targeted therapy (Cohort 1); pts previously treated with ERBB-targeted therapies (exploratory Cohort 2) and pts with tumors harboring additional molecular alterations (exploratory Cohort 3). Here, we present updated efficacy results for pts in Cohort 1 dosed at 3 g IV QW. Safety data are evaluated for pts enrolled in Cohort 1 and exploratory Cohorts 2 and 3. Results: As of Dec 2, 2022, 51 pts were enrolled across all cohorts with 30 pts in Cohort 1 dosed at 3 g IV QW. Median age was 62 years (range 19-84); median prior lines of therapy was 2 (range 1-7); tumor types included non-small cell lung cancer (NSCLC, n=30), pancreatic adenocarcinoma (PDAC, n=6), biliary tract/cholangiocarcinoma (CCA, n=6), breast (n=4), and others (n=5); 15 different NRG1 fusion partners were identified with CD74 (22%) and SLC3A2 (16%) as the most frequently reported. In the overall safety population, 41 pts (80%) reported at least one treatment-related adverse event (TRAE). The most common TRAEs (occurring in ≥20% of pts) were diarrhea (41%), fatigue (29%), rash (24%), and nausea (22%). Four pts (8%) experienced Gr 3/4 TRAEs; no Gr 5 TRAEs. The safety profile for Cohort 1 was similar to the overall safety population. Among the 30 pts in Cohort 1, 22 were evaluable for investigator assessed (INV) response per RECIST v1.1; 2 pts (9%) had confirmed complete response (CR), 6 pts (27%) had confirmed partial response (PR), and 13 pts (59%) had stable disease (SD) as their best overall response (BOR). The INV objective response rate (ORR, confirmed PR + CR) was 36% and disease control rate (DCR, confirmed PR+CR+SD) was 95%. The overall duration of response ranged from 1.4 to 17.2 months. In pts with NSCLC, the INV-ORR was 39% and DCR was 94%. Conclusions: Seribantumab has an acceptable safety and tolerability profile as a single agent in pts with solid tumors harboring NRG1 fusions. Updated efficacy data indicate seribantumab has robust and durable clinical activity, including CRs, across different tumor types harboring an NRG1 fusion and is a promising treatment option. Citation Format: Tejas Patil, Daniel R. Carrizosa, Mark E. Burkard, Karen L. Reckamp, Jayesh Desai, Young Kwang Chae, Stephen V. Liu, Kartik Konduri, Shirish M. Gadgeel, Jessica J. Lin, Parneet K. Cheema, David R. Spigel, Alison M. Schram, Valerie M. Jansen, Yasir Y. Elamin. CRESTONE: A Phase 2 study of seribantumab in adult patients with neuregulin-1 (NRG1) fusion positive locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT229.