Abstract 3305: Notch mutations in subjects with recurrent or metastatic adenoid cystic carcinoma treated with rivoceranib from study RM-202

Abstract Background: Activating NOTCH mutations are present in approximately 20% of metastatic adenoid cystic carcinomas (ACC) leading to an aggressive tumor phenotype and poor clinical prognosis, yet less common pathogenic NOTCH mutations are poorly characterized. RM-202 was an international, single-arm, open-label phase 2 trial of oral VEGFR-2 tyrosine kinase inhibitor, rivoceranib, in patients with histologically confirmed recurrent or metastatic (R/M) ACC (Hanna et al. 2023 Clin Cancer Res 29(22): 4555). Herein, we report the mutational analysis NOTCH genes 1-4 (NOTCH1-4) in a subset of ACC samples from RM-202. Methods: Patients (n=72) enrolled in RM-202 received oral rivoceranib 700 mg once daily for a 28-day cycle. The co-primary endpoints were objective response rate (ORR) assessed by both investigator and a blinded independent review committee (BIRC). RNA seq was performed on ACC tumor samples from 27 patients. Complete coding sequences were analyzed with NOTCH1-4 variants identified and cross-referenced with Tempus and public databases to categorize mutations according to pathogenicity. Results: The investigator and BIRC assessed objective response rates were 15.3% (95%CI, 7.9-25.7) and 9.7% (95% CI, 4.0-19.0), respectively. The median duration of response was 14.9 months (95% CI, 4.9-17.3) and median progression free survival was 9.0 months (95% CI, 7.3-11.5). Grade 3 treatment related adverse events occurred in 70% of patients, with hypertension (42.5%) and stomatitis (7.5%) being the most common. A total of 477 variants were identified in NOTCH1-4 from 27 RM-202 ACC tumor samples, of which 463 (97%) mutants had been previously reported by Tempus DNA sequencing of germline and somatic variants across multiple tumor types. Three pathogenic NOTCH1 mutations (two nonsense mutations and 1 in-frame deletion) were identified across 2 tumor samples. Two of these mutations had not been previously reported in ACC. Forty-five additional non-synonymous variants were identified in NOTCH1-4. Of those, NOTCH4 L16 mutations occurred in 17/27 (63%) of tumors, with 12/27 (44%) tumors harboring L16 deletions, 4/27 (15%) of tumors with L16 duplications, and 1/27 (4%) that had both an L16 deletion and an L16 duplication. The frequency of L16 mutant sequences in tumors ranged from 8%-67% suggesting subclonal variation and potential pathogenicity. Conclusions: Previously unreported pathogenic NOTCH1-4 mutations were identified in ACC tumor samples from the RM-202 phase II trial. High rates of NOTCH4 L16 mutations suggest a novel mechanism of Notch pathway activation in ACC and represents a potential therapeutic target in this rare disease. Citation Format: Ari Rosenberg, James Bugni, Lissa Nazal, Chris Galloway, Kristin Ryan. Notch mutations in subjects with recurrent or metastatic adenoid cystic carcinoma treated with rivoceranib from study RM-202 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3305.