Abstract CT021: Preliminary safety and clinical activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with previously treated KRAS G12D non-small cell lung cancer (NSCLC)

Abstract Background: Patients (pts) with previously treated advanced NSCLC have a high unmet medical need, with a median reported overall survival (OS) of <1 year. KRAS G12D mutations occur in approximately 4% of pts with NSCLC, for which there is currently no approved RAS-targeted therapy. Zoldonrasib (RMC-9805) is a potent, oral, covalent, RAS(ON) G12D-selective, tri-complex inhibitor targeting the active, GTP-bound state of RAS G12D isoforms. Here we present an updated analysis for zoldonrasib monotherapy in previously treated pts with KRAS G12D NSCLC from the ongoing Phase 1 Study (NCT06040541). Methods: Pts with KRAS G12D solid tumors received escalating zoldonrasib doses (150-1200 mg once daily [QD] or 300-600 mg twice daily). 1200 mg QD was identified as the recommended Phase 2 dose in NSCLC. Antitumor activity was assessed every 6 weeks for the first 24 weeks followed by every 9 weeks. Safety and tolerability are reported for all NSCLC pts (across all lines of therapy) treated at 1200 mg QD (N=40). Clinical efficacy is reported for pts with NSCLC treated at 1200 mg QD, who had received a prior immune checkpoint inhibitor and platinum chemotherapy (concurrent or sequential), and had not previously received docetaxel (N=27). Results: As of Dec 1, 2025, 40 pts were evaluated for safety and had received a median of 2 prior lines of therapy. 68% of pts had an ECOG status of 1 and 45% were never smokers. The median study follow up was 13.1 mo (range: 9.1, 19.9) in both the safety and efficacy populations. Treatment-related adverse events (TRAEs) occurring in ≥15% of pts were nausea (43%), vomiting (33%), diarrhea (30%), and rash (18%). TRAEs were primarily Grade 1 (58%) or Grade 2 (20%) in severity. Grade 3 TRAEs were reported in 13% of pts, including diarrhea (3%) and anemia (3%); no Grade 4 or 5 TRAEs were observed. TRAEs led to dose interruptions in 15% of pts, dose reductions in 3% of pts, and dose discontinuations in 5% of pts. The mean relative dose intensity was 94%. In the 27 pts evaluated for efficacy, the confirmed objective response rate was 52% (95% CI: 32, 71) and the disease control rate was 93% (95% CI: 76, 99). Median duration of response was not estimable (NE) (95% CI: 8.3m, NE). Median progression free survival was 11.1 mo (95% CI: 5.3, NE). The median OS was not reached (95% CI: NE, NE) with a 12 mo OS landmark rate of 73%. Conclusions: Zoldonrasib (1200 mg QD) demonstrated durable clinical efficacy in pts with previously treated KRAS G12D NSCLC with a favorable safety and tolerability profile, requiring minimal dose modification. Further evaluation of zoldonrasib in KRAS G12D NSCLC is ongoing both as monotherapy in previously treated pts and in combination with standard of care in treatment naive pts (NCT06162221). Citation Format: Jonathan Riess, Eric B. Haura, Rona Yaeger, Melissa Johnson, Jia Luo, Aparna R. Parikh, Douglas Orr, Salman R. Punekar, Kyriakos Papadopoulos, John H. Strickler, John Powderly, Judy S. Wang, Patricia LoRusso, Alexander Spira, Maria Filippou-Frye, Hina Patel, Satwant Lally, Michelle Yang, David S. Hong, Kathryn C. Arbour. Preliminary safety and clinical activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with previously treated KRAS G12D non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT021.