Abstract LB218: Early reduction in circulating tumor DNA (ctDNA) is associated with clinical activity of daraxonrasib (RMC-6236) in RAS mutant non-small cell lung cancer (NSCLC)

Background: Patients with previously treated NSCLC have a high unmet medical need, with a reported median overall survival (OS) of <1 year. RAS mutations are the most common driver mutation found in approximately 30% of patients with NSCLC. Daraxonrasib (RMC-6236) is an oral, RAS(ON), multi-selective, noncovalent, tri-complex inhibitor of GTP-bound mutant and wild-type RAS. As of a 30 Sep 2024 data cutoff, daraxonrasib monotherapy demonstrated manageable safety and tolerability at 120-220 mg QD with few ≥Grade (G) 3 treatment-related adverse events in ≥ 2 patients (rash [6.8%], vomiting and anemia [2.7% each]), and no G4 or 5 TRAEs. Encouraging clinical activity was seen at 120-220 mg (confirmed ORR=38%, median PFS=9.8 months, and median OS=17.7 months). Here, we present an exploratory analysis of ctDNA from patients with NSCLC treated with daraxonrasib. Methods: Patients with advanced RAS mutant tumors were treated in the Phase 1 study (NCT05379985). Dose optimization was performed at 120-300 mg. In NSCLC, 300 mg was not considered for further development due to a less favorable tolerability profile and reduced dose intensity; 200 mg daily is the proposed dose for NSCLC. The efficacy evaluable population (EE, N=40) was defined as patients with RAS G12X mutant (nonsynonymous mutations at codon 12 in K, H, or NRAS) NSCLC treated with 120-220 mg, receiving 1 or 2 prior lines of therapy, including prior immunotherapy and platinum chemotherapy, who have not received docetaxel previously. Responses were assessed per RECIST v1.1. Paired plasma samples (collected at baseline and day 1 of cycle 2 or 3) were analyzed, by Guardant Infinity, for changes in RAS mutant variant allele frequency (VAF) in ctDNA. Results: As of September 30, 2024, paired plasma samples were tested from 54 patients with RAS G12X mutant NSCLC who received 120-220 mg daily daraxonrasib as second line or later therapy. A RAS G12X mutant allele was detected in baseline ctDNA in 59% (32/54) of patients. In these patients, response or stable disease (SD) was observed across a wide range of baseline RAS mutant VAFs (0.04-52.05% VAF). Complete ctDNA clearance (i.e., 100% RAS VAF decrease from baseline) was seen in 89% (8/9) of responders, 70% (14/20) of patients with SD, and 0% (0/3) of patients with progressive disease (PD), across different RAS G12X mutations. In contrast, incomplete ctDNA clearance was seen in 11% (1/9) of responders, 30% (6/20) of patients with SD, and all patients with PD (p=0.018, Freeman-Halton Fisher exact test). In the EE, 23 patients were ctDNA evaluable; complete ctDNA clearance was seen in 86% (6/7) of responders and 63% (10/16) of patients with SD. Conclusions: These data demonstrate that clinical response to the multi-selective, RAS(ON) inhibitor, daraxonrasib, is associated with early on-treatment complete clearance of ctDNA for multiple RAS G12X mutations in NSCLC. Citation Format: Jia Luo, Salman R. Punekar, Kathryn C. Arbour, Melissa Johnson, Alex Spira, Ignacio Garrido-Laguna, Jonathan W. Goldman, Benjamin Herzberg, Sai-Hong Ignatius Ou, Dae Won Kim, Lijia Wang, Li Cheng, Vidya Seshadri, Sumit Kar, Minoti Hiremath, David S. Hong. Early reduction in circulating tumor DNA (ctDNA) is associated with clinical activity of daraxonrasib (RMC-6236) in RAS mutant non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB218.