Abstract 1008: Effect of the KRAS G12C inhibitor MK-1084 on circulating tumor DNA levels in participants with KRAS G12-mutated tumors

Abstract Background: Preliminary data from the phase 1 KANDLELIT-001 trial (NCT05067283) showed a manageable safety profile and preliminary antitumor activity for MK-1084, a next-generation, selective KRAS G12C-GDP covalent inhibitor, in participants (pts) with previously treated, KRAS G12C-mutant solid tumors. Here, we examine the effect of MK-1084 monotherapy on KRAS G12C variant allele frequency (VAF) and maximum somatic allele frequency (MSAF) ctDNA levels in pts with advanced KRAS G12C-mutant solid tumors during the monotherapy dose escalation phase of KANDLELIT-001. Methods: KANDLELIT-001 enrolled pts with any KRAS G12C-mutated advanced solid tumor to receive MK-1084 alone or in various combination therapies. Pts with any advanced solid tumor and ≥1 prior systemic therapy received MK-1084 monotherapy PO QD or BID in Arm 1 (total daily dose, 25-800 mg). Serial blood samples collected from pts enrolled in Arm 1 were evaluated for changes in ctDNA KRAS-G12C VAF and MSAF levels at baseline, and before beginning cycle 1 and cycle 3 using the Guardant Health OMNI panel. Differences in ctDNA levels were assessed using descriptive statistics. Results: In Arm 1, 22 of 23 pts were evaluable for changes in ctDNA levels. Median KRAS G12C VAF and MSAF ctDNA levels decreased ≥90% each from 14% to 0.9% and from 25% to 2%, respectively, from cycle 1 (pre-dose, day 0) to cycle 3 (day 42 on treatment); 6 (26%) pts achieved complete clearance of KRAS G12C VAF ctDNA. Greater reductions in tumor size were observed in pts who achieved complete clearance of KRAS G12C ctDNA. Larger reductions in ctDNA levels were seen in pts with a complete or partial response (responders) vs those with no response. Co-occurring mutations in PI3KCA, KEAP1, and KRAS G12D, Q61H, and BRAF were detected at baseline. Conclusions: In a cohort of 23 patients with KRAS G12C mutations receiving MK-1084 monotherapy, tumor response was associated with reductions in KRAS G12C VAF and MSAF ctDNA levels. This potentially reflects the molecular activity and therapeutic effect of MK-1084 in KRAS G12C-mutated tumors. The small sample size of this analysis limits interpretation of these findings. Citation Format: Carlos Rojas, Matteo Simonelli, Adrian Sacher, Mehmet Ali Sendur, Rafal Dziadziuszko, Joon Oh Park, Victor Moreno Garcia, Jair Bar, Yun Fan, Mustafa Erman, Shun Lu, Jenny H. Lee, Rosalyn A. Juergens, Bangwei Cao, Cai Chen, Razvan Cristescu, Thomas Jemielita, Yewon Sofia Choi, Mark D. Ayers, Iwona Lugowska. Effect of the KRAS G12C inhibitor MK-1084 on circulating tumor DNA levels in participants with KRAS G12-mutated tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1008.