Abstract
Abstract Introduction: While tumor imaging has a fundamental role in drug development as a determinant of clinical response it may not always be a rapid measure of treatment effect. Changes in plasma ctDNA levels, on the other hand, has the potential to be a more readily available measure of response. Here we report on early plasma response measurements of KRAS G12C ctDNA by digital droplet PCR (ddPCR) in a Phase 2 trial of Adagrasib, a potent, orally available, small molecule covalent inhibitor of KRAS G12C, in patients with advanced non-small cell lung cancer with KRAS G12C mutation. Methods/Results: To study the timing of plasma response, we performed serial ddPCR on 60 KRAS G12C-mutant NSCLC patients that participated in cohort A of the KRYSTAL-1 phase 2 clinical trial. Cohort A evaluated adagrasib at 600 mg orally BID in patients with NSCLC previously treated with platinum-based chemotherapy. We analyzed the change in ctDNA levels at 2 specific intervals: between cycles 1 and 2 (i.e. initial change) and at start of cycles 4. Of 60 pts, 7 pts were excluded because of missing C1D1 draws, 13 pts were excluded for non-detectable KRAS G12C level at C1D1 and 1 patient was excluded because of a missing C2D1 draw leaving us with 39 evaluable patients for plasma response assessment. We found that most of the response in ctDNA could be seen during the initial 3-4 week treatment period, well before the first scan at 6-8 weeks. 38 pts (97.4%) showed any decrease in plasma levels from baseline levels. 35 patients (89.7%) show a decrease >90% and 33 pts (84.6%) achieved complete clearance at C2D1. Patients with complete ctDNA clearance at C2D1 showed improved ORR (60.6% vs 33.3%), while ctDNA clearance at C4 was associated with an improved survival (12.6 months vs 5.4 months) and PFS (HR 0.3). Conclusion: Our results support using early plasma response of KRAS G12C assessed at 2-3 weeks to inform the interpretation of initial imaging performed at 6-8 weeks Citation Format: Cloud Paweletz, Grace A. Heavey, Yanan Kuang, Thian Kheoh, Kenna Anderes, James Christensen, Pasi A. Jänne. Early changes in circulating cell free KRAS G12C as a possible blood-based response biomarker for adagrasib in non-small cell lung cancer (NSCLC). </title> [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A002.
Published Version
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