Data from Early changes in circulating cell free <i>KRAS</i> G12C predicts response to adagrasib in KRAS mutant non-small cell lung cancer patients

Abstract

<div>Abstract<p>Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here we report on early ctDNA changes of <i>KRAS </i>G12C in a Phase 2 trial of adagrasib in patients with advanced, <i>KRAS</i> G12C mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 <i>KRAS</i>G12C-mutant lung cancer patients that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared to clinical and radiographic response. Results: We found that, in general, a maximal response in <i>KRAS </i>G12C ctDNA levels could be observed during the initial ~3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in <i>KRAS </i>G12C cfDNA >90% and 33 pts (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared to patients with incomplete ctDNA clearance (60.6% vs 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 months vs 5.4 months) and progression free survival (HR 0.3). Conclusion: These results support using early plasma response of <i>KRAS</i> G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.</p></div>