Early Changes in Circulating Cell-Free KRAS G12C Predict Response to Adagrasib in KRAS Mutant Non–Small Cell Lung Cancer Patients

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 KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C-mutant lung cancer.We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRAS G12C-mutant patients with lung cancer 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 with clinical and radiographic response.We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial approximately 3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA >90% and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared with 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 vs. 5.4 months) and progression-free survival (HR, 0.3).These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.