Early changes in circulating cell free KRAS G12C predicts response to adagrasib in KRAS mutant non-small cell lung cancer patients

by Selleckchem | Sep 06 2023

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 KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C mutant lung cancer.

Experimental design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRASG12C-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 KRAS 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 KRAS 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 KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.

Comments:

The purpose of the study was to investigate the potential of non-invasive monitoring of circulating tumor DNA (ctDNA) as a means of predicting clinical response in patients with advanced, KRAS G12C mutant lung cancer. The researchers conducted a Phase 2 clinical trial, specifically focusing on the use of adagrasib.

The experimental design involved analyzing ctDNA using serial droplet digital PCR (ddPCR) and plasma next-generation sequencing (NGS). They examined the changes in ctDNA at two specific time intervals: between cycles 1 and 2, and at cycle 4. The researchers compared these ctDNA changes with the clinical and radiographic responses observed in the patients.

The results indicated that the maximal response in KRAS G12C ctDNA levels occurred within the initial three weeks of treatment, prior to the first scan at approximately six weeks. A significant decrease in KRAS G12C ctDNA (>90%) was observed in 35 patients (89.7%), and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients who achieved complete ctDNA clearance at cycle 2 exhibited an improved objective response rate (ORR) compared to those with incomplete ctDNA clearance (60.6% vs. 33.3%). Additionally, complete ctDNA clearance at cycle 4 was associated with improved overall survival (14.7 months vs. 5.4 months) and progression-free survival.

In conclusion, the findings suggest that early assessment of plasma response to KRAS G12C, approximately three weeks into treatment, can serve as an indicator of the likelihood of a favorable objective clinical response. Monitoring ctDNA changes could potentially provide a readily available measure for predicting treatment response in patients with KRAS G12C mutant lung cancer.