3511 Background: Phase 3 CodeBreaK 300 (NCT05198934) explored two doses of sotorasib (soto) (240 mg and 960 mg) in combination with panitumumab (pani) 6 mg/kg versus investigator's choice (IC) and demonstrated superior progression-free survival (PFS) with soto 960 mg+pani versus IC in chemorefractory KRAS G12C-mutant mCRC. We evaluated whether early ctDNA clearance could serve as non-invasive biomarker of treatment (tx) response using one of the largest cohorts of mCRC patients (pts) treated with a KRAS G12C inhibitor plus an EGFR antibody and the only longitudinal ctDNA dataset from a KRAS G12C inhibitor trial in mCRC. Methods: ctDNA analyzed using the Guardant Infinity assay was quantified using KRAS G12C variant allele frequency (VAF) and methylation-based circulating tumor fraction (cTF) metrics. Clearance was defined at ≥50%, ≥80%, ≥90% and 100% reduction thresholds. Associations with objective response rate (ORR), PFS, and overall survival (OS) were assessed using logistic regression, Fisher-exact tests, Cox proportional hazards models, and Kaplan–Meier methods. Results: A total of 142 pts had evaluable baseline and Cycle 2 Day 1 ctDNA results. Early ctDNA clearance was more frequent in the soto arms than in the IC arm. This finding was consistent across ctDNA assessment methods, with high concordance between VAF and cTF. At ≥80% threshold, VAF clearance rates (95% CI) were 77.3% (62.2–88.5) and 65.9% (50.1–79.5) in the soto 960 mg and 240 mg arms (each N=44), respectively, compared with 15% (5.7–29.8) in the IC arm (N=40). Complete (100%) VAF clearance (95% CI) was observed in 45.5% (30.4–61.2), 31.8% (18.6–47.6), and 5.0% (0.6–16.9) of pts in the 960 mg, 240 mg, and IC arms, respectively. Reductions in ctDNA were correlated with radiographic tumor shrinkage. Lack of ctDNA clearance was associated with non-response, whereas pts achieving clearance were more likely to respond. Among pts treated with soto 960 mg who achieved ≥80% ctDNA clearance, the ORR (95% CI) by VAF was 35.3% (12/34; 19.7–53.5) and 32.3% (10/31; 16.7–51.4) by cTF. Decline in ctDNA was associated with improved PFS and OS independent of tx arm, confirming the role of ctDNA as a prognostic marker. Increasing clearance stringency did not enhance prognostic value. Conclusions: Early ctDNA clearance, assessed by KRAS G12C VAF or cTF, is prognostic for improved outcomes, supporting its utility as an early response biomarker. Clinical trial information: NCT05198934 . Survival (months) by VAF clearance (≥80%). Cohort VAF Clearance N mPFS (95% CI) mOS (95% CI) IC N 34 2.0 (1.9–4) 10.3 (6.6–14) IC Y 6 8.4 (3.7–NE) NE Soto 240 N 15 2.6 (1.8–3.8) 5.1 (3.2–7.5) Soto 240 Y 29 5.6 (3.8–8.5) 14.0 (8.4–NE) Soto 960 N 10 1.9 (1.6–3.8) 4.9 (1.6–7) Soto 960 Y 34 5.8 (5–7.5) NE (10.8–NE) m, median; NE, not evaluable; N, no; Y, yes.
Pietrantonio et al. (Wed,) studied this question.