Circulating Tumor DNA Dynamics Reveal KRAS G12C Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors

Choi, Y; Dharia, NV; Jun, T; Chang, J; Royer-Joo, S; Yau, KK; Assaf, ZJ; Aimi, J; Sivakumar, S; Montesion, M; Sacher, A; LoRusso, P; Desai, J; Schutzman, JL; Shi, Z; GO42144 study group

Author(s): Choi, Y; Dharia, NV; Jun, T; Chang, J; Royer-Joo, S; Yau, KK; Assaf, ZJ; Aimi, J; Sivakumar, S; Montesion, M; Sacher, A; LoRusso, P; Desai, J; Schutzman, JL; Shi, Z; GO42144 study group;
Details: Publication Year 2024-09-03,Volume 30,Issue #17,Page 3788-3797
Journal Title: Clinical Cancer Research
Publication Type: Research article
Abstract: PURPOSE: To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. EXPERIMENTAL DESIGN: Plasma samples were collected for serial ctDNA profiling at baseline (cycle 1 day 1 prior to treatment) and multiple on-treatment time points (cycle 1 day 15 and cycle 3 day 1). RESULTS: KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as cycle 1 day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. CONCLUSIONS: Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.
Publisher: American Association for Cancer Research
Keywords: Humans; *Circulating Tumor DNA/genetics/blood; *Proto-Oncogene Proteins p21(ras)/genetics; *Mutation; Female; Male; Middle Aged; Aged; *Biomarkers, Tumor/genetics; Neoplasms/genetics/drug therapy/pathology/blood; Prognosis; Adult; Genetic Heterogeneity; Treatment Outcome; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung/genetics/drug therapy/pathology/blood
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1158/1078-0432.Ccr-24-0255
Open Access at Publisher's Site: https://doi.org/10.1158/1078-0432.Ccr-24-0255
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-09-10 04:41:09

Last Modified: 2024-09-10 04:41:22