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Clinical Trial
. 2024 Sep 3;30(17):3788-3797.
doi: 10.1158/1078-0432.CCR-24-0255.

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

Yoonha Choi  1 , Neekesh V Dharia  1 , Tomi Jun  1 , Julie Chang  1 , Stephanie Royer-Joo  1 , Kenneth K Yau  2 , Zoe J Assaf  1 , Junko Aimi  1 , Smruthy Sivakumar  3 , Meagan Montesion  3 , Adrian Sacher  4   5   6 , Patricia LoRusso  7 , Jayesh Desai  8 , Jennifer L Schutzman  1 , Zhen Shi  1 ; and the GO42144 study group
Affiliations
Clinical Trial

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

Yoonha Choi et al. Clin Cancer Res. .

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.

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Conflict of interest statement

Y. Choi reports personal fees from Genentech and F. Hoffmann La Roche outside the submitted work. N.V. Dharia reports other support from Genentech Inc., a member of the Roche Group, during the conduct of the study. T. Jun reports other support from Genentech during the conduct of the study and from Sema4 outside the submitted work. J. Chang reports other support from Genentech outside the submitted work. S. Royer-Joo reports other support from Genentech/Roche during the conduct of the study. K.K. Yau reports being an employee (and shareholder) of Hoffmann-La Roche Ltd. as noted in the author affiliations. Z.J. Assaf reports other support from Roche/Genentech during the conduct of the study and from Roche/Genentech outside the submitted work. J. Aimi reports other support from Roche/Genentech during the conduct of the study. S. Sivakumar reports personal fees from Foundation Medicine and other support from Roche during the conduct of the study. M. Montesion reports personal fees from Foundation Medicine and Roche Holding AG outside the submitted work. A. Sacher reports being a member of the Consulting and Advisory Board (no personal fees) for AstraZeneca, Genentech-Roche, Merck, and Amgen as well as being an Institutional Research and Clinical Trial PI for AstraZeneca, Amgen, Genentech, Merck, Lilly, Pfizer, BMS, Spectrum, GSK, Iovance, CRISPR Therapeutics, BridgeBio, HotSpot Therapeutics, and AdaptImmune. P. LoRusso reports other support from AbbVie, Roche-Genentech, Takeda, SOTIO, Agenus, IQVIA, Pfizer, GlaxoSmithKline, QED Therapeutics, AstraZeneca, EMD Serono, Kyowa Kirin Pharmaceutical Development, Kineta, Zentalis Pharmaceuticals, Molecular Templates, ABL Bio, STCube Pharmaceuticals, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanistic, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, Roivant Sciences, NeuroTrials, Actuate Therapeutics, Atreca Development, Amgen CodeBreak 202, Cullinan, DrenBio, Quanta Therapeutics, Schrodinger, and Boehringer Ingelheim outside the submitted work. J. Desai reports grants, personal fees, and non-financial support from BeiGene, Amgen, and from Roche/Genentech during the conduct of the study; personal fees from Pierre-Fabre, Bayer, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, Pfizer, Ellipses Pharma, and from Incyte outside the submitted work; grants and non-financial support from GlaxoSmithKline and AstraZeneca; and non-financial support from Bristol Myers Squibb. J.L. Schutzman reports other support from Genentech during the conduct of the study. Z. Shi reports other support from Roche/Genentech during the conduct of the study.

Figures

Figure 1.
Figure 1.
ctDNA profiling in the phase I GO42144 study, single-agent divarasib treatment arms. A, Diagram depicting plasma sample collection time points for ctDNA profiling. B, Venn diagram showing the number of ctDNA-evaluable samples at baseline (C1D1) and early on-treatment time points (C1D15 and C3D1). C, CONSORT diagram for ctDNA profiling.
Figure 2.
Figure 2.
Association of baseline ctDNA tumor fraction with disease and clinical characteristics. A, Box plot showing baseline ctDNA tumor fraction by tumor type. B, Box plot showing baseline ctDNA tumor fraction by tumor type and the KRAS G12C mutation detectability in plasma samples. C, Scatter plot showing the association between ctDNA tumor fraction and tumor volume (SLD of target lesion) at baseline. D, Box plot showing baseline ctDNA tumor fraction by number of metastatic sites. E–G, Box plot showing baseline ctDNA tumor fraction by site of metastasis among patients with NSCLC (E) and colorectal cancer (F and G), respectively. H, Box plot showing baseline ctDNA tumor fraction by prior lines of systemic therapy. For the box and whisker plots in A, B, D–H, the center line represents the median, the (top) and (bottom) of the box the interquartile range, and the Ι bars 1.5 times the interquartile range.
Figure 3.
Figure 3.
Association of baseline ctDNA tumor fraction with confirmed ORR and PFS. A and B, Confirmed ORR (A) and Kaplan–Meier curves showing PFS (B) by baseline ctDNA tumor fraction in patients with NSCLC and colorectal cancer, respectively. The 95% CI is shown in the square brackets. mPFS, median PFS.
Figure 4.
Figure 4.
Association of ctDNA tumor fraction dynamics with best overall response and PFS. A and B, Shown are ctDNA tumor fraction at baseline (C1D1) and early on-treatment time points (C1D15 and C3D1) according to the best response among patients with measurable disease at baseline. Each line represents one patient. A, NSCLC: CR/PR, n = 18; SD/PD, n = 7; B, colorectal cancer: PR, n = 15; SD/PD, n = 22. C and D, Shown are changes in ctDNA tumor fraction from baseline to C1D15 or C3D1 according to the best overall response among patients with NSCLC (C) or colorectal cancer (D) with measurable disease at baseline. For the box and whisker plots in A–D, the center line represents the median, the top and bottom of the box the interquartile range, and the Ι bars 1.5 times the interquartile range. E, Forest plot showing the PFS HR (95% CI) in patients with a ctDNA reduction ≥ median vs. a ctDNA reduction < median. F and G, Kaplan–Meier curves showing PFS according to the ctDNA dynamics in patients with NSCLC (F) and colorectal cancer (G). mPFS with 95% CI in the square brackets were shown.
Figure 5.
Figure 5.
Rare cases of KRAS G12C mutation heterogeneity. A and B, Scatter plot showing the association between the change in ctDNA tumor fraction and changes in KRAS G12C VAF from baseline (C1D1) to C1D15 (A) or C3D1 (B). C–E, Shown are three cases where the KRAS G12C mutation was identified to be subclonal. Spaghetti plot showing the VAF of specific RAS/RAF oncogenic driver mutations, TP53 alterations, and overall ctDNA tumor fraction as assessed by longitudinal ctDNA profiling.
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