Abstract 2137: Clinical utility of circulating tumor DNA in patients with advanced KRAS G12C-mutated NSCLC treated with sotorasib
Authors: Ernst Sophie M. , van Marion Ronald , Atmodimedjo Peggy N. , de Jonge Evert , Mathijssen Ron H. , Paats Marthe S. , de Bruijn Peter , van Schaik Ron H.N. , Dubbink Hendrikus J. , Dingemans Anne-Marie C. 
Published: April 2023

Abstract
Introduction: The CodeBreaK 200 trial showed that in patients (pts) with advanced KRAS G12C mutated (KRAS+) NSCLC sotorasib, a KRAS G12C-specific inhibitor, is superior to docetaxel for progression free survival (PFS) (HR 0.66) with a one-year PFS of 25%. We hypothesized that the detection of circulating tumor DNA (ctDNA) in plasma could allow for treatment response prediction and longitudinal monitoring. We analyzed serial plasma samples at baseline and within 3 months of start of sotorasib to evaluate ctDNA changes and correlation with clinical response.
Methods: Pts with sotorasib treated KRAS+ NSCLC were prospectively enrolled in our biomarker START-TKI study (NCT05221372) after written informed consent. Plasma samples were collected prior to treatment (T0) and at first response evaluation (T1). The TruSight Oncology 500 ctDNA panel was used for mutation detection in cell-free DNA (cfDNA). cfDNA KRAS/TP53/STK11/KEAP1 status was determined and compared to tumor tissue pathology reports to filter out false positives. Radiological response and PFS was assessed per RECIST 1.1.
Results: Between May 2021 and August 2022, 35 pts were included (table 1). Of these, 29 (83%) had detectable ctDNA KRAS G12C at T0, and 24 had both T0 and T1 samples. A decrease in variant allele frequency (VAF) at T1 compared to T0 was observed in 88% (n=21); 42% (n=10) showed complete clearance of ctDNA KRAS G12C. Six-months PFS was 83% in T0 negative pts (n=6) versus 43% in T0 positive pts (n=29); and 65% in pts with complete clearance (n=10) versus 14% in pts with incomplete clearance (n=11). VAF increase was seen in 3 pts, of which 1 had progression at T1.
Conclusions: In pts with KRAS+ NSCLC treated with sotorasib, baseline ctDNA and ctDNA clearance within 3 months of treatment correlated with treatment response. Pts with undetectable KRAS ctDNA at baseline, or with complete clearance at first evaluation, had superior PFS. PFS will be updated as follow-up duration extends.
Table 1. Patient cohort Liver metastasis KRAS p.G12C ctDNA at T0, median VAF % (range) KRAS p.G12C ctDNA at T1, median VAF % (range) Median change in VAF % (range) TP53/STK11/KEAP1 ctDNA T0 T1 response Reason EOT ꝉ Time on treatment (months) * Negative at T0 (n=6) No = 6 0 NE NE NE 1x PR; 4x SD; 1x PD 2x PD; 4x ongoing &gt;8 months 6 (1 - 11) Positive at T0 (n=29) No = 20; Yes = 9 2.6 (0.1 - 46.7) 0.6 (0.1 - 38.9) -95% (-100 - +39) 4x TP53; 2x STK11; 1x STK11●; 2x KEAP1; 2x KEAP1●; 2x TP53 + KEAP1; 1x TP53 + STK11● 4x PR; 21x SD; 2x PD; 2x NE 19x PD; 3x toxicity; 6x ongoing &gt;4 months; 1x loss to follow up 3 (1 - 15) Complete clearance at T1 (n=10) No = 6; Yes = 4 1.4 (0.1 - 8.4) 0 100% 2x TP53; 1x TP53 + KEAP1; 1x KEAP1; 1x KEAP1● 1x PR; 9x SD 6x PD; 1x toxicity; 2x ongoing &gt;6 months; 1x loss to follow up 5 (1 - 11) Incomplete clearance at T1 (n=11) No = 7; Yes = 4 3.6 (1.3 - 46.7) 0.4 (0.1 - 29.4) -89% (-23 - -99) 2x TP53; 1x STK11; 1x STK11●; 2x TP53 + STK11●; 1x TP53 + STK11 + KEAP1; 1x STK11 + KEAP1 3x PR; 7x SD; 1x PD 8x PD; 2x toxicity; 1x ongoing &gt;4 months 3 (1 - 8) Increase in VAF at T1 (n=3) No = 2; Yes = 1 1.0 (0.5 - 35.2) 1.1 (0.6 - 38.9) +11% (+10 - +39) 1x TP53●; 1x TP53 + KEAP1; 1x STK11● + KEAP1● 1x PD; 2x SD 3x PD 3 (1 - 15) Positive T0, no T1 available (n=5) No = 5 6.2 (0.3 - 24.6) NE NE 1x TP53; 1x TP53●; 1x KEAP1; 1x STK11 + KEAP1 3x SD; 2x NE 2x PD; 3x ongoing &gt;3 months 2 (1 - 3) NE = Not evaluated; ● = Positive cell-free DNA (cfDNA), not tested in tumor tissue; PR = Partial response; SD = Stable disease; PD = Progressive disease; EOT = End of treatment; ꝉ for PFS analysis patients who discontinued treatment due to toxicity were censored at treatment discontinuation, and patients with ongoing sotorasib treatment were censored at data cut off (16-Nov-2022); * = excluding ongoing patients.
Citation Format: Sophie M. Ernst, Ronald van Marion, Peggy N. Atmodimedjo, Evert de Jonge, Ron H. Mathijssen, Marthe S. Paats, Peter de Bruijn, Ron H.N. van Schaik, Hendrikus J. Dubbink, Anne-Marie C. Dingemans. Clinical utility of circulating tumor DNA in patients with advanced KRAS G12C-mutated NSCLC treated with sotorasib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2137.