Abstract CT181: Clinical validation of plasma cell-free DNA (cfDNA) sequencing in the phase 2 trial of sotorasib in patients (pts) with KRAS p.G12C mutated NSCLC
Authors: Bauml Joshua M. , Li Bob T. , Velcheti Vamsidhar , Govindan Ramaswamy , Fontecedro Alessandra Curioni , Dooms Christophe , Takahashi Toshiaki , Duda Andrew W. , Odegaard Justin , Cruz-Guilloty Fernando , Jin Liming , Zhang Ying , Skoulidis Ferdinandos 
Published: July 2021

Abstract
Introduction The phase 2 CodeBreaK 100 trial evaluated the first-in-class KRASG12C inhibitor, sotorasib, in pts with advanced NSCLC. Pts were enrolled based on the positive KRAS p.G12C status, as determined using tissue-based Qiagen Therascreen KRAS RGQ PCR kit test. Guardant360 (G360) CDx utilizes circulating cfDNA from plasma for sequencing and has been approved by FDA as a companion diagnostic to detect genomic mutations in pts with solid tumors. In this study, we used data from the trial to compare the efficacy of sotorasib in pts positive for KRAS p.G12C by cfDNA with that in the overall population identified by tissue. The concordance between the two assays was evaluated. Methods Key inclusion criteria: centrally confirmed KRAS p.G12C and progression on prior therapies. Primary endpoint was objective response rate (ORR) assessed by central review. Pts who had adequate pretreatment plasma sample were included in the validation. Due to the lack of KRAS p.G12C-negative tissue specimens from the trial population, paired blood and tissue samples from an additional NSCLC cohort of pts were sourced for the concordance study. Results Overall, 126 pts were enrolled based on tissue result. 124 were evaluable for efficacy per central review. 77 of 107 evaluable pts eligible for G360 testing tested positive for KRAS p.G12C. The ORR was 37.1% in pts positive by tissue and 36.4% in those positive by cfDNA (Table). In 189 pts eligible for concordance study, the overall concordance was 81.5%, with positive and negative % agreements of 70.1% and 100.0%, respectively.
Conclusions In the phase 2 CodeBreaK 100 trial of sotorasib, efficacy in pts positive for KRAS p.G12C by the plasma-based G360 CDx was comparable to that in the overall population identified by tissue testing, with high concordance demonstrated between the two assays and a negative % agreement of 100%. Plasma cfDNA may be used to identify pts who may benefit from sotorasib.
cfDNA by G360 CDx N=77Tissue by Therascreen N=124Best overall response - n (%)Complete response0 (0.0)3 (2.4)Partial response28 (36.4)43 (34.7)Stable disease32 (41.6)54 (43.5)Progressive disease13 (16.9)20 (16.1)Not evaluable/Not done4 (5.2)4 (3.2)Objective response rate - % (95% Cl)36.4 (25.7, 48.1)37.1 (28.6, 46.2)
Citation Format: Joshua M. Bauml, Bob T. Li, Vamsidhar Velcheti, Ramaswamy Govindan, Alessandra Curioni Fontecedro, Christophe Dooms, Toshiaki Takahashi, Andrew W. Duda, Justin Odegaard, Fernando Cruz-Guilloty, Liming Jin, Ying Zhang, Ferdinandos Skoulidis. Clinical validation of plasma cell-free DNA (cfDNA) sequencing in the phase 2 trial of sotorasib in patients (pts) with KRAS p.G12C mutated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT181.