Abstract 412: Correlation of drug sensitivity to clinical response in XPDX models established from patients treated with KRAS-G12C-inhibitor therapy
Authors: Flores Johnnie , Simonson Alyssa , Forofontov Peter , Stackpole Anna , Rasco Drew , Patnaik Amita , Papadopoulos Kyriakos , DesRochers Teresa , Williams Natalie , Drengler Ronald , Smith Lon , Wick Michael J. 
Published: June 2022

Abstract
Background: We previously reported (RAS AACR 2022) a preclinical screen testing KRASG12C-inhibitors (KRASG12C-i) in 13 colorectal and 13 lung KRASG12C XPDX models; all tested models were from patients naïve to KRASG12C-i. To better understand mechanisms of resistance in this agent class, we established three lung XPDX models designated ST5185B, ST5431B, and ST5489 from patients before therapy with a KRASG12C-i. We also established one colorectal XPDX, designated ST4859, post therapy. Once established these models were molecularly characterized, in vivo sensitivity to sotorasib and adagrasib determined, and results compared with clinical response. Ex vivo cultures and 3D-XPDX࣪ studies were also performed evaluating both compounds comparing drug sensitivity.
Methods: Lung: ST5185B was established from a pretreated 68-year-old male; ST5431B was established from a chemo-naïve 67-year-old male; additional samples were collected during and after progression on KRASG12C-i and are currently in development. ST5489 was established from a pretreated 64-year-old female. CRC: ST4859 was established from a 57-year-old female pretreated with a KRASG12C-i; all patients received at least one cycle of KRASG12C-i therapy. Models were WES and RNA sequenced and sotorasib and adagrasib sensitivity determined. For each study, agents were dosed PO once daily at 100 mg/kg; study endpoints included tumor volume and time from treatment initiation with %T/C values reported at study completion; a %T/C of ≤ 20% was considered sensitive.
Results: In all models sequencing confirmed KRASG12C and other variants previously identified with clinical studies. In vivo studies identified ST5185B as resistant to sotorasib (%T/C=70%) and adagrasib (%T/C=86%); this donor patient progressed after six weeks on KRASG12C-i therapy. ST5431B reported sensitivity to both therapies; this donor patient had a partial response (50% decrease) for six months prior to progression. ST5489 reported sensitivity to sotorasib (%T/C=14%) and adagrasib (%T/C=8%); this donor patient interrupted dosing due to KRASG12C-i intolerance and discontinued therapy, with disease progression after five weeks. ST4859 reported resistance to both drugs; this donor patient had stable disease on KRASG12C-i therapy for approximately seven months prior to progression. Ex vivo cultures and 3D-XPDX࣪ studies from all models reported sensitivity to both agents similar to in vivo studies.
Summary: We developed, evaluated, and correlated in vivo sensitivity of sotorasib and adagrasib in a panel of four XPDX models established from patients receiving KRASG12C-i therapy. Studies are underway to generate drug-resistant clones of sensitive models and to elucidate mechanisms of drug resistance in ST4859.
Citation Format: Johnnie Flores, Alyssa Simonson, Peter Forofontov, Anna Stackpole, Drew Rasco, Amita Patnaik, Kyriakos Papadopoulos, Teresa DesRochers, Natalie Williams, Ronald Drengler, Lon Smith, Michael J. Wick. Correlation of drug sensitivity to clinical response in XPDX models established from patients treated with KRAS-G12C-inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 412.