Abstract 1212: Impact of KEAP1/STK11 co-mutations and NRF2 signaling on resistance to adagrasib in advanced NSCLC
Authors: Negrao Marcelo V. , Molkentine David , Paula Alvaro G. , Hover Laura , Nilsson Monique , Vokes Natalie , Engstrom Lars , Calinisan Andrew , Waters Laura , Briere David M. , Hallin Jill , Blumenschein George R. , Skoulidis Ferdinandos , Kopetz Scott E. , Hong David S. , Gibbons Don L. , Olson Peter , Christensen James , Heymach John V. 
Published: March 2024

Abstract
Background: KRAS G12C inhibitors (G12Ci) are revolutionizing the therapeutic landscape of advanced NSCLC, but mechanisms of limited clinical efficacy observed in some patients (pts) merit continued exploration. In the largest cohort of advanced KRAS G12C-mutant (KG12C) NSCLC pts treated with G12Ci, we demonstrated KEAP1 and STK11 co-mutations are enriched in early progression to G12Ci. Yet the independent predictive role of KEAP1 and STK11 co-mutations and the impact of enhanced NRF2 signaling in clinical outcomes to G12Ci remains incompletely characterized.
Methods: Clinico-genomic data were collected from 129 pts with advanced KG12C NSCLC treated with adagrasib (ada) (KRYSTAL-1 - NCT03785249). NRF2 signaling was estimated by NRF2 score (HTG transcriptome panel). Kaplan-Meier estimates of PFS and OS were assessed with log-rank test. Hazard ratios (HR) were estimated using Cox regression model. KG12C NSCLC cell lines and CDX/PDX models were used for pre-clinical experiments.
Results KEAP1 and STK11 co-mutations were each associated with significantly shorter survival upon ada treatment (KEAP1: PFS 4.1 vs 9.9 mo, HR 2.7, p&lt;0.01; OS 5.4 vs 19.0 mo, HR 3.6, p&lt;0.01; STK11: PFS 4.2 vs 11.0 mo, HR 2.2, p&lt;0.01; OS 9.8 mo vs not reached [NR], HR 2.6, p&lt;0.01). KEAP1WT/STK11WT status identified a group of pts with significantly longer PFS (16.85 mo) and OS (NR) upon treatment with ada. In cell viability and colony formation assays, KEAP1 re-expression sensitized all KEAP1MUT/STK11MUT KG12C NSCLC cell lines to ada treatment. Similar results were observed with STK11/LKB1 re-expression. KEAP1MUT was linked to limited response to ada across a broad panel of NSCLC PDX/CDX. In vivo drug anchored CRISPR screens in the ada-sensitive LU99 cell line identified KEAP1 as the most significant gene promoting resistance to ada. KEAP1 KO in the LU99 model determined early onset of ada resistance. In vitro drug screens showed high synergy scores and higher anti-tumor activity for mTOR inhibitor (mTORi) and ada combinations in KG12C KEAP1MUT/STK11MUT NSCLC. High NRF2 score was associated with significantly shorter survival with ada (PFS: 4.2 vs 8.4 mo, HR 2.0, p=0.02; OS: 6.5 vs 19.0 mo, HR 2.8, p&lt;0.01) even in KEAP1WT NSCLC pts. Integration of KEAP1WT, STK11WT and low NRF2 score status identified pts - 32% - with significant and meaningfully longer survival when treated with ada (PFS 12.0 vs 4.2 mo, HR 0.2, P&lt;0.01; OS NR vs 8.0 mo, HR 0.1, p&lt;0.01).
Conclusions: Co-mutations in KEAP1 and STK11 and NRF2 signaling define a subgroup of KG12C NSCLC pts with markedly distinct outcomes upon treatment with ada. The mTORi and ada combination shows high efficacy for targeting KG12C NSCLC harboring KEAP1 and STK11 co-mutations. The clinical safety and efficacy of mTORi nab-sirolimus and ada will be determined in the ongoing KRYSTAL-19 trial (NCT05840510).
Citation Format: Marcelo V. Negrao, David Molkentine, Alvaro G. Paula, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, Laura Waters, David M. Briere, Jill Hallin, George R. Blumenschein, Ferdinandos Skoulidis, Scott E. Kopetz, David S. Hong, Don L. Gibbons, Peter Olson, James Christensen, John V. Heymach. Impact of KEAP1/STK11 co-mutations and NRF2 signaling on resistance to adagrasib in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1212.