Abstract 918: Real-world clinical characteristics and treatment (tx) outcomes by co-mutation status in patients (pts) with KRAS G12C-mutated non-small cell lung cancer (NSCLC)
Authors: Negrao Marcelo V. , Wu Wen-Hsing , Lindsay Colin R. , Caparica Rafael , Prêtre Vincent , Kang Yehrim , Caro Nydia , Farago Anna , Ye Fen , Castro Gilberto de 
Published: April 2023

Background: KRAS mutations occur in ~30% of NSCLC and KRAS G12C is the most common subtype (~40%). Co-mutations can impact NSCLC prognosis and tx response.

Methods: This retrospective study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB; January 1, 2011 to March 31, 2022). De-identified data originated from ~280 US cancer clinics (~800 sites of care). This study is based on tissue-based assay (FoundationOne CDx). Pts were aged ≥18 years; had KRAS G12C-mutated, advanced/metastatic NSCLC, and had received ≥1 line of tx, with 1L tx initiated after October 1, 2016. Pts were categorized by presence (m) or absence (wt) of single co-mutations in STK11, KEAP1, or TP53; pts with EGFR, ALK, ROS1, BRAF, MET, or NTRK alterations were excluded. Key endpoints included overall survival (OS) and real-world progression-free survival (rwPFS). Statistical methods included a univariate Cox hazard model.

Results: Among 847 pts with KRAS G12C-mutated NSCLC, co-mutations of STK11 were seen in 24%, KEAP1 in 14%, and TP53 in 51%. Based on non-missing records (82%), low tumor mutational burden (&lt;10 mut/Mb) was more frequent in the STK11m vs wt group (72% vs 55%; p&lt;0.001), not significantly different in the KEAP1m vs wt group (53% vs 60%; p=0.145), and less frequent in pts with TP53m vs wt (50% vs 69%; p&lt;0.001). Negative PD-L1 status (&lt;1%) was more frequent in pts with STK11 (50% vs 18%; p&lt;0.001) or KEAP1 (41% vs 23%; p&lt;0.001) mutations, and less frequent in pts with TP53 mutations (15% vs 37%; p&lt;0.001). STK11 or KEAP1 co-mutations were associated with shorter rwPFS and OS, particularly in pts treated with immunotherapy (IO)-based 1L tx (Table 1). TP53 status did not significantly impact pt outcomes in the 1L setting.

Conclusions: In this real-world analysis, STK11 or KEAP1 co-mutations were associated with PD-L1-negative tumors and poor outcomes with IO-based tx in KRAS G12C-mutated NSCLC.

Table 1. rwPFS and OS by co-mutation status, and OS by 1L treatment and co-mutation status rwPFS and OS by co-mutation status rwPFS All (N=846) STK11m (n=206) STK11wt (n=640) KEAP1m (n=121) KEAP1wt (n=725) TP53m (n=429) TP53wt (n=417) Median, months (95% CI) 5.0 (4.5-5.7) 4.0 (3.1-4.9) 5.6 (4.9-6.2) 3.8 (2.7-4.8) 5.6 (4.7-6.2) 5.3 (4.6-6.1) 4.7 (4.0-5.7) HR (95% CI); p value - 1.38 (1.16-1.64); &lt;0.001 1.46 (1.18-1.80); &lt;0.001 0.87 (0.75-1.01); 0.07 OS All (N=847) STK11m (n=206) STK11wt (n=641) KEAP1m (n=121) KEAP1wt (n=726) TP53m (n=429) TP53wt (n=418) Median, months (95% CI) 11.9 (10.2-14.3) 9.4 (7.2-13.8) 12.4 (10.8-15.0) 7.6 (5.4-9.4) 13.5 (11.0-15.1) 11.0 (9.2-14.4) 12.7 (10.4-15.3) HR (95% CI); p value - 1.40 (1.15-1.70); &lt;0.001 1.59 (1.26-2.00); &lt;0.001 0.98 (0.83-1.17); 0.85 OS by 1L treatment and co-mutation status IO + chemotherapy STK11m (n=106) STK11wt (n=228) KEAP1m (n=53) KEAP1wt (n=281) TP53m (n=162) TP53wt (n=172) Median, months (95% CI) 6.9 (4.5-9.4) 11.3 (9.0-14.8) 7.9 (4.5-10.3) 10.2 (7.7-12.9) 9.3 (6.6-11.9) 10.9 (7.2-14.0) HR (95% CI); p value 1.75 (1.33-2.31); &lt;0.0001 1.60 (1.13-2.26); 0.01 1.04 (0.80-1.36); 0.75 IO monotherapy STK11m (n=33) STK11wt (n=181) KEAP1m (n=29) KEAP1wt (n=185) TP53m (n=111) TP53wt (n=103) Median, months (95% CI) 9.7 (2.8-16.9) 16.1 (10.7-23.3) 5.7 (3.9-14.3) 16.6 (10.8-23.0) 15.1 (9.1-22.4) 14.6 (8.9-23.0) HR (95% CI); p value 1.54 (0.97-2.46); 0.07 1.81 (1.12-2.90); 0.01 0.96 (0.68-1.37); 0.83 Chemotherapy only STK11m (n=56) STK11wt (n=188) KEAP1m (n=28) KEAP1wt (n=216) TP53m (n=130) TP53wt (n=114) Median, months (95% CI) 18.6 (10.2-22.8) 13.5 (9.5-15.3) 7.8 (5.0-17.4) 14.5 (11.1-16.3) 12.0 (8.9-16.0) 15.0 (11.1-19.5) HR (95% CI); p value 0.84 (0.57-1.25); 0.40 1.31 (0.82-2.10); 0.26 1.12 (0.81-1.54); 0.49 CI, confidence interval; HR, hazard ratio.

Citation Format: Marcelo V. Negrao, Wen-Hsing Wu, Colin R. Lindsay, Rafael Caparica, Vincent Prêtre, Yehrim Kang, Nydia Caro, Anna Farago, Fen Ye, Gilberto de Castro Jr. Real-world clinical characteristics and treatment (tx) outcomes by co-mutation status in patients (pts) with KRAS G12C-mutated non-small cell lung cancer (NSCLC) [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 918.