Abstract 924: The prognostic impact of the KRAS G12C-mutation in non-small cell lung cancer (NSCLC): a real-world analysis
Authors: Sun Lova , Kim Julia , Patel Shetal A. , Kang Yehrim , Pretre Vincent , Caro Nydia , Knoll Stefanie , Caparica Rafael , Ye Fen , Reckamp Karen L. 
Published: April 2023

Background: KRAS mutations occur in ~30% of NSCLC; KRAS G12C is the most common subtype (~40%). Limited data exist on the prognostic impact of KRAS G12C in NSCLC.

Methods: This retrospective study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-FMI CGDB; January 1, 2011-March 31, 2022). De-identified data originated from ~280 US cancer clinics (~800 sites of care). Patients (pts) were aged ≥18 years; had advanced (adv)/metastatic NSCLC; and had received 1L treatment (tx) initiated on or after October 1, 2016. Pts with EGFR, ALK, ROS1, BRAF, MET, or NTRK alterations were excluded. Key endpoints were overall survival (OS) and real-world progression-free survival (rwPFS). Propensity score matching and a multivariate Cox hazard model were used.

Results: Analyses included pts with KRAS G12C (n=847) and KRAS wild-type (WT; n=2679) NSCLC. In comparison to WT, pts with KRAS G12C were more likely to be female (56% vs 40%), former/current smokers (97% vs 93%), have non-squamous disease (91% vs 52%), have Stage IV disease at initial diagnosis (64% vs 56%), have brain metastases (22% vs 16%), have low (&lt;10 mut/Mb) tumor mutational burden (59% vs 51%), and have high (≥50%) PD-L1 expression (43% vs 23%). Overall, 39% of KRAS G12C, and 33% of WT received chemo (CT) + immunotherapy (IO) as 1L tx. More pts with KRAS G12C vs WT did not receive 2L tx (61% vs 54%). No significant differences were seen in rwPFS and OS between KRAS G12C and WT (Table 1). In pts receiving 1L CT + IO (n=1218), pts with KRAS G12C had shorter rwPFS compared with pts with WT (adjusted hazard ratio: 1.22; p=0.04). In pts with KEAP1 or STK11 mutations, co-mutation with KRAS G12C was associated with shorter OS.

Conclusions: Pts with KRAS G12C and WT had similar overall prognosis; however, those with KRAS G12C had worse rwPFS with CT + IO tx, as opposed to a trend in the opposite direction for pts treated with IO mono. KRAS G12C imposed worse prognosis vs WT in pts with STK11 or KEAP1 mutations.

Table 1. OS and rwPFS in the overall population and subgroups PSM-based comparisona KRAS G12C KRAS WT OS N 847b 1318b Median, months (95% Cl) 11.8 (10.2-14.1) 12.5 (11.6-14.0) HR (95% CI); p value 1.05 (0.91-1.21); 0.47 rwPFS N 846b,c 1317b,c Median, months (95% Cl) 5.5 (4.9-6.2) 5.6 (5.2-5.9) HR (95% CI); p value 1.06 (0.94-1.20); 0.33 Multivariate Cox proportional hazard modela Multivariate HRd (95% CI), KRAS G12C vs KRAS WT; p value OS All pts (N=3526) 1.05 (0.92-1.10); 0.47 KEAP1 mutation (n=506) 1.64 (1.17-2.00); &lt;0.01 STK11 mutation (n=523) 1.38 (1.02-1.86); 0.04 IO monotherapy in 1L (n=752) 0.86 (0.64-1.15); 0.32 CT + IO in 1L (n=1218) 1.15 (0.92-1.44); 0.22 rwPFS All pts (N=3526) 1.06 (0.94-1.20); 0.35 KEAP1 mutation (n=506) 1.51 (1.11-2.05); &lt;0.01 STK11 mutation (n=523) 1.25 (0.97-1.61); 0.09 IO monotherapy in 1L (n=752) 0.91 (0.71-1.17); 0.46 CT + IO in 1L (n=1218) 1.22 (1.01-1.49); 0.04 aRisk factors included in PSM and the multivariate Cox model: age, gender, race, ECOG performance status, smoking status, histology, stage at initial diagnosis, presence of brain metastases, PD-L1 expression category, and 1L treatment; bAll pts in KRAS G12C and WT populations in PSM (1 to up to 2 match); cAll patients with atleast 1 progression assessment; dMultivariate Cox model HR was based on complete case analyses, i.e., pts with non-missing data. CI, confidence interval; HR, hazard ratio; PSM, propensity score matching.

Citation Format: Lova Sun, Julia Kim, Shetal A. Patel, Yehrim Kang, Vincent Pretre, Nydia Caro, Stefanie Knoll, Rafael Caparica, Fen Ye, Karen L. Reckamp. The prognostic impact of the KRAS G12C-mutation in non-small cell lung cancer (NSCLC): a real-world analysis [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 924.