Abstract 660: Real-world prevalence of metastasis and overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) with KRAS G12C and with or without STK11 or KEAP1 mutations
Authors: Julian Cristina , Pal Navdeep , Gershon Anda , Evangelista Maria , Purkey Hans , Lambert Peter , Shi Zhen , Zhang Qing 
Published: July 2021

Introduction: KRAS mt are common in lung cancer, with G12C mt being the most prevalent in pts with aNSCLC. This study assessed pts with KRAS G12C aNSCLC with or without STK11 or KEAP1 mt.

Methods: Pts diagnosed with aNSCLC between Jan 2011 and Dec 2019 in the US-based de-identified Flatiron Health-Foundation Medicine clinico-genomic database were included. Cox proportional hazards models adjusted for baseline demographics and clinical characteristics were used to analyze the effect of mutational status on OS in pts receiving immunotherapy (CIT), chemotherapy (chemo) or both (CIT+chemo).

Results: Of 2217 1L pts, 454 (20.5%), 344 (15.5%) and 163 (7.4%) had tumors with KRAS G12C, STK11 and KEAP1 mt, respectively. Of 1019 2L pts, 234 (23.0%), 191 (18.7%) and 88 (8.6%) had tumors with KRAS G12C, STK11 and KEAP1 mt, respectively. A higher proportion of pts with KRAS G12C were females, PD-L1+ and had nonsquamous histology vs KRAS wildtype (WT) pts. Pts with KRAS G12C tumors had a higher cumulative incidence of mets (31.5% vs 25.8%) and brain mets (26.1% vs 18.8%) vs WT pts (P&lt;0.001). No statistically significant difference was seen in the association of KRAS status with OS when stratifying by treatment type. In KRAS WT pts, STK11 mt vs WT pts had shorter OS in 1L (6.1 vs 9.4 mo) and 2L (4.5 vs 7.6 mo; Table); a similar trend was seen for pts receiving 1L CIT+chemo. In KRAS G12C pts, KEAP1 mt vs WT pts had shorter OS in 1L (4.9 vs 13.4 mo) and 2L (1.8 vs 9.4 mo); similar differences were seen in pts receiving 1L CIT+chemo or chemo.

Conclusions: In pts with aNSCLC and KRAS WT, STK11 mt was associated with significantly worse OS; KRAS G12C co-occurring with KEAP1 mt had a similar result. Pts with STK11/KEAP1 mt have poor prognosis and high unmet medical need. This analysis highlights the importance of evaluating genomic alterations in clinical practice to better understand the interplay between treatment and survival.

Table. Effect of KRAS mutational status and co-occurring known and likely STK11 and/or KEAP1 mutations on OS in patients with aNSCLC receiving any type of 1L or 2L therapy1L*2L†nMedian, mo (95% CI)HR‡ (95% CI)nMedian, mo (95% CI)HR‡ (95% CI)KRAS G12CSTK11WT32412.0(9.6-16.0)1.30(0.97-1.75)1699.2(7.8-11.4)1.05(0.68-1.63)STK11mt1047.5 (5.1-10.9)545.5(2.5-15.7)KEAP1WT35413.4(10.6-16.2)2.98§(1.91-4.64)1829.4(8.1-13.1)4.02§(2.10-7.70)KEAP1mt304.9(3.1-7.8)141.8(1.5-10.2)KRAS WTSTK11WT14599.4(8.5-10.6)1.57§(1.31-1.87)8477.6(6.5-8.8)1.66§(1.31-2.11)STK11mt2406.1(5.2-7.8)1374.5(3.5-7.6)KEAP1WT14059.3(8.3-10.5)1.43§(1.15-1.78)8137.6(6.4-8.8)1.25(0.93-1.68)KEAP1mt1336.2(4.7-7.8)744.9(3.3-8.0)1L, first line; 2L, second line; aNSCLC, advanced non-small cell lung cancer; HR, hazard ratio; Mb, megabase; mt; mutation; OS, overall survival; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden; WT, wildtype.*Adjusted by age, sex, race, cancer type (de novo or recurrent), histology PD-L1 status, any metastases, TMB (mutations per Mb: &lt;10 and ≥10), histology and treatment type.†Adjusted by age, sex, race, cancer type (de novo or recurrent), histology, PD-L1 status, any metastases, TMB (mutations per Mb: &lt;16 and ≥16), histology and treatment type in 1L and 2L.‡HR comparing WT vs STK11 mt+ or KEAP mt+.§P&lt;0.001.

Citation Format: Cristina Julian, Navdeep Pal, Anda Gershon, Maria Evangelista, Hans Purkey, Peter Lambert, Zhen Shi, Qing Zhang. Real-world prevalence of metastasis and overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) with KRAS G12C and with or without STK11 or KEAP1 mutations [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 660.