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. 2022 Mar;17(3):399-410.
doi: 10.1016/j.jtho.2021.10.013. Epub 2021 Nov 2.

Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status

Biagio Ricciuti  1 , Kathryn C Arbour  2 , Jessica J Lin  3 , Amir Vajdi  4 , Natalie Vokes  1 , Lingzhi Hong  5 , Jianjun Zhang  5 , Michael Y Tolstorukov  4 , Yvonne Y Li  6 , Liam F Spurr  6 , Andrew D Cherniack  6 , Gonzalo Recondo  1 , Giuseppe Lamberti  1 , Xinan Wang  7 , Deepti Venkatraman  1 , Joao V Alessi  1 , Victor R Vaz  1 , Hira Rizvi  2 , Jacklynn Egger  2 , Andrew J Plodkowski  8 , Sara Khosrowjerdi  3 , Subba Digumarthy  3 , Hyesun Park  9 , Nuno Vaz  9 , Mizuki Nishino  9 , Lynette M Sholl  10 , David Barbie  1 , Mehmet Altan  5 , John V Heymach  5 , Ferdinandos Skoulidis  5 , Justin F Gainor  3 , Matthew D Hellmann  2 , Mark M Awad  11
Affiliations

Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status

Biagio Ricciuti et al. J Thorac Oncol. 2022 Mar.

Abstract

Introduction: STK11 and KEAP1 mutations (STK11 mutant [STK11MUT] and KEAP1MUT) are among the most often mutated genes in lung adenocarcinoma (LUAD). Although STK11MUT has been associated with resistance to programmed death-(ligand)1 (PD-[L]1) inhibition in KRASMUT LUAD, its impact on immunotherapy efficacy in KRAS wild-type (KRASWT) LUAD is currently unknown. Whether KEAP1MUT differentially affects outcomes to PD-(L)1 inhibition in KRASMUT and KRASWT LUAD is also unknown.

Methods: Clinicopathologic and genomic data were collected from September 2013 to September 2020 from patients with advanced LUAD at the Dana-Farber Cancer Institute/Massachusetts General Hospital cohort and the Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center cohort. Clinical outcomes to PD-(L)1 inhibition were analyzed according to KRAS, STK11, and KEAP1 mutation status in two independent cohorts. The Cancer Genome Atlas transcriptomic data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 comutation status.

Results: In the combined cohort (Dana-Farber Cancer Institute/Massachusetts General Hospital + Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center) of 1261 patients (median age = 61 y [range: 22-92], 708 women [56.1%], 1065 smokers [84.4%]), KRAS mutations were detected in 536 cases (42.5%), and deleterious STK11 and KEAP1 mutations were found in 20.6% (260 of 1261) and 19.2% (231 of 1202) of assessable cases, respectively. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free (STK11 hazard ratio [HR] = 2.04, p < 0.0001; KEAP1 HR = 2.05, p < 0.0001) and overall (STK11 HR = 2.09, p < 0.0001; KEAP1 HR = 2.24, p < 0.0001) survival to immunotherapy uniquely among KRASMUT but not KRASWT LUADs. Gene expression ontology and immune cell enrichment analyses revealed that the presence of STK11 or KEAP1 mutations results in distinct immunophenotypes in KRASMUT, but not in KRASWT, lung cancers.

Conclusions: STK11 and KEAP1 mutations confer worse outcomes to immunotherapy among patients with KRASMUT but not among KRASWT LUAD. Tumors harboring concurrent KRAS/STK11 and KRAS/KEAP1 mutations display distinct immune profiles in terms of gene expression and immune cell infiltration.

Keywords: KEAP1; KRAS; NSCLC; PD-(L)1 blockade; STK11.

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Figures

Figure 1.
Figure 1.
PD-L1 expression according to (A) KRAS/STK11 comutation status and (B) KRAS/KEAP1 comutation status, in the DFCI/MGH, MSKCC/MDACC, and combined cohorts. (C) Tumor mutational burden according to KRAS/STK11 comutation status, in the DFCI/MGH, MSKCC/MDACC, and combined cohorts. (D) Tumor mutational burden according to KRAS/KEAP1 comutation status, in the DFCI/MGH, MSKCC/MDACC, and combined cohorts. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. DFCI, Dana-Farber Cancer Institute; MDACC, MD Anderson Cancer Center; MGH, Massachusetts General Hospital; MSKCC, Memorial Sloan Kettering Cancer Center; NS, not significant; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden; TPS, tumor proportion score
Figure 2.
Figure 2.
Objective response rate to PD-(L)1 inhibition according to STK11 mutation status among (A) KRASMUT and (B) KRASWT LUADs in the combined cohort. Objective response rate to PD-(L)1 inhibition according to KEAP1 mutation status among (C) KRASMUT and (D) KRASWT LUADs in the combined cohort. LUAD, lung adenocarcinoma; MUT, mutant; PD-(L)1, programmed death-(ligand)1; WT, wild-type.
Figure 3.
Figure 3.
(A) PFS and (B) OS to PD-(L)1 inhibition according to STK11 mutation status among KRASMUT LUADs in the combined cohort (DFCI/MGH + MSKCC/MDACC). (C) PFS and (D) OS to PD-(L)1 inhibition according to STK11 mutation status among KRASWT LUADs in the combined cohort (DFCI/MGH + MSKCC/MDACC). CI, confidence interval; DFCI, Dana-Farber Cancer Institute; HR, hazard ratio; LUAD, lung adenocarcinoma; MDACC, MD Anderson Cancer Center; MGH, Massachusetts General Hospital; MSKCC, Memorial Sloan Kettering Cancer Center; MUT, mutant; OS, overall survival; PD-(L)1, programmed death-(ligand)1; PFS, progression-free survival; WT, wild-type.
Figure 4.
Figure 4.
(A) PFS and (B) OS to PD-(L)1 inhibition according to KEAP1 mutation status among KRASMUT LUADs in the combined cohort (DFCI/MGH + MSKCC/MDACC). (C) PFS and (D) OS to PD-(L)1 inhibition according to KEAP1 mutation status among KRASWT LUADs in the combined cohort (DFCI/MGH + MSKCC/MDACC). CI, confidence interval; DFCI, Dana-Farber Cancer Institute; HR, hazard ratio; LUAD, lung adenocarcinoma; MDACC, MD Anderson Cancer Center; MGH, Massachusetts General Hospital; MSKCC, Memorial Sloan Kettering Cancer Center; MUT, mutant; OS, overall survival; PD-(L)1, programmed death-(ligand)1; PFS, progression-free survival; WT, wild-type.
Figure 5.
Figure 5.
(A) Objective response rate, (B) PFS, and (C) OS to PD-(L)1 inhibition according to STK11/KEAP1 comutation status, among patients with KRASMUT lung adenocarcinoma in the combined cohort. CI, confidence interval; MUT, mutant; OS, overall survival; PD-(L)1, programmed death-(ligand)1; PFS, progression-free survival; WT, wild-type.
Figure 6.
Figure 6.
(A) Bubble plot revealing the 13 prioritized immune-related pathways which are significantly down-regulated in KRASMUT/STK11MUT compared with KRASMUT/STK11WT LUADs, but not in KRASWT/STK11MUT compared with KRASWT/STK11WT LUADs. (B) Bubble plot revealing the 11 prioritized immune-related pathways which are significantly down-regulated in KRASMUT/KEAP1MUT compared with KRASMUT/KEAP1WT LUADs, but not in KRASWT/KEAP1MUT compared with KRASWT/KEAP1WT LUADs. (C) Cell-type enrichment analysis using xCell revealing the cell types that are uniquely enriched in KRASMUT/STK11WT compared with KRASMUT/STK11MUT LUADs, but not in KRASWT/STK11WT compared with KRASWT/STK11MUT LUADs. (D) Cell-type enrichment analysis using xCell revealing the cell types that are uniquely enriched in KRASMUT/KEAP1WT compared with KRASMUT/KEAP1MUT LUADs, but not in KRASWT/KEAP1WT compared with KRASWT/KEAP1MUT LUADs. LUAD, lung adenocarcinoma; MUT, mutant; NK, natural killer; NS, not significant; WT, wild-type. *p < 0.05, **p < 0.01, ***p < 0.001. # Sum of B cells, CD4+ T cells, CD8+ T cells, Dendritic cells, Eosinophils, Macrophages, Monocytes, Mast cells, Neutrophils, NK cells. § Composite score of ImmuneScore + Stroma Score (Adipocytes, Endothelial cells, Fibroblasts)
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