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. 2025 Jun;20(6):725-738.
doi: 10.1016/j.jtho.2025.01.016. Epub 2025 Jan 27.

Gene Copy Deletion of STK11, KEAP1, and SMARCA4: Clinicopathologic Features and Association With the Outcomes of Immunotherapy With or Without Chemotherapy in Nonsquamous NSCLC

Malini M Gandhi  1 , Arielle Elkrief  2 , Catherine Gutierrez Moore  1 , Biagio Ricciuti  1 , Joao V Alessi  1 , Allison L Richards  3 , Sam Tischfield  3 , Jessica Williams  4 , Giuseppe Lamberti  1 , Federica Pecci  1 , Alessandro Di Federico  1 , Maisam Makarem  1 , Bruce E Johnson  1 , Mizuki Nishino  5 , Lynette M Sholl  4 , Adam J Schoenfeld  2 , Mark M Awad  6
Affiliations

Gene Copy Deletion of STK11, KEAP1, and SMARCA4: Clinicopathologic Features and Association With the Outcomes of Immunotherapy With or Without Chemotherapy in Nonsquamous NSCLC

Malini M Gandhi et al. J Thorac Oncol. 2025 Jun.

Abstract

Introduction: Mutations in STK11, KEAP1, and SMARCA4 predispose to inferior immune checkpoint inhibitor (ICI) efficacy in NSCLC, particularly among KRAS-mutant cases. Nevertheless, the frequency, clinicopathologic features, and clinical impact of deletions in these genes are poorly characterized.

Methods: Clinicopathologic correlates of STK11, KEAP1, and SMARCA4 deletion were analyzed in cases of nonsquamous NSCLC at Dana-Farber Cancer Institute (DFCI). mRNA and LKB1 protein levels were assessed using The Cancer Genome Atlas. Clinical outcomes were analyzed in patients who received ICI with or without chemotherapy at DFCI and Memorial Sloan Kettering Cancer Center. Analyses of each deletion excluded cases with mutations in that gene.

Results: Among the 3194 cases of nonsquamous NSCLC, 14.7% had STK11 deletion (STK11DEL), 13.5% KEAP1 deletion (KEAP1DEL), and 13.7% SMARCA4 deletion (SMARCA4DEL). These deletions correlated with lower programmed death-ligand 1 expression and higher disease stage, tumor mutational burden, and aneuploidy. STK11DEL, KEAP1DEL, and SMARCA4DEL each correlated with lower corresponding mRNA expression, and STK11DEL with lower LKB1 protein expression. Among 767 patients treated with chemoimmunotherapy, these deletions were associated with worse objective response rates (STK11 31% versus 45%, p = 0.005; KEAP1 33% versus 45%, p = 0.03; SMARCA4 29% versus 45%, p = 0.0007), progression-free survival (STK11 hazard ratio [HR] = 1.5, p = 0.0001; KEAP1 HR = 1.4, p = 0.002; SMARCA4 HR = 1.6, p < 0.0001), and overall survival (STK11 HR = 1.7, p < 0.0001; KEAP1 HR = 1.5, p = 0.003; SMARCA4 HR = 1.7, p < 0.0001). The effect of these deletions on chemoimmunotherapy outcomes was comparable to the effect of mutations in these genes. Among 1267 patients treated with ICI alone, these deletions did not impact outcomes in the Memorial Sloan Kettering Cancer Center cohort but were generally associated with worse outcomes in the DFCI cohort among KRAS-mutant cases.

Conclusions: STK11, KEAP1, and SMARCA4 deletions correlate with distinct clinicopathologic features, reduced programmed death-ligand 1 expression, and poor chemoimmunotherapy efficacy in NSCLC.

Keywords: Genomics; Immunotherapy; KEAP1; Non–small cell lung cancer; SMARCA4; STK11.

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Conflict of interest statement

Disclosure Dr. Elkrief reports consulting for Bristol-Myers Squibb, AstraZeneca, and Merck; and grants from Kanvas Bioscience. Dr. Ricciuti reports consulting for Regeneron, AstraZeneca, AMGEN, Bayer, and Bristol-Myers Squibb; and speaker payment/honoraria from AstraZeneca, SITC, Targeted Oncology, and OncoLive. Dr. Alessi reports holding positions on the advisory boards of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, AstraZeneca, and Janssen. Dr. Di Federico reports consulting for Hanson-Wade, Novartis, and IQVIA; honoraria from SITC; and travel support from Johnson & Johnson. Dr. Johnson reports consulting for Novartis, Checkpoint Therapeutics, AstraZeneca, Daiichi Sankyo, Genentech, Bluedot Bio, Jazz Pharmaceuticals, Merus, Abdera, and Simcere Pharmaceutical; post Marketing Royalties for EGFR mutation testing from DFCI; being a paid Member of a Data Safety Monitoring Committee for Revolution Medicine and Merck; and being an unpaid Member of Steering Committee for Pfizer. Dr. Nishino reports consulting for AstraZeneca; and institutional funding from Canon Medical Systems and Konica-Minolta. Dr. Sholl reports consulting for Genentech and Eli Lilly; and institutional funding from Genentech and Bristol-Myers Squibb. Dr. Schoenfeld reports consulting/advising roles in J&J, Bayer, KSQ therapeutics, Bristol-Myers Squibb, Merck, AstraZeneca, Synthekine, cTRL therapeutics, Regeneron, Enara Bio, Perceptive Advisors, Oppenheimer and Co, Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Obsidian Therapeutics, Prelude Therapeutics, Immunocore, Lyell Immunopharma, Amgen and Heat Biologics; and institutional funding from GlaxoSmithKline, Obsidian, Eli Lilly, PACT pharma, Iovance Biotherapeutics, Achilles therapeutics, Merck, Synthekine, Bristol-Myers Squibb, Harpoon Therapeutics, AffiniT therapeutics, Legend Therapeutics, Synthekine, and Amgen. Dr. Awad reports consulting for Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Blueprint Medicine, Synthekine, AbbVie, Gritstone, Mirati, Regeneron, AffiniT, EMD Serono, Novartis, Janssen, Coherus, D3Bio, Pfizer, Eli Lilly, Seagen, and Gilead; and institutional funding from Bristol-Myers Squibb, Eli Lilly, Genentech, AstraZeneca, and Amgen. The remaining authors declare no conflict of interest.

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