biostudies-literatureSkoulidis FNCATS NIH HHSNCI NIH HHSNIH HHS462-471https://www.ebi.ac.uk/biostudies/studies/S-EPMC11560846biostudies-literatureUnknown635(8038)For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB^1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial³. Unbiased geneNatureCTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors.PMC11560846P30 CA016058S10 OD024977R01 CA276917P30 CA016672P50 CA070907P30 CA016042R01 CA279452P30 CA008748T32 CA009172R01 CA205150UL1 TR001863R01 CA262469Carbone DPJohnson MLMurray JCKillam JZhang JGarassino MCGray JEElamin YYPoteete AHellmann MDVenkatraman DByers LAHerbst RSHeymach JVPecot CVShaish HAraujo HAMontesion MScheffler MDigumarthy SJanne PAKatz SAwad MMWinslow MMMarrone KAGay CJuan JMMezquita LTsao AScagliotti GVPlanchard DGoldberg SBLau SCMLee RGaron EBZhu ZGalan-Cobo AJahchan NLevy BHellyer JAMooradian MJBehrens CShu CABlumenschein GRRitterhouse LBesse BYu YBivona TGLam VKMolkentine DWistuba IIDimou ASchalper KStewart RKemp HNZhou TSwisher SCascone TLe JTForde PMStewart TBlakely CMNi YRizvi NAQian YMann HDavies KDSchmidt STGandara DRRudin CMNegrao MVKong YTakehara TLeighl NBMarmarelis MEGibbons DLCarter BTabbo FOwen DHRosen MJWakelee HAMemmott RPeters SAnagnostou VLee JJGainor JFCummings ALBestvina CMHuang ASegal JRoth JAShaw ATBrahmer JRAzok JTSun XJohnson RPRiess JWWoodcock MGRicciuti BAggarwal CLe XCamidge DRWinters IPMin CAlbacker LSacher AGLacroix LArbour KCWong KKDo MTWalther ZGoldman JWSaltos ANPapadimitrakopoulou VASkoulidis FVan Allen EMWolf JVokes NPan XNeal JWPalmer RKier MPatil PDParra Cuentas ERPaula AGLai ZJewsbury PRotow JLiu CLewis WEPennell NAfalseCTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors.For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB^1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial³. Unbiased gene2024-01-01T00:00:00Z2024 Nov2026-06-01T17:41:45.011Z2025-04-04T02:46:50.569ZS-EPMC115608463938503510.1038/s41586-024-07943-7