TY - JOUR
T1 - Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status
AU - Ricciuti, Biagio
AU - Arbour, Kathryn C.
AU - Lin, Jessica J.
AU - Vajdi, Amir
AU - Vokes, Natalie
AU - Hong, Lingzhi
AU - Zhang, Jianjun
AU - Tolstorukov, Michael Y.
AU - Li, Yvonne Y.
AU - Spurr, Liam F.
AU - Cherniack, Andrew D.
AU - Recondo, Gonzalo
AU - Lamberti, Giuseppe
AU - Wang, Xinan
AU - Venkatraman, Deepti
AU - Alessi, Joao V.
AU - Vaz, Victor R.
AU - Rizvi, Hira
AU - Egger, Jacklynn
AU - Plodkowski, Andrew J.
AU - Khosrowjerdi, Sara
AU - Digumarthy, Subba
AU - Park, Hyesun
AU - Vaz, Nuno
AU - Nishino, Mizuki
AU - Sholl, Lynette M.
AU - Barbie, David
AU - Altan, Mehmet
AU - Heymach, John V.
AU - Skoulidis, Ferdinandos
AU - Gainor, Justin F.
AU - Hellmann, Matthew D.
AU - Awad, Mark M.
N1 - Funding Information:
The work of Dr. Ricciuti was supported by the International Association for the Study of Lung Cancer Fellowship Award 2020 and by the 2020 Conquer Cancer Foundation of ASCO Young Investigator Award. The Mark Foundation for Cancer Research (Grant # 19-029 MIA) supported in part the collection, management, analysis, and interpretation of the data at the MD Anderson Cancer Center (MDACC). The MD Anderson Cancer Center Support Grant P30 CA01667 supported in part the collection, management, analysis, and interpretation of the data at the MDACC. The generous philanthropic contributions to The University of Texas MD Anderson Lung Moon Shot Program supported in part the collection, management, analysis, and interpretation of the data at the MDACC.
Funding Information:
Disclosure: Dr. Hellmann reports receiving research support from Bristol-Myers Squibb; has been a compensated consultant for Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles, and Arcus; receiving travel support/honoraria from AstraZeneca, Eli Lilly, and Bristol-Myers Squibb; has options from Shattuck Labs, Immunai, and Arcus; and has a patent filed by his institution related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics. Dr. Lin has served as a compensated consultant or received honorarium from Chugai Pharma, Boehringer Ingelheim, Pfizer, C4 Therapeutics, Nuvalent, Turning Point Therapeutics, and Genentech; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, and Novartis; received CME funding from OncLive, MedStar Health, and Northwell Health; and received travel support from Pfizer. Dr. Nishino reports serving as consultant to Daiichi Sankyo and AstraZeneca; receiving research grant from Merck, Canon Medical Systems, AstraZeneca, and Daiichi Sankyo; receiving honorarium from Roche; and being supported by R01CA203636 and U01CA209414 (NCI). Dr. Arbour reports serving as a consultant for AstraZeneca and Iovance Biotherapeutics and receiving research support through her institution on her behalf from Novartis, Takeda, and Nektar. Dr. Gainor reports serving as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo Oncology/Eli Lilly, Blueprint, Oncorus, Regeneron, EMD Serono, Gilead, AstraZeneca, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, and Array; receiving research support from Novartis, Genentech/Roche, and Ariad/Takeda; receiving institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; and having an immediate family member who is an employee of Ironwood Pharmaceuticals. Dr. Awad reports serving on the consultant/advisory board for Bristol-Myers Squibb, AstraZeneca, Achilles, AbbVie, Neon, Maverick, Nektar, Hegrui, Syndax, and Gritstone and receiving research funding from Bristol-Myers Squibb, AstraZeneca, Eli Lilly, and Genentech. Dr. Sholl reports serving as consultant for Foghorn Therapeutics. Dr. Barbie reports serving as consultant for N of One/Qiagen and Tango Therapeutics; receiving research grants from Bristol-Myers Squibb, Novartis, Eli Lilly, and Gilead Sciences; and being a cofounder and serving on the scientific advisory board of Xsphera Biosciences Inc. Dr. Zhang reports receiving grants from Merck and Johnson and Johnson and personal fees from Bristol-Myers Squibb, AZ, GenePlus, and Innovent. Dr. Heymach reports serving as a consultant to AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Guardant Health, Kairos Venture Investments, BrightPath Biotherapeutics, Hengrui Therapeutics, Eli Lilly, Spectrum, EMD Serono, Roche, and Foundation One Medicine; receiving research grant from the National Institutes of Health/National Cancer Institute, American Cancer Society, Cancer Prevention & Research Institute of Texas, American Association for Cancer Research Johnson & Johnson Lung Cancer, AstraZeneca, Spectrum, and Checkmate Pharmaceuticals; and having royalties from Bio-Tree Systems, Inc. Dr. Skoulidis reports receiving personal fees from Tango Therapeutics and grants from Amgen. Dr. Altan reports receiving research funding from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol-Myers Squibb, Eli Lilly, and Adaptimmune and serving on the advisory board of GlaxoSmithKline and Shattuck Lab. The remaining authors declare no conflict of interest.
Publisher Copyright:
© 2021 International Association for the Study of Lung Cancer
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - KEAP1
KW - KRAS
KW - NSCLC
KW - PD-(L)1 blockade
KW - STK11
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U2 - 10.1016/j.jtho.2021.10.013
DO - 10.1016/j.jtho.2021.10.013
M3 - Article
C2 - 34740862
AN - SCOPUS:85119579058
SN - 1556-0864
VL - 17
SP - 399
EP - 410
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 3
ER -