Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC.

Autor:	Mok TSK; State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China. Electronic address: tony@clo.cuhk.edu.hk., Lopes G; Sylvester Comprehensive Cancer Center at the University of Miami, Miami, FL, USA., Cho BC; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea., Kowalski DM; Maria Sklodowska-Curie National Research Institute of Oncology, Department of Lung Cancer and Thoracic Tumours, Warsaw, Poland., Kasahara K; Kanazawa University Hospital, Kanazawa, Japan., Wu YL; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China., de Castro G Jr; Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil., Turna HZ; Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey., Cristescu R; Merck & Co., Inc., Rahway, NJ, USA., Aurora-Garg D; Merck & Co., Inc., Rahway, NJ, USA., Loboda A; Merck & Co., Inc., Rahway, NJ, USA., Lunceford J; Merck & Co., Inc., Rahway, NJ, USA., Kobie J; Merck & Co., Inc., Rahway, NJ, USA., Ayers M; Merck & Co., Inc., Rahway, NJ, USA., Pietanza MC; Merck & Co., Inc., Rahway, NJ, USA., Piperdi B; Merck & Co., Inc., Rahway, NJ, USA., Herbst RS; Yale University School of Medicine, Yale Cancer Center, New Haven, CT, USA.
Jazyk:	angličtina
Zdroj:	Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2023 Apr; Vol. 34 (4), pp. 377-388. Date of Electronic Publication: 2023 Jan 25.
DOI:	10.1016/j.annonc.2023.01.011
Abstrakt:	Background: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial. Patients and Methods: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. Results: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. Conclusion: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status. (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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