Sistema de Salut de Catalunya
Institut Català de la Salut
[Garassino MC] Section of Hematology/Oncology, Thoracic Oncology program, University of Chicago, Chicago, Illinois, and IRCCS Istituto Nazionale dei Tumori, Milano. [Gadgeel S] Division of Hematology/Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health System, Detroit, Michigan. [Novello S] Department of Oncology, University of Turin, Orbassano, Italy. [Halmos B] Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York. [Felip E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Speranza G] Centre integré de cancérologie de la Montérégie, Université de Sherbrooke, Greenfield Park, Quebec, Canada
Vall d'Hebron Barcelona Hospital Campus
2023-03-09T11:04:54Z
2023-03-09T11:04:54Z
2023-01
Biomarker; Pembrolizumab; Tissue tumor mutational burden
Biomarcador; Pembrolizumab; Càrrega mutacional del tumor tissular
Biomarcador; Pembrolizumab; Carga mutacional del tumor tisular
Introduction We evaluated tissue tumor mutational burden (tTMB) and mutations in STK11, KEAP1, and KRAS as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials. Methods This retrospective exploratory analysis evaluated prevalence of high tTMB and STK11, KEAP1, and KRAS mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and STK11, KEAP1, and KRAS mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome. Results Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, n = 293; KEYNOTE-407, n = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided p > 0.05) or placebo-combination (Wald test, two-sided p > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of KEAP1, STK11, or KRAS mutation status. Conclusions These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, STK11, KEAP1, or KRAS mutation status as a biomarker for this regimen.
All authors’ institutions received research funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, for the conduct of this study.
Article
Published version
English
Pulmons - Càncer - Tractament; Marcadors tumorals; Quimioteràpia combinada; DISEASES::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung; CHEMICALS AND DRUGS::Biological Factors::Biomarkers::Biomarkers, Tumor; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas; COMPUESTOS QUÍMICOS Y DROGAS::factores biológicos::biomarcadores::marcadores tumorales; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada
Elsevier
JTO Clinical and Research Reports;4(1)
https://doi.org/10.1016/j.jtocrr.2022.100431
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
