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Article: Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC

TitleAssociations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC
Authors
KeywordsBiomarker
Metastatic non‒small-cell lung cancer
Pembrolizumab
Single-gene genetic alterations
Tissue tumor mutational burden
Issue Date8-Nov-2021
PublisherElsevier
Citation
JTO Clinical and Research Reports, 2023, v. 4, n. 1 How to Cite?
Abstract

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 STK11KEAP1, 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 KEAP1STK11, 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.


Persistent Identifierhttp://hdl.handle.net/10722/340989
ISSN
2023 Impact Factor: 3.0
2023 SCImago Journal Rankings: 1.321
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGarassino, MC-
dc.contributor.authorGadgeel, S-
dc.contributor.authorNovello, S-
dc.contributor.authorHalmos, B-
dc.contributor.authorFelip, E-
dc.contributor.authorSperanza, G-
dc.contributor.authorHui, R-
dc.contributor.authorGaron, EB-
dc.contributor.authorHorinouchi, H-
dc.contributor.authorSugawara, S-
dc.contributor.authorRodriguez-Abreu, D-
dc.contributor.authorReck, M-
dc.contributor.authorCristescu, R-
dc.contributor.authorAurora-Garg, D-
dc.contributor.authorLoboda, A-
dc.contributor.authorLunceford, J-
dc.contributor.authorKobie, J-
dc.contributor.authorAyers, M-
dc.contributor.authorPiperdi, B-
dc.contributor.authorPietanza, MC-
dc.contributor.authorPaz-Ares, L-
dc.date.accessioned2024-03-11T10:48:50Z-
dc.date.available2024-03-11T10:48:50Z-
dc.date.issued2021-11-08-
dc.identifier.citationJTO Clinical and Research Reports, 2023, v. 4, n. 1-
dc.identifier.issn2666-3643-
dc.identifier.urihttp://hdl.handle.net/10722/340989-
dc.description.abstract<h3>Introduction</h3><p>We evaluated tissue tumor mutational burden (tTMB) and mutations in <em>STK11, KEAP1,</em> and <em>KRAS</em> as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (<a href="http://clinicaltrials.gov/">ClinicalTrials.gov</a>, NCT02578680; nonsquamous) and KEYNOTE-407 (<a href="http://clinicaltrials.gov/">ClinicalTrials.gov</a>, NCT02775435; squamous) trials.</p><h3>Methods</h3><p>This retrospective exploratory analysis evaluated prevalence of high tTMB and <em>STK11, KEAP1</em>, and <em>KRAS</em> mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and <em>STK11</em>, <em>KEAP1</em>, and <em>KRAS</em> 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.</p><h3>Results</h3><p>Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, <em>n</em> = 293; KEYNOTE-407, <em>n</em> = 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 <em>p</em> > 0.05) or placebo-combination (Wald test, two-sided <em>p</em> > 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 <em>KEAP1</em>, <em>STK11,</em> or <em>KRAS</em> mutation status.</p><h3>Conclusions</h3><p>These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, <em>STK11, KEAP1,</em> or <em>KRAS</em> mutation status as a biomarker for this regimen.</p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofJTO Clinical and Research Reports-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectBiomarker-
dc.subjectMetastatic non‒small-cell lung cancer-
dc.subjectPembrolizumab-
dc.subjectSingle-gene genetic alterations-
dc.subjectTissue tumor mutational burden-
dc.titleAssociations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC-
dc.typeArticle-
dc.identifier.doi10.1016/j.jtocrr.2022.100431-
dc.identifier.scopuseid_2-s2.0-85145099498-
dc.identifier.volume4-
dc.identifier.issue1-
dc.identifier.eissn2666-3643-
dc.identifier.isiWOS:001165404600001-
dc.identifier.issnl2666-3643-

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