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

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...

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Vydáno v:JTO clinical and research reports Ročník 4; číslo 1; s. 100431
Hlavní autoři: Garassino, Marina C., Gadgeel, Shirish, Novello, Silvia, Halmos, Balazs, Felip, Enriqueta, Speranza, Giovanna, Hui, Rina, Garon, Edward B., Horinouchi, Hidehito, Sugawara, Shunichi, Rodriguez-Abreu, Delvys, Reck, Martin, Cristescu, Razvan, Aurora-Garg, Deepti, Loboda, Andrey, Lunceford, Jared, Kobie, Julie, Ayers, Mark, Piperdi, Bilal, Pietanza, M. Catherine, Paz-Ares, Luis
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 01.01.2023
Elsevier
Témata:
Biomarker
Hematology, Oncology, and Palliative Medicine
Metastatic non‒small-cell lung cancer
Original
Pembrolizumab
Single-gene genetic alterations
Tissue tumor mutational burden
Pembrolizumab
Biomarker
Tissue tumor mutational burden
Single-gene genetic alterations
Metastatic non‒small-cell lung cancer
ISSN:2666-3643, 2666-3643
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Shrnutí: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. 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. 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. 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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2666-3643
2666-3643
DOI:10.1016/j.jtocrr.2022.100431