Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study

Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1...

Full description

Saved in:
Bibliographic Details
Published in:The lancet oncology 2020-10, Vol.21 (10), p.1353-1365
Main Authors: Marabelle, Aurélien, Fakih, Marwan, Lopez, Juanita, Shah, Manisha, Shapira-Frommer, Ronnie, Nakagawa, Kazuhiko, Chung, Hyun Cheol, Kindler, Hedy L, Lopez-Martin, Jose A, Miller, Wilson H, Italiano, Antoine, Kao, Steven, Piha-Paul, Sarina A, Delord, Jean-Pierre, McWilliams, Robert R, Fabrizio, David A, Aurora-Garg, Deepti, Xu, Lei, Jin, Fan, Norwood, Kevin, Bang, Yung-Jue
Format: Article
Language:English
Subjects:
Aged
Antibodies
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - adverse effects
Antineoplastic Agents, Immunological - administration & dosage
Antineoplastic Agents, Immunological - adverse effects
Biomarkers
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Cancer therapies
Clinical outcomes
Clinical trials
Colitis
Drug-Related Side Effects and Adverse Reactions
Endometrium
Female
Humans
Immune checkpoint
Immunotherapy
Intolerance
Life span
Lung cancer
Male
Medical research
Melanoma
Mesothelioma
Metastases
Metastasis
Middle Aged
Monoclonal antibodies
Mutation
Neoplasms - genetics
Neoplasms - pathology
Neoplasms - therapy
Oncology
Paraffin
Patients
PD-1 protein
Pembrolizumab
Prospective Studies
Response Evaluation Criteria in Solid Tumors
Sarcoma
Solid tumors
Survival Analysis
Targeted cancer therapy
Thyroid
Thyroid gland
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treate
ISSN:1470-2045
1474-5488
DOI:10.1016/S1470-2045(20)30445-9