ArticlesAssociation 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
Introduction
Tumour mutational burden (TMB), defined as the total number of somatic mutations per coding area of a tumour genome, is a measure of all non-synonymous coding mutations in a tumour exome1, 2 that has been shown to vary widely from patient to patient and across tumour types.1, 3 Because highly mutated tumours can produce many neoantigens, some of which might increase T-cell reactivity, high TMB has been hypothesised to be associated with improved response to treatment with immune checkpoint blockade, including anti-PD-1 agents.2, 4
Several analyses have shown a correlation between high TMB (measured with various methods and cutpoints across studies) and the clinical benefit of antibodies targeted against CTLA-4,5 PD-1,6, 7, 8, 9, 10 and PD-L1.11, 12, 13, 14 For example, in patients with non-small-cell lung cancer (NSCLC) treated with the anti-PD-1 monoclonal antibody pembrolizumab as monotherapy, high tissue TMB (tTMB-high; defined as >200 mutations per exome) were associated with durable clinical benefit and extended progression-free survival.10 Similarly, tTMB of at least 10 mutations per megabase has been associated with improved clinical outcomes in patients with NSCLC treated with the monoclonal antibodies nivolumab (anti-PD-1) combined with ipilimumab (anti-CTLA-4).6, 9 Higher tTMB (assessed by whole-exome sequencing and measured as a continuous variable) has also been associated with improved outcomes in patients with melanoma who were given ipilimumab.5 Additionally, when measured on circulating tumour DNA in blood samples, a TMB of at least 16 mutations per megabase was associated with improved clinical outcomes in patients with NSCLC who were given durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4),11 or atezolizumab (anti-PD-L1).13 Data from small, retrospective studies have also suggested an association between tTMB and improved outcomes with immune checkpoint blockade across several tumour types,15, 16 and a meta-analysis showed that increased levels of tTMB were associated with higher response rates with anti-PD-1 or anti-PD-L1 therapy across multiple tumour types.12 Notably, robust antitumour activity was shown with pembrolizumab in the phase 2 KEYNOTE-158 study in patients who had tumours with high microsatellite instability (MSI-H), a DNA mismatch repair deficiency that can result in increased TMB.17 As a result, pembrolizumab monotherapy is approved in several countries, including the USA, Japan, and Australia, for use in patients with previously treated, MSI-H, advanced, solid tumours. Considered together, the data suggest TMB might be a useful biomarker for response with immune checkpoint blockade. Importantly, because most analyses were done in study populations with a single cancer type, whether any predictive effect of tTMB for checkpoint blockade therapy applies only to specific tumour types or whether tTMB might be a tumour-agnostic biomarker is uncertain.
In this prospective exploratory analysis of the KEYNOTE-158 study, we assessed the association between tTMB and clinical outcomes with pembrolizumab monotherapy across ten different solid tumour types. The objective of this analysis was to explore the association of tTMB with clinical outcomes in patients with select previously treated advanced solid tumours treated with pembrolizumab monotherapy in ten cohorts of the phase 2 KEYNOTE-158 study. We used a prespecified cutpoint of at least 10 mutations per megabase to define tTMB-high tumours and less than 10 mutations per megabase for non-tTMB-high tumours, on the basis of the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA), because this cutpoint approximates to one previously shown to optimise for clinical utility using whole-exome sequencing methods,18 and is the minimum threshold established by a multi-stakeholder group convened by the Friends of Cancer Research in an effort to harmonise use of a standard cutoff across clinical trials.4, 19
Section snippets
Study design and participants
The KEYNOTE-158 study is a multicohort, single-arm, open-label, phase 2 study assessing pembrolizumab monotherapy in patients with less frequently occurring types of solid tumours. In this prospective, exploratory, biomarker analysis of the KEYNOTE-158 study, we used data from patients who were enrolled into the study from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe (appendix pp 15–18). Patients were enrolled into one of
Results
Between Jan 15, 2016, and June 25, 2019, 1073 patients from 81 sites in 21 countries were enrolled in ten cohorts (A–J) of KEYNOTE-158 (data for cohort K are reported elsewhere17). 1066 patients had received pembrolizumab as of data cutoff (June 27, 2019), of whom 805 (76%) had evaluable TMB scores. Of 805 patients, 105 (13%) had tTMB-high status and comprised the safety population (appendix p 5). Among the 1050 patients who enrolled at least 26 weeks before data cutoff and who had received
Discussion
In this prospective analysis from the KEYNOTE-158 study, we found that tTMB-high status (defined as ≥10 mutations per megabase, per the FoundationOne CDx panel) assessed in tumour tissue was associated with a higher proportion of patients with an objective response than non-tTMB-high status among patients who received pembrolizumab monotherapy for previously treated solid tumours. The proportion of patients with an objective response—the primary endpoint of KEYNOTE-158—in the tTMB-high group
Data sharing
The data sharing policy of Merck Sharp & Dohme (a subsidiary of Merck & Co., Kenilworth, NJ, USA), including restrictions, is available online. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to [email protected].
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