Elsevier

The Lancet Oncology

Volume 21, Issue 10, October 2020, Pages 1353-1365
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(20)30445-9Get rights and content

Summary

Background

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.

Methods

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.

Findings

Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0–38·3). Objective responses were observed in 30 (29%; 95% CI 21–39) of 102 patients in the tTMB-high group and 43 (6%; 5–8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3–5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related.

Interpretation

tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours.

Funding

Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

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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