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

Our plain-English summary of 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, by A. Marabelle, M. Fakih, J. Lopez, et al (The Lancet. Oncology, 2020).

The study

• Authors: A. Marabelle, M. Fakih, J. Lopez, M. Shah, R. Shapira-Frommer, K. Nakagawa, H.C. Chung, H.L. Kindler, J.A. Lopez-Martin, W.H. Miller, A. Italiano, S. Kao, S.A. Piha-Paul, J.P. Delord, R.R. McWilliams, D.A. Fabrizio, D. Aurora-Garg, L. Xu, F. Jin, K. Norwood, Y.J. Bang
• Journal: The Lancet. Oncology
• Published: 2020;21(10):1353-1365
• Cited by: 2,141 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

Copyright © 2020 Elsevier Ltd. All rights reserved.

In plain English

This article reported a prespecified, exploratory biomarker analysis from KEYNOTE-158, a single-arm phase 2 trial of pembrolizumab in previously treated advanced solid tumours. One of its ten cohorts was malignant pleural mesothelioma; patients received 200 mg every 3 weeks. The authors compared patients with high tissue tumour mutational burden (tTMB-high, at least 10 mutations per megabase) against non-tTMB-high patients with evaluable lower values. Of 790 patients analysed for efficacy, tumours responded in 30 of 102 (29%; 95% CI 21 to 39) tTMB-high patients and 43 of 688 (6%; 5 to 8) non-tTMB-high patients. Median overall survival was 11.7 months (95% CI 9.1 to 19.1) in the tTMB-high group and 12.8 months (11.1 to 14.1) in the non-tTMB-high group. One tTMB-high patient had mesothelioma, and mesothelioma was one of three cohorts lacking higher response with tTMB-high status. Among 105 tTMB-high patients assessed for safety, 16 (15%) had grade 3 to 5 treatment-related adverse events, including one treatment-related fatal pneumonia. The authors concluded tTMB could usefully predict response to pembrolizumab. They noted the single-arm design and small cohorts limited interpretation. The article did not address asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective, exploratory biomarker analysis within a multicohort, single-arm, open-label, non-randomised phase 2 trial (KEYNOTE-158)
• Who was studied: 1073 adults with previously treated advanced solid tumours were enrolled from 81 sites in 21 countries between January 2016 and June 2019, in ten tumour cohorts including malignant pleural mesothelioma (cohort H). The efficacy analysis included 790 patients with evaluable tTMB who were treated and enrolled at least 26 weeks before data cutoff: 102 tTMB-high and 688 non-tTMB-high.
• Exposure: Patients were treated with pembrolizumab (an anti-PD-1 antibody), 200 mg intravenously every 3 weeks for up to 35 cycles. They were grouped by tissue tumour mutational burden: high was defined as at least 10 mutations per megabase on the FoundationOne CDx assay, and non-high as fewer than 10. No asbestos or fiber exposure was studied.
• Main results:
  • Objective response occurred in 30 (29%; 95% CI 21 to 39) of 102 tTMB-high patients and in 43 (6%; 5 to 8) of 688 non-tTMB-high patients.
  • After excluding patients with high microsatellite instability or missing microsatellite status, 23 (28%; 95% CI 19 to 40) of 81 tTMB-high patients had an objective response.
  • Median duration of response was not reached in the tTMB-high group and was 33.1 months in the non-tTMB-high group.
  • Median progression-free survival was 2.1 months in both groups. Median overall survival was 11.7 months (95% CI 9.1 to 19.1) in the tTMB-high group and 12.8 months (11.1 to 14.1) in the non-tTMB-high group.
  • In the efficacy population, 1 of the 102 tTMB-high patients and 84 of the 688 non-tTMB-high patients had mesothelioma.
  • The anal, biliary and mesothelioma cohorts were exceptions to the finding of higher response with tTMB-high status. In the mesothelioma cohort, median tTMB was 1.26 mutations per megabase in both responders and non-responders.
  • Among 105 tTMB-high patients in the safety population, 11 (10%) had treatment-related serious adverse events and 16 (15%) had grade 3 to 5 treatment-related adverse events. One fatal pneumonia was assessed by the investigator as treatment related.
• The authors' conclusion: The authors concluded that tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab, and that tTMB could be a useful predictive biomarker for response in previously treated advanced solid tumours.
• Limitations the authors state:
  • A single-arm study across multiple tumour types restricts interpretation of tTMB as a predictor of survival outcomes.
  • Some tumour cohorts had small numbers of patients.
  • Tumour-specific factors could not be assessed, so their influence is unknown.
  • Survival comparisons across tumour types are complicated by confounding factors, such as differing previous and subsequent therapies.
  • No formal statistical tests were done in this exploratory analysis.

Topics

Medical terms in this study, explained in our Lexicon: Pembrolizumab (Keytruda), Biomarker, Monoclonal Antibody, Unresectable, Mesothelioma, Performance Status, Life Expectancy.

Related studies

• Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial — B. Geoerger, H.J. Kang, et al. (2020)
• Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study — T.A. Yap, K. Nakagawa, et al. (2021)
• Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial — E.W. Alley, J. Lopez, et al. (2017)
• Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors — D.P. Hurkmans, S.D.T. Sassen, et al. (2021)
• A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors — J.P. Sharman, J.J. Wheler, et al. (2019)
• Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors — J.J. Luke, F. Barlesi, et al. (2021)

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