Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study

Our plain-English summary of Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study, by T.A. Yap, K. Nakagawa, N. Fujimoto, et al (The Lancet. Respiratory Medicine, 2021).

The study

• Authors: T.A. Yap, K. Nakagawa, N. Fujimoto, K. Kuribayashi, T.K. Guren, L. Calabrò, R. Shapira-Frommer, B. Gao, S. Kao, I. Matos, D. Planchard, A. Chatterjee, F. Jin, K. Norwood, H.L. Kindler
• Journal: The Lancet. Respiratory Medicine
• Published: 2021;9(6):613-621
• Cited by: 66 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study.

Methods: The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067.

Findings: Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation.

Interpretation: Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated.

Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Copyright © 2021 Elsevier Ltd. All rights reserved.

In plain English

This open-label, single-arm phase 2 trial was one cohort of the KEYNOTE-158 study. It tested the immunotherapy drug pembrolizumab alone in adults with malignant pleural mesothelioma that had worsened after standard therapy, or who could not have it. In 2016, 118 patients at 35 sites in 14 countries received pembrolizumab 200 mg intravenously every 3 weeks. The study did not examine asbestos exposure. Ten of 118 patients (8% [95% CI 4 to 15]) had a partial response, meaning tumour shrinkage; none had a complete response. Responses lasted a median of 14.3 months. Responses occurred in 6 of 77 patients with PD-L1-positive tumours and 4 of 31 with PD-L1-negative tumours. Median overall survival was 10.0 months (95% CI 7.6 to 13.4); 103 patients had died by the June 2019 data cutoff. Treatment-related side effects occurred in 82 patients and were severe (grade 3 to 4) in 19. One patient died of apnoea (stopping breathing) judged treatment-related. The authors concluded pembrolizumab showed durable activity and manageable toxicity regardless of PD-L1 status. They noted the trial had no comparison group.

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: Open-label, single-arm, non-randomised phase 2 trial; this report covers the malignant pleural mesothelioma cohort (cohort H) of the multicohort KEYNOTE-158 study
• Who was studied: 118 adults with previously treated, incurable malignant pleural mesothelioma, enrolled February 9 to August 16, 2016, at 35 academic and community sites in Australia, Canada, Denmark, France, Israel, Italy, Japan, South Korea, Netherlands, Norway, Spain, Taiwan, UK and the USA; 85 (72%) male; 77 (65%) PD-L1-positive, 31 (26%) PD-L1-negative, 10 (8%) not evaluable
• Exposure: Treatment with pembrolizumab (an anti-PD-1 antibody) 200 mg intravenously every 3 weeks for up to 35 cycles (about 2 years). No asbestos exposure was studied; asbestos is mentioned only as background in the introduction.
• Main results:
  • Objective response in 10 of 118 patients (8% [95% CI 4 to 15]); all were partial responses, with no complete responses
  • Among the 10 responders, median duration of response was 14.3 months (range 4.0 to 33.9+); 60% were estimated to have responses lasting at least 12 months
  • Responses in 6 (8% [95% CI 3 to 16]) of 77 PD-L1-positive patients and 4 (13% [95% CI 4 to 30]) of 31 PD-L1-negative patients; median response duration 17.7 months in the PD-L1-positive subgroup and 10.2 months in the PD-L1-negative subgroup
  • Median progression-free survival in all 118 patients was 2.1 months (95% CI 2.1 to 3.9)
  • Median overall survival in all 118 patients was 10.0 months (95% CI 7.6 to 13.4); 45% were estimated to be alive at 12 months; 103 (87%) of 118 had died by the data cutoff
  • Treatment-related adverse events occurred in 82 (69%) of 118 patients; serious treatment-related adverse events occurred in 14 (12%)
  • Grade 3 to 4 treatment-related adverse events occurred in 19 (16%) patients; one patient died of apnoea, which was considered treatment-related because a relationship could not be excluded
  • 13 (11%) patients stopped treatment because of treatment-related adverse events; progressive disease was the most common reason for stopping (88 of 113 who discontinued)
• The authors' conclusion: The authors concluded that pembrolizumab showed durable antitumour activity and manageable toxicity in some patients with previously treated advanced malignant pleural mesothelioma, regardless of PD-L1 status, while stating that no definitive conclusion could be drawn about the role of PD-L1
• Limitations the authors state:
  • Single-arm design with no comparator arm
  • Not powered to definitively assess efficacy in PD-L1-positive or PD-L1-negative subgroups
  • No power calculation was possible because sample size and response rate were unknown
  • MSI-high tumours were too rare in this cohort for meaningful conclusions

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pembrolizumab (Keytruda), Mesothelioma, Pleural Mesothelioma, PD-L1, Performance Status, Biomarker, Median Overall Survival, Progression-Free Survival.

Related studies

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• 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)
• 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)
• Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study — L. Calabrò, A. Morra, et al. (2015)
• Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial — L. Calabrò, A. Morra, et al. (2013)
• 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)

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