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

Our plain-English summary of 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, by E.W. Alley, J. Lopez, A. Santoro, et al (The Lancet. Oncology, 2017).

The study

• Authors: E.W. Alley, J. Lopez, A. Santoro, A. Morosky, S. Saraf, B. Piperdi, E. van Brummelen
• Journal: The Lancet. Oncology
• Published: 2017;18(5):623-630
• Cited by: 392 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis and few treatment options following progression on platinum-containing chemotherapy. We assessed the safety and efficacy of pembrolizumab (an anti-programmed cell death receptor 1 [PD-1] antibody) in advanced solid tumours expressing programmed cell death ligand 1 (PD-L1) and report here on the interim analysis of the malignant pleural mesothelioma cohort.

Methods: Previously treated patients with PD-L1-positive malignant pleural mesothelioma were enrolled from 13 centres in six countries. Patients received pembrolizumab (10 mg/kg every 2 weeks) for up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria included measurable disease, failure of standard therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1. PD-L1 positivity was defined as expression in 1% or more of tumour cells by immunohistochemistry. Response was assessed based on investigator review using the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Primary endpoints were safety and tolerability, analysed in the all-patients-as-treated population, and objective response, analysed for the full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT02054806, and is ongoing but not recruiting participants.

Findings: As of June 20, 2016, 25 patients received pembrolizumab. 16 (64%) patients reported a treatment-related adverse event; the most common adverse event were fatigue (six [24%]), nausea (six [24%]), and arthralgia (five [20%]). Five (20%) patients reported grade 3 treatment-related adverse events. Three (12%) patients required dose interruption because of immune-related adverse events: one (4%) of 25 each had grade 3 rhabdomyolysis and grade 2 hypothyroidism; grade 3 iridocyclitis, grade 1 erythema multiforme, and grade 3 erythema; and grade 2 infusion-related reaction. No treatment-related deaths or discontinuations occurred. Five (20%) patients had a partial response, for an objective response of 20% (95% CI 6·8-40·7), and 13 (52%) of 25 had stable disease. Responses were durable (median response duration 12·0 months [95% CI 3·7 to not reached]); two patients remained on treatment at data cutoff.

Interpretation: Pembrolizumab appears to be well tolerated and might confer anti-tumour activity in patients with PD-L1-positive malignant pleural mesothelioma. Response durability and efficacy in this patient population warrants further investigation.

Funding: Merck.

Copyright © 2017 Elsevier Ltd. All rights reserved.

In plain English

This article reported interim results from the malignant pleural mesothelioma group of KEYNOTE-028, a phase 1b, non-randomised, open-label trial. Patients received the immunotherapy drug pembrolizumab intravenously at 10 mg/kg every 2 weeks. The 25 patients had malignant pleural mesothelioma that tested positive for the protein PD-L1. They were enrolled in 2014 from 13 centres in six countries. Treatment-related side effects were reported by 16 of 25 patients. The most frequent included fatigue, nausea and joint pain (arthralgia). Five patients had grade 3 treatment-related side effects, no patient had grade 4 or 5, and there were no treatment-related deaths. Five patients (20%) had a partial response (95% confidence interval 6.8% to 40.7%) and 13 (52%) had stable disease; none had a complete response. Among the five responders, responses lasted a median of 12.0 months (95% confidence interval 3.7 months to not reached). Median overall survival was 18.0 months (95% confidence interval 9.4 months to not reached). The authors concluded that pembrolizumab might be safe, with encouraging signs of anti-tumour activity, and that larger randomised trials were needed. The study did not examine asbestos exposure.

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: Interim analysis of one cohort of an ongoing phase 1b, multicentre, non-randomised, open-label, multicohort drug trial (KEYNOTE-028)
• Who was studied: 25 previously treated adults with PD-L1-positive, incurable, locally advanced or metastatic malignant pleural mesothelioma and ECOG performance status 0 or 1. They were enrolled from 13 centres in six countries between May 13, 2014, and Aug 20, 2014. Of 83 patients screened for PD-L1, 38 (46%) were PD-L1-positive. Median age was 65; 17 were men and 8 women; 18 (72%) had epithelioid histology.
• Exposure: Treatment with pembrolizumab (an anti-PD-1 antibody), 10 mg/kg intravenously every 2 weeks, for up to 24 months. Asbestos exposure was not studied.
• Main results:
  • 16 (64%) of the 25 patients reported treatment-related adverse events
  • The most frequent treatment-related adverse events (in at least 10% of patients) were fatigue, nausea, arthralgia, pruritus, decreased appetite and dry mouth
  • Five (20%) patients had grade 3 treatment-related adverse events; there were no grade 4 or 5 treatment-related adverse events
  • There were no treatment-related deaths and no discontinuations attributable to treatment-related adverse events
  • Immune-related adverse events occurred in three (12%) patients, each of whom required dose interruption
  • In the full-analysis set (n=25), five (20%) patients had a partial response (objective response 20%, 95% CI 6.8 to 40.7), 13 (52%) had stable disease, and none had a complete response
  • Clinical benefit (complete or partial response, or stable disease for 6 months or more) was 40% (95% CI 21.1 to 61.3)
  • Median duration of response, analysed among all responders (the five patients with a partial response), was 12.0 months (95% CI 3.7 to not reached)
  • Median progression-free survival was 5.4 months (95% CI 3.4 to 7.5)
  • Median overall survival was 18.0 months (95% CI 9.4 to not reached); 14 (56%) of 25 patients had died by data cutoff, nine (36%) due to disease progression
  • Tumour size in target lesions decreased from baseline in 14 (56%) of 23 assessable patients
• The authors' conclusion: The authors concluded that pembrolizumab might be safe for treating malignant pleural mesothelioma, with encouraging signs of anti-tumour activity, and that larger randomised trials are required.
• Limitations the authors state:
  • The time between initial diagnosis and first dose, and progression-free survival from first diagnosis, were not collected, so there is no information on the natural history of the patients' tumours
  • Modified mesothelioma-specific RECIST criteria were not used to assess disease progression for the primary analysis
  • Comparison with other studies is difficult because of differences in patient numbers, entry criteria, design and treatment history
  • Patients with severely disabling disease were not included (only ECOG performance status 0 or 1), and tumours had to be PD-L1-positive

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), Pleural Mesothelioma, Prognosis, Chemotherapy, PD-L1, Performance Status, Immunohistochemistry, Immune-Related Adverse Events.

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• 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)
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