Molecular and immunological features of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged with pembrolizumab

Our plain-English summary of Molecular and immunological features of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged with pembrolizumab, by A. Minchom, W. Yuan, M. Crespo, et al (Journal for Immunotherapy of Cancer, 2020).

The study

• Authors: A. Minchom, W. Yuan, M. Crespo, B. Gurel, I. Figueiredo, A. Wotherspoon, S. Miranda, R. Riisnaes, A. Ferreira, C. Bertan, R. Pereira, M. Clarke, C. Baker, J.E. Ang, N. Fotiadis, N. Tunariu, S. Carreira, S. Popat, M. O'Brien, U. Banerji, J. de Bono, J. Lopez
• Journal: Journal for Immunotherapy of Cancer
• Published: 2020;8(1)
• Type of article: Case report
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: This case represents an exceptional response to pembrolizumab in a patient with epithelioid mesothelioma with a further response on rechallenge.

Case Presentation: A 77-year-old woman with advanced epithelioid mesothelioma extensively pretreated with chemotherapy demonstrated a prolonged response of 45 months to 52 cycles of pembrolizumab. On rechallenge with pembrolizumab, further disease stability was achieved. Serial biopsies and analysis by immunohistochemistry and immunofluorescence demonstrated marked immune infiltration and documented the emergency of markers of immune exhaustion. Whole exome sequencing demonstrated a reduction in tumor mutational burden consistent with subclone elimination by immune checkpoint inhibitor (CPI) therapy. The relapse biopsy had missense mutation in BTN2A1.

Conclusion: This case supports rechallenge of programme death receptor 1 inhibitor in cases of previous CPI sensitivity and gives molecular insights.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This case report described one 77-year-old woman with advanced epithelioid malignant pleural mesothelioma, diagnosed in 2009, who had already received several rounds of chemotherapy. The article does not describe her asbestos exposure. From June 2014 to June 2016 she received 52 cycles of the immunotherapy drug pembrolizumab on the KEYNOTE-028 trial. Her target lesions shrank by 91%, and the authors reported a response lasting 45 months. In April 2018, 21 months after stopping, the disease grew again. After three cycles of restarted pembrolizumab the tumor was 12% smaller, and it stayed stable for 25 cycles before progressing. Compared with the 2014 biopsy, the 2018 relapse biopsy had more T cells, more regulatory T cells and more PD-L1 staining. It also had fewer somatic mutations (0.26 versus 0.92 per Mbp) and one new BTN2A1 mutation of unclear meaning. The authors found no reason for her prolonged sensitivity. They concluded that cases like this support retreating with immunotherapy if the patient's condition allows. They noted that single biopsies may not reflect the whole tumor.

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: Case report (single patient), with laboratory analysis of two biopsies taken before treatment and at relapse
• Who was studied: One 77-year-old Caucasian woman with left epithelioid mesothelioma, diagnosed by biopsy in 2009, treated on the KEYNOTE-028 trial. The authors and the ethics approval were at the Royal Marsden Hospital, UK.
• Exposure: The article does not describe the patient's asbestos exposure. The treatment studied was pembrolizumab (an anti-PD-1 antibody), 52 cycles at 10 mg/kg every 2 weeks from June 2014 to June 2016, followed by rechallenge on the same schedule from 2018. Earlier treatments were cisplatin and pemetrexed (twice), a trial of NGR-hTNF, and carboplatin and gemcitabine.
• Main results:
  • During the first pembrolizumab course, a partial response was seen after 3 months, with a 91% reduction in target lesions maintained until June 2016. The response lasted 45 months in total.
  • Side effects during the first course were a grade 2 itchy (pruritic) rash and grade 1 mucositis.
  • In April 2018, 21 months after completing 2 years of pembrolizumab, small-volume disease progression without symptoms was seen. On rechallenge, the tumor was 12% smaller after three cycles, and stable disease lasted for 25 cycles until progression was confirmed.
  • In the relapse biopsy compared with the baseline biopsy, PD-L1 staining was increased (1% to 49% in the relapse biopsy by SP263), and intratumoral CD3 T-cell density was higher (2092.06 per mm2 versus 348.53 per mm2).
  • By immunofluorescence, intratumoral CD8 T cells rose from 128.60 to 565.67 per mm2 (almost fivefold), and CD4+ FOXP3+ (regulatory) T cells rose from 2.62 to 88.89 per mm2 (over 30-fold), between the baseline (2014) and relapse (2018) biopsies. CD4 T cells fell from 172.03 to 113.13 per mm2.
  • Whole exome sequencing found 0.92 somatic mutations per Mbp in the baseline biopsy and 0.26 in the relapse biopsy. No mutations were found in key drivers such as BAP1, NF2, TP53, LATS2 and SETD2.
  • None of the immune-related mutations seen in the baseline biopsy were present at relapse. The relapse biopsy had a missense mutation in BTN2A1 (c.1352G>C), whose implications the authors called unclear.
• The authors' conclusion: The authors concluded that this case supports trial data that mesothelioma can respond to checkpoint inhibitors, and that no reason for the prolonged immune sensitivity was identified. They also concluded that serial biopsies showed both immune activation and emerging immune exhaustion, and that such cases support attempts to retreat with checkpoint inhibitors if the patient's clinical condition allows.
• Limitations the authors state:
  • Only single biopsies were taken at each time point, and immune infiltrates may vary across the tumor.
  • Transcriptome analysis was not performed.
  • Whole exome sequencing does not fully assess chromothripsis or loss of heterozygosity, and does not evaluate epigenetic changes such as methylation.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pembrolizumab (Keytruda), Epithelioid, Mesothelioma, Chemotherapy, Immunohistochemistry, Tumor Mutational Burden (TMB), checkpoint inhibitors.

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)
• 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)
• 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 — A. Marabelle, M. Fakih, et al. (2020)
• Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement — G. Bronte, A. Delmonte, et al. (2020)
• Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors — D.P. Hurkmans, S.D.T. Sassen, et al. (2021)
• Tumor PD-L1 expression in malignant pleural and peritoneal mesothelioma by Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx assays — D.B. Chapel, R. Stewart, et al. (2019)

Browse more research in Journal for Immunotherapy of Cancer, or return to medical research.