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Molecular and immunological features of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged
Anna Minchom,1 Wei Yuan,1 Mateus Crespo,1 Bora Gurel,1 Ines Figueiredo,1 Andrew Wotherspoon,2 Susana Miranda,1 Ruth Riisnaes,1 Ana Ferreira,1 Claudia Bertan,1 Rita Pereira,1 Matt Clarke,1 Chloe Baker,1 Joo Ern Ang,1 Nicos Fotiadis,3 Nina Tunariu,1 Suzanne Carreira ,1 Sanjay Popat,4
Mary O'Brien,5 Udai Banerji,1 Johann de Bono,1 Juanita Lopez1
To cite: Minchom A, Yuan W, Crespo M, et al. Molecular and immunological features
of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged with pembrolizumab. Journal for ImmunoTherapy of Cancer 2020;8:e000713. doi:10.1136/ jitc-2020-000713
► Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/jitc- 2020-000713).
Accepted 05 February 2020
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.
Mesothelioma is a rare cancer of the pleura and mesothelial membranes associated with asbestos exposure and a poor prog- nosis. Subtypes include epithelioid, biphasic and sarcomatoid. A multimodal approach that may include surgery, radiotherapy and chemotherapy is often attempted for poten- tially resectable disease, but a proven survival benefit has not, as yet, been demonstrated.1 The majority of patients have inoperable disease. Treatment for inoperable disease has previously been with chemotherapy, though with relatively poor rates and duration of response, novel therapeutic strategies are required.2 Recent trials have assessed the utility of checkpoint inhibitor (CPI). The
documentation of responses suggest that mesothelioma is a relatively ‘immunogenic’ tumor.3 4 Pembrolizumab is an antiprogramme death receptor 1 (PD-1) antibody investigated in mesothelioma. KEYNOTE-028 recruited 25 patients with PD-L1 (programmed death- ligand 1) positive pleural mesothelioma and has reported interim results: objective response rate of 20%, disease control rate of 52% and a median duration of response of 12.0 months (95% CI of 3.7 to not reached).5
The patient is a 77-year-old Caucasian woman. She was diagnosed with a left epithe- lioid mesothelioma on video-assisted thora- scopic biopsy in 2009 with pleurally based nodules in the left hemothorax on radiologic assessment. She underwent talc pleurod- esis and four cycles of cisplatin and peme- trexed. Sixteen months later, she developed progressive disease and was treated on a trial of NGR-hTNF (a selective vascular inhibitor) for 4months to disease progression. She underwent rechallenge with four cycles of pemetrexed and cisplatin, achieving disease stability for 11 months. She then received six cycles of carboplatin and gemcitabine achieving disease stability for 6 months.
From June 2014 to June 2016, she received 52 cycles of pembrolizumab (MK-3475) at a dose of 10mg/kg every 2weeks on a phase Ib clinic trial (KEYNOTE-028). The tumor biopsy fulfilled criteria for PD-L1 positivity as per trial protocol. She tolerated drug well
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Minchom A, et al. J Immunother Cancer 2020;8:e000713. doi:10.1136/jitc-2020-000713 1