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Case Reports
. 2020 Mar;8(1):e000713.
doi: 10.1136/jitc-2020-000713.

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

Anna Minchom  1 , Wei Yuan  2 , Mateus Crespo  2 , Bora Gurel  2 , Ines Figueiredo  2 , Andrew Wotherspoon  3 , Susana Miranda  2 , Ruth Riisnaes  2 , Ana Ferreira  2 , Claudia Bertan  2 , Rita Pereira  2 , Matt Clarke  2 , Chloe Baker  2 , Joo Ern Ang  2 , Nicos Fotiadis  4 , Nina Tunariu  2 , Suzanne Carreira  2 , Sanjay Popat  5 , Mary O'Brien  6 , Udai Banerji  2 , Johann de Bono  2 , Juanita Lopez  2
Affiliations
Case Reports

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

Anna Minchom et al. J Immunother Cancer. 2020 Mar.

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.

Keywords: PD-1; PD-L1; TMB; immunotherapy; mesothelioma.

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Conflict of interest statement

Competing interests: AM: honoraria from FARON and Bayer. AW: advisory boards for Bayer, Bristol-Myers Sqibb and Celgene. SP: honoraria from Boehringer Ingelheim, AstraZeneca, Roche, Takeda and Chugai Pharma; advisory boards from Boehringer Ingelheim, AstraZeneca, Roche, Novartis, Pfizer, Bristol-Myer Squibb, MSD, Guardant Health, Abbvie, EMD Serono and Takeda; expenses from Boehringer Ingelheim, Bristol-Myer Squibb and Merck Sharp & Dohme. MO: advisory boards for MSD, Abbvie, BMS, BI, Pierre Fabre. UB: honoraria from Astellas, Novartis, Karus Therapeutics, Phoenix Solutions, Eli Lilly, Astex and Vernalis; funding for phase I investigator-initiated trials from Onyx Pharmaceuticals, BTG International, Chugai, Astrazeneca and Verastem. JdB: personal fees and non-financial support from Astellas Pharma, Genentech/Roche, Pfizer, Sanofi, Bayer, Boehringer Ingelheim, Merck Serono and Merck Sharp & Dohme; grants, personal fees and non-financial support from AstraZeneca; non-financial support from Genmab, GlaxoSmithKline, Orion Pharma GmbH, Qiagen, Taiho Pharmaceutical and Vertex. In addition, JdB has a patent Abiraterone Rewards to Inventors with royalties paid to institution, no personal income and a patent PARP inhibitors and DNA repair defects with royalties paid to institution, no personal income. JL: research funding from Roche Genentech, Genmab and Basilea Travel from Basilea.

Figures

Figure 1
Figure 1
(A) Axial enhanced CT of thorax. Upper left panel a: baseline prior to commencing pembrolizumab trial (June 2014) with left posterior parietal malignant pleural disease (white circle). Upper right panel b: maintained partial response after 52 cycles pembrolizumab (April 2016) with minimal residual pleural thickening (white arrow). Lower left panel c: disease progression (July 2018) at site of previous disease along the left posterior parietal pleura (white circle). Lower right panel d: partial response in left parietal posterior pleural disease following three cycles pembrolizumab rechallenge. (B) Tumor response.
Figure 2
Figure 2
(A) PD-L1 IHC by Dako 22C3 in baseline (left panel) and relapse (right panel) biopsy. (B) CD3 by immunohistochemistry in baseline (left panel) and relapse (right panel) biopsy.
Figure 3
Figure 3
Multicoloured immunofluorescence panel for T cells in baseline (upper panels) and relapse (lower panels) biopsy.
Figure 4
Figure 4
Circos plot of CNA and somatic mutations. From outermost to innermost track: progression sample CNA (log2R), baseline sample CNA (log2R), progression sample mutations and baseline sample mutations. CNAs, copy number alterations.
See this image and copyright information in PMC

References

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