DNA Report Page 5
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than 20 weeks following administration, which is longer than might be anticipated from previous pharmacoki- netic data.13 Nevertheless, the relapse in this patient occurred long after the elimination of all residual drug. Most CPI trials demonstrate, a ‘tail to the curve’ with a small number of patients who achieve a prolonged response.14 Study of these ‘exceptional responders’ can potentially inform on biologic features that mark prolonged response and be hypothesis generating for further research into mechanisms of drug resistance and sensitivity.
WES results reveal a TMB low tumor. Mesothelioma is classically a TMB low tumor. Analysis of 74 cases revealed a somatic mutation rate of less than two per megabase in all but one case.15 Moreover, in keeping with published data is the CNA seen in this case. Others report frequent CNA in keeping with mesothelioma being driven by loss of tumor suppressors rather than an oncogenic driven cancer.15 Transcriptome analysis was not performed. Others have identified expression of the negative CPI VISTA commonly in mesothelioma, which may have implications on CPI response.15
Proposed resistance mechanisms to CPI are numerous and may be multifactorial.16 The only immune-related mutated gene evidenced in the relapse biopsy was BTN2A1. This is a T cell immunomodulatory molecule coregulated with MHC class II.17 Its role in CPI resistance is not described. As the BTN2A mutation was seen on the relapse biopsy (postrelapse but prerechallenge), the implications of the mutation (if any) is unclear, whether having a role in emerging resistance or sensitivity to rechallenge.
It is also interesting to consider the patient’s prior response to chemotherapy. She achieved an unusual (though not unique) 16-month progression free survival with first-line cisplatin pemetrexed chemotherapy and further response on two chemotherapy rechallenges. The phase II MAPS2 trial of nivolumab or nivolumab- ipilimumab in relapsed mesothelioma included an post hoc analysis showing that in the nivolumab group patients who had relapse at least 3 months after pemetrexed chemotherapy had a small survival benefit.18 Whether these findings are replicated in other trials and whether this simply represents a more globally indolent disease or whether there is a biologic rationale for chemotherapy response correlating with benefit from CPI remains to be seen.
the case in context as a response to pembrolizumab rechallenge
This patient’s cancer is also exceptional in its responsive- ness to pembrolizumab on rechallenge. This phenomena has not be studied in detail. Though others report the potential for a response with CPI rechallenge,19 this is the first report, to our knowledge, of disease response on CPI rechallenge in mesothelioma.
ConCLusion
In conclusion, this case represents a prolonged response to pembrolizumab in a patient with epithelioid meso- thelioma to PD-1 inhibition with further durable clinical benefit on rechallenge. This supports trial data from KEYNOTE-028 and others that mesothelioma can be responsive to CPI. In this case, no reason for prolonged immune sensitivity was identified. The tumor, though PD-L1 positive, did not demonstrate a very high level of PD-L1 expression. WES did not shed light on reasons for prolonged sensitivity to CPI, chromothripsis and loss of heterozygosity are not fully assessed on WES and epigen- etic modifications such as methylation are not evaluated by WES.
Serial biopsies demonstrate both the primary immune activation and emerging immune exhaustion. Future research may shed light on the mechanisms of resistance and pave the way for drug combinations to overcome CPI resistance. Cases such as this support attempts to retreat with CPI if a patient clinical condition allows. Further research into the degree to which a ‘partially exhausted’ immune environment can be reactivated by further stim- ulation are warranted.
Author affiliations
1Drug Development Unit, Royal Marsden Hospital/ Institute of Cancer Research, Sutton, UK
2Department of Histopathology, Royal Marsden Hospital, London, UK 3Department of Radiology, Royal Marsden Hospital, London, UK
4Lung Unit, Royal Marsden Hospital, London, UK 5Lung Unit, Royal Marsden Hospital, Sutton, UK
Contributors AM: data collection, data analysis, data interpretation and manuscript preparation. WY: data analysis and data interpretation. MC, BG, IF, AW, SM, RR, AF, CB, RP, MC and CB: laboratory analysis. JEA: data collection. NF: tissue specimens. NT: radiology data preparation and interpretation. SC: laboratory analysis and
data interpretation. SP, MO, UB and JdB: data review and interpretation. JL: data analysis, data interpretation and manuscript preparation. All authors: manuscript review.
Funding This study represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research.
disclaimer The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
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.
patient consent for publication Obtained.
Minchom A, et al. J Immunother Cancer 2020;8:e000713. doi:10.1136/jitc-2020-000713
the case in context as a response to pembrolizumab rechallenge
This patient’s cancer is also exceptional in its responsive- ness to pembrolizumab on rechallenge. This phenomena has not be studied in detail. Though others report the potential for a response with CPI rechallenge,19 this is the first report, to our knowledge, of disease response on CPI rechallenge in mesothelioma.