Abstract
PurposeImmune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response marker in patients with GI cancers treated with immune checkpoint inhibitors.MethodsDetailed clinical and response data were collected from six patients with metastatic MSI-H/dMMR GI cancers treated with immune checkpoint inhibitors. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumors and matched normal tissue were profiled by targeted next generation sequencing (127 gene panel, size 0.8 Mb). Impact of included mutation types, germline filtering methodology and different variant allele frequency thresholds on TMB estimation was assessed.ResultsObjective radiographic responses were observed in all six patients, and complete response was achieved in two of the six patients. Responses were durable (minimum 25 months). TMB estimates were clearly above the two recently reported cut-offs for metastatic colorectal cancer of 12 or 37 mutations per megabase for five of six patients, respectively, while one patient had borderline TMB elevation. TMB did not show an association with extent and duration of response but was influenced by included mutation types, germline filtering method and variant allele frequency threshold.ConclusionOur case series confirms the clinical benefit of immune checkpoint blockade in patients with metastatic MSI-H/dMMR GI cancers and illustrates the vulnerability of TMB as predictive marker in a subset of patients.
Highlights
In 2017, the U.S Food and Drug Administration (FDA) granted approval to the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab for patients with unresectable or metastatic, microsatellite instabilityhigh (MSI-H) or mismatch repair-deficient solid tumors that have progressed following prior treatment and who have no alternative treatment options as well as for patients with MSI-H/dMMR metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan
PD-1 inhibition for all patients was started between June 2016 and August 2017
Four patients were treated with pembrolizumab, while one patient received a combination of radiotherapy and nivolumab, and one patient nivolumab alone
Summary
In 2017, the U.S Food and Drug Administration (FDA) granted approval to the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab for patients with unresectable or metastatic, microsatellite instabilityhigh (MSI-H) or mismatch repair-deficient (dMMR) solid tumors that have progressed following prior treatment and who have no alternative treatment options as well as for patients with MSI-H/dMMR metastatic colorectal cancer (mCRC) after failure of fluoropyrimidine, oxaliplatin, and irinotecan. This approval was recognized as a breakthrough given the fact that this was FDA’s first tumor siteagnostic approval. The use of checkpoint inhibitors administered only twice during the waiting period for curative surgery in early stage colon cancer led to complete pathological remissions in four of seven patients with MSI-H colon cancer, while none of eight patients with a microsatellite stable tumor exhibited signs of major pathohistological remission (Chalabi et al 2018)
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