The anti-PD-1 antibody pembrolizumab is an FDA-approved treatment of PD-L1-positive metastatic gastric cancer; however, only a subset of patients respond to this agent. Now, data from a phase II trial shed some light on the reasons for these variable responses.
“We designed a phase II trial, with integrated genomic analysis of all baseline tumour tissue samples and genomic profiling of circulating tumour DNA (ctDNA) samples in order to understand the disease characteristics of responders and nonresponders,” explains senior investigator Jyun Lee. This open-label trial included 61 patients with metastatic and/or recurrent gastric adenocarcinomas. The cohort included six patients with Epstein–Barr virus (EBV)-positive disease and seven with microsatellite-instability high (MSI-H) disease.
Similar to the findings of previous trials, an overall response rate (ORR) of 24.6% was observed. Notably, 85.7% of patients with MSI-H tumours, and all patients with EBV-positive disease, responded to pembrolizumab.
Researchers also investigated the relationship between biopsy-based tumour mutational burden (TMB) and response, observing a positive correlation with response to pembrolizumab (area under the curve 0.74; P = 0.006). A similar relationship was observed between ctDNA-based TMB, quantified using a 73-gene next-generation sequencing panel, and response to pembrolizumab. In a longitudinal analysis of samples from a subset of patients, changes in ctDNA level at 6 weeks after treatment with pembrolizumab were found to be predictive of a response: all four patients with increased ctDNA levels at 6 weeks had disease progression within 100 days of starting treatment.
“changes in ctDNA level at 6 weeks after treatment with pembrolizumab were found to be predictive of a response”
“The most significant finding of this work is that patients with MSI-H- or EBV-positive gastric cancer have robust and sustained responses to pembrolizumab monotherapy,” summarizes Lee, adding, “we also demonstrated that ctDNA mutational burden correlates very well with TMB and that decreasing ctDNA levels are a statistically significant predictor of prolonged progression-free survival.” Prospective validation of these findings, which have the potential to substantially improve the treatment of metastatic gastric cancer, is eagerly awaited.
This article is modified from the original in Nat. Rev. Clin. Oncol. (https://doi.org/10.1038/s41571-018-0079-y).
Kim, S. T. et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat. Med. https://doi.org/10.1038/s41591-018-0101-z (2018)
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Sidaway, P. Immunotherapy-responsive gastric cancers identified. Nat Rev Gastroenterol Hepatol 15, 582 (2018). https://doi.org/10.1038/s41575-018-0063-0
Cancer Science (2019)