Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Feb;6(1):100036.
doi: 10.1016/j.esmoop.2020.100036. Epub 2021 Jan 15.

Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials

F Pietrantonio  1 , G Randon  2 , M Di Bartolomeo  2 , A Luciani  3 , J Chao  4 , E C Smyth  5 , F Petrelli  3
Affiliations

Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials

F Pietrantonio et al. ESMO Open. 2021 Feb.

Abstract

Background: Several post hoc analyses of randomized controlled trials (RCTs) suggested the importance of microsatellite instability (MSI) as a positive predictive factor to immunotherapy in patients with advanced gastric cancer (GC); however, individually these have low statistical power.

Methods: RCTs investigating treatment with or without an anti-programmed cell death protein 1 (PD-1) agent for advanced GC and providing outcome according to MSI status were selected. The hazard ratio (HR) and the odds ratio were used to compare the treatment effect on survival outcomes and tumor response, respectively, for anti-PD-1-based therapy compared with standard therapy. Evidence for treatment effect by MSI status was evaluated by a test of interaction.

Results: The phase III KEYNOTE-062, CheckMate-649, JAVELIN Gastric 100 and KEYNOTE-061 trials were included. A total of 2545 patients with evaluable MSI status were included and 123 (4.8%) had MSI-high cancers. The HR for overall survival benefit with anti-PD-1-based regimens was 0.34 (95% CI: 0.21-0.54) for MSI-high cancers versus 0.85 [95% confidence interval (CI): 0.71-1.00] for microsatellite stable. The treatment effect was significantly different in the two subgroups (P for interaction 0.003). In the MSI-high subgroup, the HR for progression-free survival was 0.57 (95% CI: 0.33-0.97; P = 0.04) and the odds ratio for response was 1.76 (95% CI: 1.10-2.83; P = 0.02).

Conclusions: Patients with MSI-high GC should be regarded as a specific and highly immunosensitive population worthy of dedicated clinical trials.

Keywords: advanced gastric cancer; immune checkpoint inhibitors; meta-analysis; microsatellite instability; randomized clinical trials.

PubMed Disclaimer

Conflict of interest statement

Disclosure FP reports personal fees from Amgen, Roche, Sanofi, Bayer, Servier, Merck-Serono, Lilly; advisory role with Amgen, Bayer, Servier, Merk-Serono and research grants from Bristol-Myers Squibb. AIRC under IG 2019 - ID. 23624 project – P.I. Pietrantonio Filippo. JC reports grants and personal fees from Merck, Amgen, Macrogenics, Ono Pharmaceuticals, Foundation Medicine, Daiichi-Sankyo and Bristol Myers Squibb. ES reports personal fees from AstraZeneca, Astellas, Bristol Myers Squibb, Celgene, Five Prime, Gritstone, Merck, Roche, Servier and Zymworks. The other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Forest plots showing (A) hazard ratio for overall survival, (B) progression-free survival and (C) overall response rate for anti-programmed cell death protein 1 (PD-1)-based treatment in MSI-high metastatic gastric cancer patients. CI, confidence interval; CT, chemotherapy; df, degrees of freedom; ICI, immune checkpoint inhibitor.
See this image and copyright information in PMC

References

    1. Le D.T., Durham J.N., Smith K.N. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413. - PMC - PubMed
    1. Bonneville R., Krook M.A., Kautto E.A. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017;2017 PO.17.00073. - PMC - PubMed
    1. Overman M.J., McDermott R., Leach J.L. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–1191. - PMC - PubMed
    1. Overman M.J., Lonardi S., Wong K.Y.M. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773–779. - PubMed
    1. Le D.T., Kim T.W., Van Cutsem E. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. 2020;38(1):11–19. - PMC - PubMed

MeSH terms

Substances