Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers.

Abstract

BACKGROUND:

Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs.

METHODS:

We conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset.

RESULTS:

The mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement.

CONCLUSIONS:

Patients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.

• Authors: Giovanni Fucà, Romain Cohen, Sara Lonardi, Kohei Shitara, Maria Elena Elez, Marwan Fakih, Joseph Chao, Samuel J Klempner, Matthew Emmett, Priya Jayachandran, Francesca Bergamo, Marc Díez García, Giacomo Mazzoli, Leonardo Provenzano, Raphael Colle, Magali Svrcek, Margherita Ambrosini, Giovanni Randon, Aakash Tushar Shah, Massimiliano Salati, Elisabetta Fenocchio, Lisa Salvatore, Keigo Chida, Akihito Kawazoe, Veronica Conca, Giuseppe Curigliano, Francesca Corti, Chiara Cremolini, Michael Overman, Thierry Andre, Filippo Pietrantonio
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 10 Issue 2 (02 2022) ISSN: 2051-1426 [Electronic] England
• PMID: 35110358 (Publication Type: Journal Article, Multicenter Study)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Immune Checkpoint Inhibitors

Topics

• Aged
• Ascites (etiology, pathology)
• Colorectal Neoplasms (complications, drug therapy, mortality)
• Female
• Humans
• Immune Checkpoint Inhibitors (adverse effects, pharmacology)
• Male
• Microsatellite Instability
• Neoplasm Metastasis
• Retrospective Studies
• Stomach Neoplasms (complications, drug therapy, mortality)
• Survival Analysis