Primary resistance to immunotherapy in patients with a dMMR/MSI metastatic gastrointestinal cancer: who is at risk? An AGEO real-world study

• Published in: British journal of cancer 2024-02, Vol.130 (3), p.442-449
• Main Authors: Flecchia, Clémence, Auclin, Edouard, Alouani, Emily, Mercier, Mathilde, Hollebecque, Antoine, Turpin, Anthony, Mazard, Thibault, Pernot, Simon, Dutherage, Marie, Cohen, Romain, Borg, Christophe, Hautefeuille, Vincent, Sclafani, Francesco, Ben-Abdelghani, Meher, Aparicio, Thomas, De La Fouchardière, Christelle, Herve, Camille, Perkins, Geraldine, Heinrich, Kathrin, Kunzmann, Volker, Gallois, Claire, Guimbaud, Rosine, Tougeron, David, Taieb, Julien
• Format: Article
• Language: English
• Subjects: 631/67/1059/2325; 692/699/67/1504; Biomedical and Life Sciences; Biomedicine; Brain Neoplasms; Cancer; Cancer Research; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; DNA Mismatch Repair; Drug Resistance; Epidemiology; Gastrointestinal cancer; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - genetics; Humans; Immune checkpoint inhibitors; Immunotherapy; Life Sciences; Liver Neoplasms - genetics; Liver Neoplasms - therapy; Metastases; Metastasis; Microsatellite Instability; Middle Aged; Molecular Medicine; Neoplastic Syndromes, Hereditary; Oncology; Patients; Retrospective Studies
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-023-02524-3

Background The outstanding efficacy of immunotherapy in metastatic dMMR/MSI gastro-intestinal (GI) cancers has led to a rapid increase in the number of patients treated. However, 20-30% of patients experience primary resistance to immune checkpoint inhibitors (ICIPR) and need better characterization. Methods This AGEO real-world study retrospectively analyzed the efficacy and safety of ICIs and identified clinical variables associated with ICIPR in patients with metastatic dMMR/MSI GI cancers treated with immunotherapy between 2015 and 2022. Results 399 patients were included, 284 with colorectal cancer (CRC) and 115 with non-CRC, mostly treated by an anti-PD(L)1 (88.0%). PFS at 24 months was 55.8% (95CI [50.8–61.2]) and OS at 48 months was 59.1% (95CI [53.0–65.9]). ORR was 51.0%, and 25.1% of patients were ICIPR. There was no statistical difference in ORR, DCR, PFS, or OS between CRC and non-CRC groups. In multivariable analysis, ICIPR was associated with ECOG-PS ≥ 2 (OR = 3.36), liver metastases (OR = 2.19), peritoneal metastases (OR = 2.00), ≥1 previous line of treatment (OR = 1.83), and age≤50 years old (OR = 1.76). Conclusion These five clinical factors associated with primary resistance to ICIs should be considered by physicians to guide treatment choice in GI dMMR/MSI metastatic cancer patients.