dMMR/MSI tumour occurrence during follow-up of patients with Lynch syndrome treated with immune checkpoint inhibitors for a metastatic digestive cancer between 2015 and 2024: A retrospective monocentric cohort.

96 Background: Immune check point inhibitor(s) (ICIs) transformed the prognosis of patients with metastatic dMMR/MSI cancers especially for patients with Lynch syndrome (LS). The aim of our study was to describe a population of LS carrier patients treated with ICI(s) for metastatic digestive cancer, specifically assessing the risk of developing metachronous cancer. Methods: We collected data of 93 patients with LS, treated by ICI(s) for a metastatic digestive tumour. These patients were selected from the “immunoMSI” patient cohort, which included all patients presenting with a MSI and/or dMMR digestive cancer treated with ICI(s) between February 2015 and April 2024 in the medical oncology department of Saint-Antoine Hospital (Paris, France). Our primary outcome was the cumulative risk of metachronous MSI/dMMR cancer; secondary outcomes included cumulative risk and time to de novo colorectal polyps, as well as PFS and OS under ICI(s). We performed a cox model to assess the association of predefined variables with OS and PFS under ICI(s). Results: Patients most frequently carried a germline pathogenic variant on the MSH2 (or EPCAM ) gene (47%) or on the MLH1 gene (30%). The majority presented with colorectal cancer (CRC) as their primary cancer (83%), followed by small intestine tumours (6%), stomach and pancreatic cancers (4%) and bile duct cancer (1%). Median age at cancer index was 62 years-old (26-77). A total of 12 out of 93 patients presented metachronous cancers during or after treatment with ICI(s). Ten of these metachronous cancers were dMMR or within the LS spectrum (urothelial n=4, CRC n=2, bilio-pancreatic n=1 and 3 skin cancers including 2 kerato-acanthomas). All patients who developed a metachronous cancer had a complete or partial response under ICI(s) for the index cancer. During a median follow-up of 47.8 months, 44 patients had colonoscopies and a total of 17 patients (39,5 %) developed pre neoplastic colorectal polyps. In multivariate analysis, PS ≥ 2 and age ≥ 70 years were associated with poorer OS with HRs of 6.3 (95% CI [1.5-25.9], p=0.01) and 5.5 (95% CI [1.6-18.9], p=0.006) respectively. Conclusions: Our results show that ICI(s) for patients with LS treated for an MSI/dMMR metastatic digestive cancer can still develop metachronous cancers and pre neoplastic polyps, which underlines the importance of maintaining dedicated follow-up after ICI(s) treatment in this population.