Curative immune checkpoint inhibitors therapy in patients with mismatch repair-deficient locally advanced rectal cancer: a real-world observational study

Sustained clinical complete remissions were reported in all of 23 mismatch repair deficient/microsatellite instable (dMMR/MSI) locally advanced rectal cancer (LARC) patients treated with dostarlimab alone in a recent phase II study. These results led to off-label use of dostarlimab or other immune checkpoint inhibitors (ICIs) in dMMR/MSI-LARC even before regulatory approval. The present study [STAR(t)-IT-REDUCE] describes the outcome of dMMR/MSI-LARC patients treated with ICI in Italy. Investigator-initiated, observational, retrospective-cohort, multicentric study of ICI treatment in dMMR/MSI-LARC. Patients were eligible if treated with ≥1 ICI dose from July 2022 to December 2023 (date of approval of dostarlimab for this indication in Italy). Seventeen dMMR/MSI-LARC patients (13 of 17 treatment-naïve) were eligible. Fourteen patients completed 6 months of treatment, two discontinued after four doses and one after five doses because of immune-related pneumonia, social constraints, or non-oncological bowel obstruction, respectively. Overall, 16 of 17 assessable patients [94.1%; 95% confidence interval (CI) 69.24% to 99.69%, ‘ITT analysis’] achieved complete clinical response (cCR). Ten of 11 treatment-naïve patients completing 6 months of treatment had cCR (90.9%; 95% CI 57.12% to 99.52%, ‘per-protocol analysis’). One patient with near-CR underwent rectal surgery and minimal residual intramucosal tumor was found. With a median follow-up of 9.5 months, no local relapse occurred. One patient developed unconfirmed lung metastases. Two grade 3 and no grade 4 adverse events were reported. The present STAR(t)-IT-REDUCE study documents the immunoablative and curative activity of ICI monotherapy in dMMR/MSI-LARC. Toxicity and compliance issues inherent to real-world practice are limited and do not affect achievement of initial complete tumor response but may limit response duration. •All LARC must be tested for MMR status before treatment decision.•Durable complete responses can be achieved by sole ICI immunotherapy in dMMR/MSI-LARC.•ICI immunotherapy in dMMR/MSI-LARC can spare chemotherapy, radiotherapy, or surgery.