Total neoadjuvant immunochemotherapy for proficient mismatch repair or microsatellite stable locally advanced rectal cancer.

Objective: Our goal was to assess the efficacy of integrating PD-1 inhibitors with total neoadjuvant treatment (iTNT) in enhancing complete response (CR) rates and the propensity for watch-and-wait (WW) strategies in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). Methods: A retrospective analysis of data prospectively collected was performed. Enrolled patients were divided into Group SCRT-IC, which received short-course radiotherapy (SCRT) followed by six cycles of consolidation immunotherapy with capecitabine and oxaliplatin, or to Group IC-SCRT, which underwent two cycles of induction immunotherapy followed by SCRT and the remaining four cycles of chemotherapy. The primary endpoint was CR. Results: A total of 141 patients were included (72 in Group SCRT-IC and 69 in Group IC-SCRT). At a median follow-up of 29 months, the CR rates were 55.6% in Group SCRT-IC and 53.6% in Group IC-SCRT. The pCR rates were reported at 50% for both groups. Seventeen patients in each group were treated with WW and remained disease-free. The most prevalent grade 3 to 4 toxicities were thrombocytopenia and neutropenia. The cCR rate was a little higher in Group SCRT-IC (56.9% compared to 53.6%), and the incidence of grade 3 to 4 thrombocytopenia was lower in Group SCRT-IC (24.2% vs. 33.9%). Conclusion: iTNT regimen has significantly improved the CR rate for pMMR/MSS LARC compared to historical standards, with acceptable toxicity. The approach of prioritizing SCRT followed by immunotherapy is a promising strategy for definitive investigation in future studies.