Immunotherapy-based total neoadjuvant therapy with or without short-course radiotherapy for locally advanced rectal cancer: Preliminary results of TORCH-iTNT.

3644 Background: In patients with proficient mismatch repair (pMMR) locally advanced rectal cancer (LARC), the integration of PD-1 inhibitor into total neoadjuvant chemoradiotherapy (iTNT) has demonstrated promising potential to enhance complete response (CR) rates and facilitate organ preservation. However, the combined use of radiotherapy and surgical intervention frequently leads to increased functional impairment relative to either modality administered independently. Concurrently, the combination of chemotherapy and PD-1 inhibitor has been shown to promote tumor downstaging, thereby enabling sphincter-preserving surgery while mitigating radiation-induced injury. This trial evaluates oncological efficacy and functional outcomes of two iTNT regimens: CAPOX plus PD-1 inhibitor with or without SCRT in neoadjuvant treatment of pMMR LARC patients. Methods: The TORCH-iTNT trial (NCT06281405) is a prospective, multicenter, randomized phase II study involving 192 patients with pMMR LARC (T3-4/N+M0). Participants were randomized into Group A (6 cycles of CAPOX plus toripalimab) or Group B (SCRT [25Gy/5Fx] followed by 6 cycles of CAPOX plus toripalimab). Patients achieving clinical complete response (cCR) were offered a watch-and-wait (W&W) strategy, while those without cCR were advised to undergo surgery. Group A patients with positive circumferential margins received adjuvant chemoradiotherapy. The primary endpoint was CR rate (pathological complete response [pCR] plus cCR). Secondary endpoints included organ preservation rate, anorectal function, adverse effects, and survival outcomes. Results: By December 31, 2025, 192 patients were enrolled, with 137 completing treatment (Group A: 65; Group B: 72). Baseline characteristics were balanced, with 97.1% (133/137) exhibiting at least one high-risk feature: lower tumor location (≤5cm), cT4, cN2, MRF+, or EMVI+. In Group A, 5 patients achieved cCR and adopted W&W, compared to 22 in Group B. Of the 54 and 49 patients in Group A and B who underwent surgery, pCR was observed in 19 (35.2%) and 22 (44.9%) cases, respectively. Five non-cCR patients in Group A declined surgery or were still undergoing treatment. Disease progression occurred in one patient per group. The overall CR rates were 36.9% (24/65) in Group A and 61.1% (44/72) in Group B. The most frequent grade 3-4 toxicity was thrombocytopenia (Group A: 12.3%; Group B: 12.5%). Conclusions: This study is the first comparative analysis of two iTNT regimens in LARC. Unprecedentedly, neoadjuvant CAPOX plus PD-1 inhibitor achieved a promising CR rate in pMMR LARC, and this CR rate can be further enhanced with the addition of SCRT prior to immunochemotherapy. Further follow-up is necessary to assess long-term efficacy and functional endpoints. Clinical trial information: NCT06281405 .