Immunotherapy combined with hypofractionated radiotherapy and chemotherapy for locally recurrent rectal cancer (TORCH-R): A prospective, single-arm, two-cohort, phase II trial.

3523 Background: To assess whether the integration of PD-1 inhibitor with hypofractionated radiotherapy and chemotherapy therapy can lead to an improvement in objective responses in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) locally recurrence rectal cancer (LRRC). Methods: We did a prospective, single-arm, two-cohort, phase 2 trial in LRRC patients without or with oligometastases. Eligible patients with previously untreated (cohort A) or progressive disease after first line therapy (cohort B), were assigned received 25-40 Gy/5 Fx irradiation or 15–30 Gy/5 Fx reirradiation for pelvic recurrence, followdd by 18 weeks of chemotherapy, toripalimab, and stereotactic ablative radiotherapy (SABR) for all metastatic lesions between chemoimmunotherapy cycles. The primary endpoint was confirmed local recurrence objective response rate (ORR). The study is registered with ClinicalTrials.gov, NCT05628038. Results: Between Oct 15, 2022, and Aug 31, 2024, We enrolled 67 patients: 41 in cohort A and 26 in cohort B. Median follow-up duration was 10.5 months (IQR 7.3-15.5 months). The local recurrence ORR was achieved at 82.9% (34 of 41 patients) in cohort A and 65.4% (17 of 26 patients) in cohort B. Six patients (14.7%) underwent radical resections (R0) in cohort A and two patients (7.7%) in cohort B. The CR rate was 34.1% (12 cCR patients + 2 pCR patients) in cohort A and 11.5% (2 cCR patients + 1 pCR patients) in cohort B. The most frequent grade 3-4 toxicities were neutropenia (10.8% in cohort A and 25.0% in cohort B) and diarrhea (16.2% in cohort A and 20.8% in cohort B). Conclusions: The PD-1 inhibitor remarkably improved ORR in pMMR/MSS LRRC compared with historical benchmark with acceptable toxicity. Up-front immunochemotherapy combined with hypofractionated radiotherapy was selected for future definitive study. Clinical trial information: NCT05628038 .