Neoadjuvant immunotherapy combined with radiochemotherapy vs chemotherapy alone in pMMR colon cancers: The TORCH-C randomized phase 2 clinical trial.

3634 Background: The prognosis for locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4 stage remains poor, with high rates of recurrence and metastasis. Immunotherapy has become the standard treatment for deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) colon cancer. However, there has been little progress for the majority of cases, which was mismatch-repair proficient or microsatellite stable (pMMR/MSS). For locally advanced colon cancer with T4b stage or bulky lymph nodes, neoadjuvant chemotherapy is currently widely used. Whether combining it with immunotherapy and radiotherapy can improve efficacy is worthy of exploration. TORCH-C is the first study to evaluate this combination. Methods: TORCH-C is a prospective, multicenter, randomized phase 2 study that enrolled patients from April 3, 2023, through September 9, 2025. A total of 120 high-risk LACC (T4/bulky N+M0，pMMR/MSS) patients were 1:1 randomized to either an immunotherapy combined with SCRT and CAPOX chemotherapy group (group A) or a chemotherapy alone group (group B). Patients in the group B received 4 cycles of CAPOX (oxaliplatin 130 mg/m 2 intravenously day 1 and capecitabine 1000 mg/m 2 orally days 1-14). Patients in the group A received SCRT (25Gy in 5 fraction) and 4 cycles of the PD-1 inhibitor (serplulimab, 300mg intravenously day 1) combined with CAPOX. The radiotherapy target volume includes only the primary colon tumor and enlarged lymph nodes, without elective nodal irradiation. After neoadjuvant therapy, patients will be evaluated for radical colon resection. All patients will receive adjuvant chemotherapy of four cycles of CAPOX. The primary outcome was pathological complete response (pCR) rate. The secondary outcomes included tumor downstaging, R0 resection, 3-year disease free survival (DFS), 3-year overall survival (OS), 3-year local recurrence-free survival and treatment-related toxicity. Results: 120 patients have been enrolled and randomized. 107 patients were included in the mITT analysis (54 in group A and 53 in group B). 103 have received surgery (50 in the chemotherapy group, 53 in the radiotherapy group). The pCR rate was 10% (5/50) in chemotherapy group (group B) and 45.3% (24/53) in the radiotherapy group (group A) ( P <0.05). The most common grade 3-4 adverse event (AE) among patients was thrombocytopenia, (22.2%, 12/54) in the group A and (18.9%, 10/53) in the group B. Conclusions: The combination of PD-1 inhibitor, SCRT, and chemotherapy shows promising efficacy and significantly improved pCR rates in patients with MSS/pMMR high-risk LACC. This regimen may provide a new therapeutic option to achieve R0 resection and improve long-term survival. Clinical trial information: NCT05732493 .