Neoadjuvant chemoradiotherapy with or without PD-1 blockade in pMMR/MSS low rectal cancer patients (CHOICE II): A multi-center, open-label, randomized controlled trial.

3640 Background: Neoadjuvant chemoradiotherapy (nCRT) combined with PD-1 blockade has shown great potential for improving the clinical complete response (cCR) rate in low rectal cancer patients in a previous exploratory clinical trial. This study aimed to further verify the efficacy and safety of nCRT with PD-1 blockade in patients with pMMR/MSS low rectal cancer. Methods: We conducted a prospective, multicenter, randomized, open-label trial (NCT05215379) with two parallel groups across 11 centers. Patients with confirmed cT 1-3a N 0-1 M 0 rectal adenocarcinoma of the pMMR/-MSS type, with an inferior margin of 5 cm from the anal verge, were randomly assigned to either the intervention group, receiving 50 Gy (2 Gy/d*25d) radiotherapy, 4 cycles of PD-1 blockade (sintilimab) and 2 cycles of CAPOX, or the control group, receiving 50 Gy (2 Gy/d*25d) radiotherapy and 2 cycles of CAPOX. After completion of neoadjuvant treatment, patients were reassessed to determine clinical efficacy. If patients achieved cCR, the Watch-and-Wait (W&W) approach was performed. If near-cCR (ncCR) was achieved, patients were re-evaluated by a multidisciplinary team to determine whether W&W, local excision, or total mesorectal excision (TME) should be performed. Patients assessed with an incomplete clinical response (iCR) received TME. The primary endpoint was the cCR rate, and the key secondary endpoints included the organ preservation (W&W and local excision) rate, disease free survival (DFS), and overall survival (OS). Results: From July 2022 to December 2024, a total of 201 patients with low rectal cancer were screened at 11 medical centers and 180 patients were finally randomly assigned. A total of 169 patients were included in the primary analysis (85 patients in the intervention group and 84 in control group). The cCR rates were 36.5% in the intervention group compared to 17.9% in the control group (p=0.007). There were 48 and 51 patients who underwent surgery in the intervention and control groups, respectively, and the pathological complete response (pCR) rates were 25.0% and 15.7% (p=0.249). The overall complete response (cCR+pCR) rates were 50.6% and 27.4% (p=0.002) in the intervention and control groups. The overall occurrence rates of adverse events (AEs) were 72.9% in the intervention group compared to 66.3% in the control group (P>0.05), and the occurrence of severe AEs (Grade III or IV) was comparable between the two groups (7.1% vs 3.8%, p=0.34). Due to the limited follow-up duration, the DFS and OS data are immature. Conclusion: In this trial, the results showed that nCRT combined with sintilimab significantly improved the cCR rate in patients with pMMR/MSS low rectal cancer with a tolerable safety profile. Clinical trial information: NCT05215379 .