Neoadjuvant PD-1 blockade with toripalimab with or without celecoxib for patients with mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): long-term outcomes of a single-centre, parallel-group, non-comparative, randomised phase 2 trial

Background: Neoadjuvant PD-1 blockade has demonstrated high rates of pathological complete response in patients with mismatch repair-deficient or microsatellite instability-high, locally advanced colorectal cancer. However, prospective data on long-term survival remain limited. Here, we report the 5-year outcomes from the phase 2 PICC study (NCT03926338) evaluating neoadjuvant toripalimab with or without celecoxib in this population. Methods: The PICC study was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study. A total of 34 patients with stage II-III mismatch repair-deficient or microsatellite instability-high colorectal cancer were enrolled between May 1, 2019, and April 1, 2021, and randomly assigned (1:1) to receive neoadjuvant toripalimab plus celecoxib or toripalimab alone every 14 days for six cycles before surgery. The primary endpoint was pathological complete response, which was previously met. Secondary endpoints included long-term oncologic outcomes, with 5-year overall, cancer-specific, disease-free, and event-free survival assessed in the modified intention-to-treat population. Quality of life was also evaluated as a secondary endpoint in this analysis. Data were analysed with a cutoff date of June 22, 2025. Findings: Of the 34 patients enrolled, all were assessable and randomised to toripalimab plus celecoxib (n = 17) or toripalimab monotherapy (n = 17). At a median follow-up of 61.9 months (IQR, 55.8-63.6), no disease recurrence was observed in either group. The 5-year overall survival rates were 100% (95% CI 100-100) and 94% (95% CI 84-99) in the combination and monotherapy groups, respectively. Cancer-specific survival at 5 years was 100% (95% CI 100-100) in both groups. The 5-year event-free survival rates were 100% (95% CI 100-100) and 93% (95% CI 80-99), and the 5-year disease-free survival rates were 100% (95% CI 100-100) and 93% (95% CI 80-99), respectively. Adverse events were mostly grade 1-2; two patients experienced grade ≥3 events during the perioperative treatment and two developed asymptomatic hypothyroidism during follow-up. At 3 years post-surgery, both groups reported high QLQ-C30 functional scores (86.7-100.0) and low symptom burden (mostly <10.0). QLQ-CR29 showed similarly preserved anxiety, body image (90.4-98.8), and low-to-moderate sexual interest (16.7-44.4), with low symptom burden (0-16.7). Interpretation: These results demonstrate encouraging long-term survival outcomes, and suggest ongoing evaluation of a therapeutic neoadjuvant toripalimab strategy, with or without celecoxib, for mismatch repair-deficient or microsatellite instability-high localized colorectal cancer patients. Funding: This study was supported by the National Natural Science Foundation of China, the National Key Clinical Discipline of China, the Program of Guangdong Provincial Clinical Research Centre for Digestive Diseases, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research Fund.