Neoadjuvant Toripalimab With or Without Celecoxib in dMMR/MSI-H Colorectal Cancer

Summary

Colorectal cancer of Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) accounts for approximately 15% of all colorectal cancer patients, with a higher proportion in right colon cancer. Previous studies have found that colon cancer patients with dMMR/MSI-H cannot benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy. Once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and the prognosis is significantly worse than that of mismatch repair-proficient (pMMR)/microsatellite stability (MSS). A phase II clinical study of anti-PD-1 immunotherapy based on mismatch repair (MMR) status published in 《N Engl J Med》 showed that the objective response rate (ORR) of advanced colorectal cancer patients with dMMR received anti-PD-1 is 40%, and a longer response time can be obtained compared to conventional chemotherapy. Anti-PD-1 neoadjuvant therapy has proven to be safe and feasible in lung cancer, bladder cancer and malignant melanoma, and can achieve more than 40% of major pathological response. However, there are no reports of anti-PD-1 neoadjuvant therapy for the dMMR/MSI-H colorectal cancer. Therefore, the aim of this study was to find the best multidisciplinary treatment for resectable colorectal cancer patient with the dMMR/MSI-H phenotype and to explore whether cyclooxygenase (COX) inhibitors combined with anti-PD-1 monoclonal antibody (mAb) could further improve efficacy.

Timeline

Start

2019-05-10

Primary completion

2027-04-01

Completion

2030-04-01

Outcome

Met primary endpoint

paper Pathological complete response was observed in 49 of 55 patients (89% [95% CI 78-96]) in the toripalimab plus celecoxib group versus 38 of 55 PMID 42385761 ↗

paper between-group difference 19 percentage points [95% CI 4-34]; p=0·014 PMID 42385761 ↗

Publications

• Hu H, Shen X, Li Y, Zhou J, Liu P, Zhang J, Hou Y, Wang X, Deng J, Zheng Z, Li J, Lan P, Wu X, Kang L, Huang M, He Z, He X, Yang Z, Huang L, Wang H, Wang H, Luo S, Chen D, Xie X, Zhang Y, Zhai X, Li S, Li W, Hu J, Yang T, Wang C, Deng W, Huang Y, Cao W, Li F, Shi L, Ling L, Deng Y. Neoadjuvant toripalimab plus celecoxib versus toripalimab monotherapy for mismatch repair-deficient or microsatellite instability-high, locally advanced colorectal cancer (PICC-2): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2026 Jul 1:S1470-2045(26)00220-2. doi: 10.1016/S1470-2045(26)00220-2. Online ahead of print.
• Cao W, Hu H, Li J, Wu Q, Shi L, Li B, Zhou J, Wang X, Chen J, Wang C, Wang H, Deng W, Huang Y, Deng Y. China special issue on gastrointestinal tumors-Radiological features of pathological complete response in mismatch repair deficient colorectal cancer after neoadjuvant PD-1 blockade: A post hoc analysis of the PICC phase II trial. Int J Cancer. 2023 Dec 1;153(11):1894-1903. doi: 10.1002/ijc.34647. Epub 2023 Jul 6.
• Hu H, Kang L, Zhang J, Wu Z, Wang H, Huang M, Lan P, Wu X, Wang C, Cao W, Hu J, Huang Y, Huang L, Wang H, Shi L, Cai Y, Shen C, Ling J, Xie X, Cai Y, He X, Dou R, Zhou J, Ma T, Zhang X, Luo S, Deng W, Ling L, Liu H, Deng Y. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2022 Jan;7(1):38-48. doi: 10.1016/S2468-1253(21)00348-4. Epub 2021 Oct 22.
• Wang D, Cabalag CS, Clemons NJ, DuBois RN. Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer. Gastroenterology. 2021 Dec;161(6):1813-1829. doi: 10.1053/j.gastro.2021.09.059. Epub 2021 Oct 2.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Celecoxib	Other / unclassified	200 mg	Oral
Subject	Toripalimab	Monoclonal antibody	3 mg/kg	Intravenous

Indications