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

Neoadjuvant PD-1 Blockade by Toripalimab With or Without Celecoxib in Mismatch-repair Deficient or Microsatellite Instability-high Locally Advanced Colorectal Cancer (PICC)

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.

The PICC trial is an investigator-initiated, multi-cohort platform trial designed to evaluate the efficacy and safety of neoadjuvant toripalimab, with or without celecoxib, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) locally advanced colorectal cancer. Each cohort within the PICC platform was independently conducted and analyzed according to prespecified objectives.

The initial exploratory cohort, PICC-1, was originally planned to enroll 20 eligible patients to receive neoadjuvant toripalimab plus celecoxib or toripalimab alone, with the primary objective of assessing feasibility and safety. The study was amended in August 2020 to change the primary objective to evaluating whether 6 cycles of neoadjuvant toripalimab with or without celecoxib improves the pathological complete response (pCR) rate compared with historical controls, with an updated planned enrollment of 34 eligible patients, who were to be randomized 1:1 between the two treatment groups. In May 2021, an additional 16 eligible patients were included in this exploratory cohort for translational research purposes.

The study was amended in April 2022 to add a new cohort, PICC-2, which was designed to formally compare the efficacy and safety of 12 cycles of neoadjuvant toripalimab plus celecoxib versus toripalimab monotherapy in patients with dMMR or MSI-H locally advanced colorectal cancer. A total of 110 eligible patients are planned to be randomized 1:1 between the two treatment groups.

The study was amended in June 2025 to add a new cohort, PICC-3, which was designed to evaluate the 3-year event-free survival (EFS) of 12 cycles of toripalimab plus celecoxib administered as neoadjuvant or definitive therapy in patients with dMMR or MSI-H locally advanced colorectal cancer. Approximately 108 eligible patients are expected to be enrolled.

Inclusion Criteria:

1. Willing and able to provide written informed consent.
2. Histological or cytological documentation of adenocarcinoma of the colon or rectum.
3. Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR).
4. Male or female subjects aged 18 to 75 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Determined CT or MRI scans (done within 14 days of registration) of the chest, abdomen and pelvis: locally advanced (cT3-4 or cN1-2 [with the definition of a clinically positive lymph node being any node ≥ 1.0 cm]).
7. Non complicated primary tumor (obstruction, perforation, bleeding).
8. No previous any systemic anticancer therapy for colorectal cancer disease.
9. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment.

Exclusion Criteria:

1. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization.
2. Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment.
3. Heart failure grade III/IV (NYHA-classification).
4. Unresolved toxicity higher than CTCAE v.4.0 Grade 1 attributed to any prior therapy/procedure.
5. Subjects with known allergy to the study drugs or to any of its excipients.
6. Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study.
7. Breast- feeding or pregnant women
8. Lack of effective contraception.
9. Previously received anti-programmed death-1 (PD-1) or its ligand (PD-L1) antibody, anti-cytotoxic T lymphocyte-associated antigen 4 (cytotoxic T-lymphocyte-associated Protein 4, CTLA-4) antibody or other drug/antibody that acts on T cell costimulation or checkpoint pathways.
10. With any distant metastasis.