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.
Willing and able to provide written informed consent.
Histological or cytological documentation of adenocarcinoma of the colon or rectum.
Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR).
Male or female subjects aged 18 to 75 years.
Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization.
Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment.
Heart failure grade III/IV (NYHA-classification).
Unresolved toxicity higher than CTCAE v.4.0 Grade 1 attributed to any prior therapy/procedure.
Sequential
Neoadjuvant toripalimab plus celecoxib for 6 cycles
DrugToripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 6 cycles, and celecoxib was given orally at 200 mg twice daily from day 1 to day 14 of each cycle, followed by surgery.
Neoadjuvant toripalimab monotherapy for 6 cycles
DrugToripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 6 cycles, followed by surgery.
Neoadjuvant toripalimab plus celecoxib for 12 cycles
DrugToripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 12 cycles, and celecoxib was given orally at 200 mg twice daily from day 1 to day 14 of each cycle, followed by surgery.
Neoadjuvant toripalimab monotherapy for 12 cycles
DrugToripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 12 cycles, followed by surgery.
Toripalimab plus celecoxib as neoadjuvant or definitive therapy
DrugToripalimab was administered intravenously over 30 minutes at a dose of 3 mg per kilogram on day 1 of each 14-day cycle, every 2 weeks for a total of 12 cycles, and celecoxib was given orally at 200 mg twice daily from day 1 to day 14 of each cycle, followed by surgery or non-operative management based on restaging (non-operative management was recommended for patients with a complete clinical response).
Pathological complete response (pCR) rates (PICC-1 and PICC-2 cohorts)
The proportion of patients who achieved a pCR, which was defined as the absence of residual viable tumor cells in the primary tumor and all sampled lymph nodes at surgery.
Event-free survival (EFS) (PICC-3 cohort)
Defined as the time from randomization until the date of one of the following events (whichever occurred first): disease progression that precluded surgery, local R2 resection, local recurrence after an R0/1 resection, distant metastases, a new primary colorectal cancer, or death from any cause.
Overall survival (OS)
Defined as the time from randomization to death from any cause.
R0 resection rates
The proportion of patients achieved a complete resection with negative margin.
Surgical and perioperative treatment safety
Assessed by evaluation of treatment-related adverse events
Surgery feasibility
Any treatment-related delays in the planned surgery of no more than 28 days after the last preoperative toripalimab dose
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