Patient case: 68-year-old male with colon cancer; genetic feature: MLH1 methylation suppression (microsatellite instability)

Clinical trial: Toripalimab With or Without Celecoxib as Neoadjuvant Therapy in Resectable dMMR/MSI-H Colon 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 colon cancer. Therefore, the aim of this study was to find the best multidisciplinary treatment for resectable colon 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.


Eligibility: Inclusion Criteria:
  1. Willing and able to provide written informed consent.
  2. Histological or cytological documentation of adenocarcinoma of the colon (≥ 15 cm from the anal verge).
  3. Determined preoperatively by either spiral or multidetector CT: high risk T3 (tumor disruption of muscle wall and extension into pericolic fat with more than 5 mm protrusion into adjacent mesenteric fat) or T4 (tumor penetrates to the surface of the visceral peritoneum or directly invades or is adherent to adjacent organs or structures).
  4. Male or female subjects > 18 years < 70 of age.
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  6. CT or MRI scans (done within 30 days of registration) of the chest, abdomen and pelvis all without clear evidence of distant metastatic (M1) disease.
  7. Non complicated primary tumor (obstruction, perforation, bleeding).
  8. No previous any systemic anticancer therapy for colon 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
  10. Tumor tissues were identified as mismatch repair-deficient (dMMR) by immunohistochemistry (IHC) method or microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR).
  Exclusion Criteria:
  1. Previous or concurrent cancer that is distinct in primary site or histology from colon 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.

Relevance to patient case: not relevant