envafolimab as neoadjuvant immuntherapy in resectable local advanced dmmr/msi-h colorectal cancer

Conditions: Colorectal Cancer; Mismatch Repair-deficient (dMMR); Microsatellite Instability-high (MSI-H); Neoadjuvant Therapy

Summary: colorectal cancer (crc) is one of the most common malignant tumours of human beings. mismatch repair-deficient (dmmr)/ microsatellite instability-high (msi-h) crc is a specific subtype of crc, which accounts for approximately 15% of all crc patients, and can not benefit from 5-fluorouracil (5-fu) adjuvant chemotherapy. once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and thus lead to much worse prognosis 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. another study (clinicaltrials.gov, nct03926338) which investigating the effect of neoadjuvant pd-1 blockade with toripalimab, with or without celecoxib, on mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer. the result revealed that all 34 patients had an r0 resection. 15 of 17 patients (88%) in the toripalimab plus celecoxib group and 11 of 17 patients (65%) in the toripalimab monotherapy group had a pathological complete response. in theory, anti-pd-l1 drugs should have fewer immune side-effects than anti-pd-1 drugs. however, there are no reports of anti-pd-l1 neoadjuvant therapy for the dmmr/msi-h colorectal cancer. therefore, the aim of this study was to investigate the efficacy and safety of anti-pd-l1 monoclonal antibody (envafolimab) as neoadjuvant immuntherapy for resectable local advanced colorectal cancer patient with the dmmr/msi-h.


Eligibility criteria:
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 \> 18 years \< 70 of age. 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 or radiologic evaluation of tumor regression \< 20% or unacceptable toxic effects during neoadjuvant chemotherapy. 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 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. 10. with any distant metastasis.