Induction Chemotherapy Combined With Neoadjuvant Immunotherapy for MSS Colon Cancer

Induction Chemotherapy Combined With Neoadjuvant Immunotherapy for MSS Colon Cancer: a Prospective Single-center Multi-arm Open-label Randomized Phase II Study

This study aims to elucidate the regression effects of neoadjuvant chemotherapy combined with immunotherapy and adjuvant therapy in locally advanced MSS colon cancer.

The standard treatment for locally advanced colon cancer is surgery followed by adjuvant chemotherapy containing oxaliplatin. The MOSAIC and 16968 studies have shown that approximately 30% of patients experience recurrence and metastasis within 6-7 years after surgery. Neoadjuvant chemotherapy may improve the prognosis of patients with malignant tumors. The significant tumor shrinkage after neoadjuvant therapy indicates a greater likelihood of long-term survival for patients. The OPTICAL and FoxTROT studies have shown that approximately 35% of patients are resistant to oxaliplatin-containing neoadjuvant chemotherapy, with a pCR rate of less than 10% and uncertain survival improvement. In addition, immunotherapy has poor efficacy for microsatellite stable (MSS) patients. Therefore, it is necessary to explore new and effective neoadjuvant treatment modalities for tumor regression.

The study will screen for individuals who are sensitive to oxaliplatin-containing regimens through induction chemotherapy. Immunogenic cell death will be enhanced by oxaliplatin-induced immunogenicity and combined with anti-programmed cell death ligand 1 (PD-L1) monoclonal antibodies for neoadjuvant therapy. In the context of cancer, the role of the intestinal microbiome in mediating immune activation induced by chemotherapy drugs has been demonstrated. Clostridium butyricum will be introduced as an adjuvant to explore the possibility of further increasing the significant response rate of neoadjuvant therapy.

The study will first conduct 2 cycles of Capox induction chemotherapy to screen for patients sensitive to chemotherapy. Patients will be randomized into three cohorts: one chemotherapy standard control cohort (continuing Capox chemotherapy for 2 cycles) and two enhancement design cohorts (Capox chemotherapy + Anti-PD-L1 monoclonal antibody for 2 cycles/Capox chemotherapy + Anti-PD-L1 monoclonal antibody + Clostridium butyricum for 2 cycles), followed by CME surgery. The study's primary endpoint is the proportion of Tumor regression grade(TRG)0/1 in the pathological specimens of surgically resected tumors.

Inclusion Criteria:

• Age ≥18 years old and ≤75 years old.
• Pathologically diagnosed MSS or pMMR-type colon adenocarcinoma.
• The lower edge of the tumor is more than 12cm from the anus as measured by colonoscopy and the lower edge of the tumor cannot be directly palpated during rectal examination.
• Enhanced CT stage T3/4 or T1-4N+ without multiple primary tumors or distant metastasis.
• Life expectancy is expected to be more than 1 year.
• First diagnosis, no previous anti-tumor treatment received, and no chemotherapy contraindications.
• Informed consent, able to understand the study protocol and willing to participate in the study, and will provide written informed consent.

Exclusion Criteria:

• Refused to participate in this study.
• Multifocal colorectal cancer.
• History of malignant tumors, except for basal cell carcinoma, papillary thyroid carcinoma, and various in situ cancers.
• Cannot tolerate chemotherapy, such as but not limited to bone marrow suppression.
• Acute exacerbation of important organ diseases (such as but not limited to COPD, coronary heart disease, and renal insufficiency) and/or severe acute infectious diseases (such as but not limited to hepatitis, pneumonia, and myocarditis), ASA score > 3 points.
• Mental disorders, illiteracy, or language communication barriers that prevent the understanding of the study protocol.
• Tumor obstruction or high risk of obstruction, bleeding, and/or perforation.
• Peripheral sensory neuropathy, unable to receive oxaliplatin-based chemotherapy.
• Pregnancy or lactation.
• Unable to undergo enhanced CT examination or having comorbidities requiring the use of glucocorticoid therapy.
• Continuous use of glucocorticoids for more than 3 days within 1 month prior to signing the informed consent form.
• CT or MRI in the mid-sagittal plane shows that the lower border of the tumor is below the line connecting the sacrococcygeal promontory and the upper border of the pubic symphysis.
• Other situations in which the researcher deems unsuitable for this study.