Overview
The objective of this clinical trial is to evaluate the efficacy and safety of cetuximab combined with PD-1 inhibitor and irinotecan in negative ultraselection RAS/BRAF wild-type refractory right-sided metastatic colorectal cancer.
Description
The present study focuses on exploring the effectiveness and safety of cetuximab combined with a PD-1 inhibitor and irinotecan in treating refractory, right-sided metastatic colorectal cancer (mCRC) patients who are negative ultraselected for RAS/BRAF mutations. Colorectal cancer ranks among the most prevalent digestive malignancies globally, with right-sided mCRC generally exhibiting poorer outcomes than left-sided cases. Current treatment guidelines vary based on genetic mutations and tumor location, recommending cetuximab for left-sided RAS/BRAF wild-type mCRC and alternative therapies for right-sided or mutated cases. Despite limited clinical data on EGFR inhibitors for right-sided mCRC, retrospective analyses suggest varying efficacy outcomes. The study aims to address these gaps by investigating cetuximab and PD-1 inhibitor combination therapy in this specific patient population, potentially enhancing treatment options for refractory mCRC.
Eligibility
Inclusion Criteria:
- Histologically confirmed colorectal adenocarcinoma.
- Primary tumor located in the right colon.
- Metastatic disease with at least one measurable lesion according to RECIST v1.1 criteria.
- Histologically tested as RAS/BRAF V600E wild-type and negative ultraselected for mutations including: RAS/BRAF V600E/PIK3CA/PTEN/EGFR (ECD), HER2 and MET amplification, and ALK/RET/NTRK1 gene fusions.
- Patients who have progressed after previous treatments including bevacizumab, irinotecan, oxaliplatin, and 5-fluorouracil, with tumor progression occurring during or within 3 months after irinotecan treatment.
- No prior treatment with anti-EGFR or PD-1 antibodies.
- Normal hematological function (platelets \>90×10\^9/L; white blood cells \>3×10\^9/L; neutrophils \>1.5×10\^9/L).
- Serum bilirubin ≤1.5 times the upper limit of normal (ULN), transaminases ≤5 times ULN.
- No ascites, normal coagulation function, albumin ≥35 g/L.
- Liver function classified as Child-Pugh grade A.
- Serum creatinine less than ULN, or calculated creatinine clearance \>50 ml/min (using the Cockcroft-Gault formula).
- At least one measurable lesion according to RECIST v1.1 criteria.
- ECOG performance status of 0-2.
- Expected survival \>3 months.
- Signed written informed consent.
- Willing and able to undergo follow-up until death or study completion or termination.
Exclusion Criteria:
- Severe arterial thrombosis or ascites.
- Bleeding tendencies or coagulation disorders.
- Hypertensive crisis or hypertensive encephalopathy.
- Severe uncontrolled systemic complications such as infections or diabetes.
- Clinically significant cardiovascular diseases such as cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), uncontrolled hypertension despite appropriate medication, unstable angina, congestive heart failure (NYHA grade 2-4), or arrhythmias requiring medication.
- History of or physical examination showing central nervous system diseases (e.g., primary brain tumor, uncontrolled epilepsy, any history of brain metastasis or stroke).
- Other malignancies within the past 5 years (except for basal cell carcinoma of the skin after curative surgery and/or carcinoma in situ of the cervix).
- Use of immunosuppressive drugs within 1 week before treatment, excluding nasal, inhaled, or other topical steroids or physiological doses of systemic steroids (i.e., not exceeding 10 mg/day of prednisone or an equivalent dose of other steroids) or steroids used to prevent contrast agent allergies.
- Steroid-dependent interstitial lung disease.
- Known active autoimmune disease requiring symptomatic treatment or history of such disease within the past 2 years. Patients with vitiligo, psoriasis, alopecia, or -Graves' disease not requiring systemic treatment within the past 2 years, hypothyroidism requiring only thyroid hormone replacement, and type I diabetes requiring only insulin replacement can be enrolled.
- Known history of primary immunodeficiency.
- Known active tuberculosis.
- Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
- Receipt of any investigational drug treatment within the last 28 days before the study.
- Allergy to any drugs in the study.
- Pregnant or breastfeeding women.
- Women of childbearing potential (within 2 years of last menstruation) or men capable of fathering a child who are not using or refuse to use effective non-hormonal contraceptive methods (e.g., intrauterine device, barrier method combined with spermicide, or sterilization).
- Inability or unwillingness to comply with the study protocol.
- Presence of any other disease, functional impairment caused by metastatic lesions, or suspicious conditions found during a physical examination indicating a contraindication to the study drugs or high risk for treatment-related complications.
