Ivosidenib Plus mFOLFOXIRI and Celecoxib for BRAF-targeted Therapy-refractory BRAF V600E-mutant Colorectal Cancer Patients

Ivosidenib Plus mFOLFOXIRI and Celecoxib as a Treatment for BRAF-targeted Therapy-refractory BRAF V600E-mutant Colorectal Cancer Patients: a Phase II Study

BRAF-mutated colorectal cancer, primarily driven by the BRAF V600E mutation, accounts for approximately 5-10% of all colorectal cancer cases and is associated with aggressive disease progression and poor prognosis, particularly in metastatic settings. Following first- and second-line treatments, including chemotherapy and targeted therapy, the median overall survival of patients is typically less than 24 months, and tumor progression is rapid once resistance develops. Previous studies have demonstrated that immune checkpoint inhibitors, such as anti-PD-1 therapies, show limited efficacy in microsatellite-stable (MSS) colorectal cancers but may hold promise when combined with other agents to overcome resistance mechanisms. Ivonescimab, a bispecific antibody targeting PD-1 and VEGF, has shown antitumor activity in various solid tumors by simultaneously inhibiting immune evasion and angiogenesis. The combination of ivonescimab with intensive chemotherapy like FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) and the COX-2 inhibitor celecoxib aims to enhance antitumor immunity, reduce inflammation, and improve vascular normalization in resistant tumors. However, there are no reported studies on this specific combination for chemotherapy- and BRAF inhibitor-resistant BRAF-mutated colorectal cancer. Therefore, the aim of this study is to evaluate the efficacy and safety of ivonescimab combined with FOLFOXIRI and celecoxib in patients with chemotherapy- and BRAF inhibitor-resistant BRAF-mutated advanced colorectal cancer, with a focus on assessing objective response rate (ORR) and tolerability.

This study is a prospective, investigator-initiated, single-arm, phase II trial to evaluate the efficacy and safety of ivonescimab (AK112) combined with FOLFOXIRI and celecoxib in patients with BRAF-mutated advanced/metastatic colorectal cancer who have developed resistance to prior chemotherapy and BRAF inhibitors . The inclusion criteria: histologically confirmed BRAF V600E-mutated advanced or metastatic colorectal cancer; documented resistance/progression after at least one line of standard chemotherapy ( FOLFOX/FOLFIRI-based) and BRAF inhibitor-based targeted therapy; measurable disease per RECIST 1.1; ECOG performance status 0-1; adequate organ function; no active brain metastases or other uncontrolled comorbidities (specific criteria can be supplemented as needed). Patients received ivonescimab combined with mFOLFOXIRI (modified FOLFOXIRI regimen) and celecoxib for up to 6-8 cycles or until progression/toxicity, followed by maintenance therapy of continued ivonescimab with 5-FU/leucovorin and celecoxib. All patients will be evaluated every four cycles of treatment using imaging CT/MRI. The primary objective is to assess the objective response rate (ORR) per RECIST 1.1, with secondary endpoints including progression-free survival (PFS), disease control rate (DCR), safety profile, and exploratory biomarkers .

Inclusion Criteria:

1. Signed the informed consent form voluntarily.
2. Aged 18-70.
3. Colorectal adenocarcinoma with definite histological evidence, with evidence of distant metastasis;
4. Diagnosed with colon or rectal adenocarcinoma, with evidence of distant metastasis;
5. Genetic testing indicates a BRAF V600E mutation;
6. Previously received first-line treatment including FOLFOX/CAPOX or FOLFIRI/CAPIRI and experienced disease progression or intolerance. Among them, patients who used oxaliplatin in adjuvant therapy should have experienced disease progression within 12 months after completing adjuvant therapy; Previously received anti-BRAF V600E targeted therapy and failed, including but not limited to vemurafenib, dabrafenib, and encorafenib;
7. Patients must have measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
8. Adequate organ function based on the following laboratory test values obtained within 7 days prior to treatment: neutrophil count ≥1.5×109/L, platelet count ≥75×109/L, serum total bilirubin ≤1.5× upper limit of normal value (UNL), aspartate transferase ≤2.5×UNL, alanine transferase ≤2.5×UNL, serum creatinine ≤2.5×UNL;
9. Female subjects must be either postmenopausal for at least 1 year, have undergone surgical sterilization at least 6 weeks prior, or must agree to use appropriate contraceptive measures;
10. Male subjects must agree to use appropriate contraceptive measures to prevent their partners from becoming pregnant;
11. Willing and able to comply with research protocols and visit plans.

Exclusion Criteria:

1. Prior to enrollment, ctDNA testing shows known KRAS mutation, NRAS mutation, or ERBB2 gene amplification; tumor tissue testing shows mismatch repair gene deficiency or high microsatellite instability, KRAS mutation, NRAS mutation, or ERBB2 gene amplification;
2. Presence of intestinal obstruction, active bleeding, or intestinal perforation requiring emergency intervention;
3. Underwent major surgery or severe trauma in the previous 4 weeks;
4. Active coronary artery disease, severe/unstable angina, or newly diagnosed angina or myocardial infarction within 12 months prior to study participation;
5. Occurrence of thrombotic or embolic events within the past 6 months;
6. New York Heart Association (NYHA) class II or higher congestive heart failure;
7. Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), untreated active hepatitis;
8. Any active, known, or suspected autoimmune disease.
9. Presence of interstitial lung disease, non-infectious pneumonia, or uncontrolled systemic disease;
10. Any unresolved treatment-related adverse events of grade 2 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (excluding peripheral neuropathy, anemia, hair loss, and skin pigmentation);
11. Previous treatment with programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibitors or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies;
12. Known or suspected history of allergy to any of the related drugs used in the study;
13. Pregnant or breastfeeding women.