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.
Signed the informed consent form voluntarily.
Aged 18-70.
Colorectal adenocarcinoma with definite histological evidence, with evidence of distant metastasis;
Diagnosed with colon or rectal adenocarcinoma, with evidence of distant metastasis;
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;
Presence of intestinal obstruction, active bleeding, or intestinal perforation requiring emergency intervention;
Underwent major surgery or severe trauma in the previous 4 weeks;
Active coronary artery disease, severe/unstable angina, or newly diagnosed angina or myocardial infarction within 12 months prior to study participation;
Single group
Ivonescimab +mFOLFOXIRI +celecoxib
DrugIvonescimab（AK112）10mg/kg, intravenously for 60 minutes, followed by mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) every 2 weeks, celecoxib 400mg oral everyday.
Objective response rate (ORR)
Defined as the proportion of patients who are assessed for best overall response as complete response (CR) or partial response (PR) according to RECIST version 1.1. If the response reaches CR or PR, it must be confirmed at least 4 weeks (28 days) after the initial evaluation.
Disease control rate (DCR)
Defined as the proportion of patients who are assessed for best overall response as CR or PR or stable disease (SD) according to RECIST version 1.1.
Progression-free survival (PFS)
Defined as the time from enrollment to the first documented tumor progression (assessed according to RECIST version 1.1, regardless of whether treatment continues) or the date of death from any cause, whichever occurs first.
Overall survival (OS)
Defined as the time from enrollment to death from any cause.
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
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