This is a multicenter, randomized, open-label, Phase 3 study
Before study entry, written informed consent must be obtained from the patient prior to performing any study-related procedures.
Male or female patients with 18 to 70 years of age at time of informed consent;
Histological or cytologically confirmed metastatic CRC
Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory (BRAFV600 is permitted)
Prior treatment with any BRAF and MEK inhibitor;
Known contraindication to receive the treatment of control arm (according to latest PI).
Symptomatic brain metastasis or leptomeningeal disease
History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization
Parallel
Tunlametinib plus Vemurafenib
Drug12mg BID Tunlametinib+720mg BID Vemurafenib
Doublets Chemotherapy ± Bevacizumab or Doublets Chemotherapy ± Cetuximab
DrugAccording to investigators' suggestion
Progression-free Survival (PFS)
defined as the time from first dose to the earliest documented disease progression or death due to any cause
Overall Survival（OS）
defined as the time from the date of taking drugs to the date of death due to any cause. After disease progression, participants in the control group can crossover to receive the experimental drug treatment if they meet the crossover enrollment criteria. The median survival time of the two groups will be estimated by Kaplan-Meier method, and the hazard ratio (HR) between the two groups will be estimated use the Cox proportional hazards model in FAS, and OS will be adjusted using the following two methods: 1. Rank Preserving Structural Failure Time Model (RPSFTM): Corrects survival outcomes for treatment crossover from the control group to the experimental group by estimating counterfactual survival times to infer the treatment effect without crossover. 2. Inverse Probability of Censoring Weighting (IPCW): Adjusts for informative censoring bias caused by treatment crossover. The weights will be derived from time-dependent censoring models.
Overall Response Rate（ORR）
Defined as the proportion of subjects with an optimal response of CR or PR over the course of the study from enrollment to disease progression
Duration of Response（DOR）
Defined as the time from the first CR or PR evaluation of tumor efficacy to the first occurrence of PD or death from any cause (whichever occurs first)
Disease control rate (DCR)
roportion of subjects with response defined as CR, PR, and SD throughout the study from subjects first dose to disease progression or death
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