Efficacy and Safety of Tunlametinib Plus Vemurafenib in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer

Inclusion Criteria:

• Inclusion Criteria:

1. Before study entry, written informed consent must be obtained from the patientprior to performing any study-related procedures.

2. Male or female patients with 18 to 70 years of age at time of informed consent;

3. Histological or cytologically confirmed metastatic CRC

4. Presence of BRAFV600E in tumor tissue as previously determined by a local assayat any time prior to Screening or by the central laboratory (BRAFV600 ispermitted)

5. Able to provide a sufficient amount of representative tumor specimen (primaryor metastatic, archival or newly obtained) for confirmatory central laboratorytesting of BRAF mutation status.

6. Progression of disease after 1 or more prior regimens in the metastatic setting

7. At least 1 site of radiographically measurable disease by RECIST 1.1

8. Eastern Cooperative Oncology Group (ECOG) Performance Status(PS) of 0 to 1;

9. Life expectancy ≥ 3 months;

10. Can swallow the medicine,

11. Adequate hematologic, renal, cardiac and liver function as defined bylaboratory values performed within 7 days prior to initiation of dosing:

12. Be willing and able to complete all the study procedures and follow-upexaminations.

Exclusion Criteria:

• Exclusion Criteria:

1. Prior treatment with any BRAF and MEK inhibitor;

2. Known contraindication to receive the treatment of control arm (according tolatest PI).

3. Symptomatic brain metastasis or leptomeningeal disease

4. History of chronic inflammatory bowel disease or Crohn's disease requiringmedical intervention (immunomodulatory or immunosuppressive medications orsurgery) ≤12 months prior to randomization

5. Known history of acute or chronic pancreatitis

6. Uncontrolled GI bleeding, Dysphagia，refractory nausea, vomiting, small bowelresection or any other gastrointestinal ailment that would preclude study drugabsorption.

7. Serious cardiovascular disease , including uncontrolled congestive heartfailure, uncontrolled hypertension, cardiac ischemia, myocardial infarction,and severe cardiac arrhythmia , deep vein thrombosis or pulmonary emboli orcerebrovascular events ≤ 6 months prior to starting study treatment;

8. History or current evidence of retinal vein occlusion or current risk factorsfor retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension,history of hyperviscosity or hypercoagulability syndromes)

9. Concurrent neuromuscular disorder that is associated with the potential ofelevated creatine (phosphor)kinase (CK) (e.g., inflammatory myopathies,muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)

10. Uncontrolled blood pressure despite medical treatment

11. Concurrent or previous other malignancy within 5 years of study entry, exceptcured basal or squamous cell skin cancer, superficial bladder cancer, prostateintraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasiveor indolent malignancy

12. Residual common terminology criteria for adverse events (CTCAE) ≥ Grade 2toxicity from any prior anticancer therapy, with the exception of Grade 2alopecia or Grade 2 neuropathy

13. Anti-HIV(+) , Anti-TP( +); Active hepatitis B or hepatitis C infection .......