Lancet oncol: RAF-MEK inhibitors are anti-tumor active in a variety of tumors carrying RAS/RAF mutations

CH5126766 (also known as VS-6766, formerly known as RO5126766) is a new MEK-pan-RAF inhibitor known to have anti-tumor activity in a variety of solid tumors;
present study is intended to assess the safety and toxicity of ch5126766 intermittent administration programs, as well as the anti-tumor activity of the drug in patients with solid and multiple myelomas with RAS-RAF-MEK pathrain mutations.
this study is a single-center, open-label Phase 1 dose increment and dose amplification study that recruits cancer patients over the age of 18 who are difficult to treat conventional treatment or who do not have conventional treatment.
in the dose increment phase, the subjects were patients with advanced or metastasis solid tumors.
in the dose expansion phase, the subjects were patients with advanced or metastasis solid tumors or multiple myelomas with RAS-RAF-MEK path pathrapy mutations.
dose increment phase, dosing programme: (1) CH5126766, 4.0 mg or 3.2 mg, 3 times/week; 3) Toxicity-directed dose interruption program, i.e. if the patient has a pre-specified toxic effect (level ≥2 diarrhea, red rash or creatophosphate kinase elevation), then the recommended phase 2 treatment dose (4.0 mg, 2 times / week) reduced to 3 weeks after continuous use of the drug stopped for one week.
dose expansion stage, the recommended phase 2 dose was used to assess the anti-tumor activity of CH5126766.
main endpoint is treatment-related dose-limiting toxicity in patients who do not exceed 1/6 of the recommended phase 2 dose therapy, as well as the safety and toxicity of each dose option.
secondary endpoint is the remission rate during the dose expansion phase.
June 5, 2013 - January 10, 2019, a total of 58 patients were recruited: 29 solid tumors were included in the dose increase queue, and 29 solid tumor or multiple myeloma patients were included in the dose expansion queue (12 cases of non-small cell lung cancer, 5 cases of gynecological malignancies, 4 cases of colorectal cancer, 1 case of melanoma and 7 cases of multiple myeloma).
follow-up for 2.3 months.
dose limit toxicity was 3 levels of double-sided retinal pigment epithelial shedding (4.0 mg 3 times/week, 1 case), red rash (3.2 mg 3 times/week, 2 cases) and creatinate kinase elevation (3.2 mg 3 times/week, 1 case).
recommended phase 2 dose is 4.0 mg, 2 times/week (Monday and Thursday, or Tuesday and Friday).
most common 3-4 adverse reactions were red rash (19%), elevated creatinate kinase (11%), hypoproteinemia (11%) and fatigue (7%).
5 patients (9%) had severe treatment-related adverse reactions.
treatment-related deaths.
8 (14%) of the 57 patients who died as a result of the disease's progress.
(27%) of the 26 patients who were assessed for remission during the expansion phase received objective remission.
addition, it is understood that this study is the first to prove that the high intermittent solution of RAF-MEK inhibitors has anti-tumor activity and acceptable tolerance in a variety of tumors carrying RAF-RAS-MEK pathrain mutations.
CH5126766 as a single drug therapy and a combination with other anti-tumor drugs deserve further study.