Editor’s Note: In January of 2020, Verastem Oncology obtained worldwide development and commercialization rights to the compound CH5126766. The compound is now referred to as VS-6766.
Intermittent schedules of CH5126766, an oral MEK-pan-RAF inhibitor, may be tolerated and effective in solid tumors and multiple myeloma, according to research in The Lancet Oncology.
Previous studies have shown CH5126766 (also known as VS-6766, and previously known as ROS5126766) to have antitumor activity in various solid tumors; however, toxicities limited further development of the drug. The current phase 1 dose-escalation and basket dose-expansion study sought to examine the safety and toxicity of an intermittent dosing schedule.
Mutations in the MAPK pathway have been associated with more than a third of solid tumors and about half of multiple myeloma cases. The study treatment inhibits MEK through the formation of a stable RAF-MEK complex. CH5126766 has a long half-life of approximately 55 hours, suggesting that an intermittent dosing schedule may provide clinically relevant drug exposure.
The authors enrolled 58 patients with solid tumors or multiple myeloma harboring RAS-RAF-MEK pathway mutations; 29 patients with solid tumors were assigned to the dose-escalation cohort, and 29 were assigned to the basket dose-expansion group (22 patients with solid tumors and 7 patients with multiple myeloma). The patients were administered CH5126766 either 2 or 3 times per week in cycles of 28 days. Treatment continued until disease progression, intolerance, or withdrawal of consent.
The median follow-up duration was 2.3 months. The most common toxicities were rash, creatinine phosphokinase elevation, visual disturbance, diarrhea, and fatigue. At least 1 dose reduction was required in 22 of 57 patients due to treatment-related adverse events. Of the patients who received 4.0 mg twice weekly, 43% (16 of 37 patients) had grade 3 or worse toxicity.
Of 26 evaluable patients in the basket dose-expansion group, 7 patients had an objective response. In addition, 6 of 20 patients with solid tumors had an objective response, and 1 patient in the dose-escalation group had a partial response. Of the 6 patients with multiple myeloma, 1 patient had a partial response with progression-free survival of 30 weeks, and another patient had durable disease stabilization.
The authors conclude that a dose of 4.0 mg twice per week was well-tolerated. Future studies with larger sample sizes of each tumor type are needed to evaluate the antitumor activity of CH5126766.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Guo C, Chénard-Poirier M, Roda D, et al. Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. Lancet Oncol. 2020;21(11):1478-1488. doi:10.1016/S1470-2045(20)30464-2