Dr Eroglu on the Safety Profile of Ceritinib Plus Trametinib in Advanced Melanoma

Zeynep Eroglu, MD, medical oncologist, Department of Cutaneous Oncology, Moffitt Cancer Center, assistant professor, Department of Oncologic Sciences, the University of South Florida, Morsani College of Medicine, discusses the safety of ceritinib (Zykadia) in combination with trametinib (Mekinist) in a phase 1/2 trial (NCT03501368) of patients with advanced, unresectable metastatic melanoma.

The open-label study was designed to determine the risks and benefits of administering ceritinib plus trametinib in patients with melanoma who have progressed on a prior anti-PD-1 agent and/or a prior BRAF/MEK inhibitor, if applicable.

The initial phase 2 portion of this study focused on evaluating ceritinib as monotherapy at the FDA-approved dose of 450 mg daily to assess its activity in metastatic melanoma, Eroglu begins. Eleven patients were treated during this phase, and safety assessments revealed that the most common grade 3/4 toxicity was liver enzyme elevation, which was manageable, she reports.

The study subsequently progressed to a phase 1 portion, combining ceritinib with trametinib once trametinib became available, Eroglu continues. Seventeen patients were enrolled in this phase, which involved dose escalation starting at a lower dose of ceritinib (300 mg) with trametinib (2 mg/day). Dose level 2 was 450 mg of ceritinib and 2 mg of trametinib daily; dose level 1 was 300 mg and 1.5 mg of the combination.

Despite efforts to manage toxicity, such as dose de-escalation, several patients experienced grade 3 adverse effects (AEs) such as rash, hypertension and ALT/AST elevation.

These subsequent AEs were addressed by adjusting the combination dosage to ceritinib 300 mg/day and trametinib 1.5 mg/day (dose level minus 1) and enrolling additional patients at this revised dosage. Despite encountering challenges with toxicity, including dose holds and reductions due to rash and other adverse effects associated with kinase inhibitors, the study continued to evaluate the safety and efficacy of the ceritinib-trametinib combination in metastatic melanoma.

Overall, the study suggests that ceritinib does not have meaningful activity as a single agent and modest activity in combination with trametinib in advanced, treatment-refractory melanoma. It is hypothesized that the inability to dose-escalate the combination due to overlapping toxicities may explain these modest benefits.