Dr Eroglu on Ceritinib With or Without Trametinib in Pretreated 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 a phase 1/2 trial (NCT03501368) assessing the efficacy and safety of ceritinib (Zykadia) as monotherapy and in combination with trametinib (Mekinist) in patients with pretreated advanced melanoma.

The study initially began with a phase 2 portion, which included 11 patients treated with ceritinib alone at the FDA-approved dose of 450 mg per day, Eroglu begins. Safety assessments revealed standard toxicity profiles associated with ceritinib, with liver enzyme elevation being the most common grade 3 adverse effect (AE) observed, she explains. However, findings presented at the 2024 AACR Annual Meeting showed that no responses were observed in patients treated with single-agent ceritinib.

Subsequently, the study progressed to a phase 1 portion, which investigated the combination of ceritinib and trametinib in 17 patients enrolled. Dose-escalation strategies were employed, starting at a lower dose of ceritinib at 300 mg combined with the standard dose of trametinib at 2 mg, which was deemed dose level 1. Eroglu explains that toxicity concerns emerged at this dose level, including instances of grade 3 rash. Consequently, a dose de-escalation was implemented to dose level –1, comprising 300 mg of ceritinib and 1.5 mg of trametinib per day, Eroglu says.

Throughout dose escalation in the combination cohort, patients were enrolled in groups of three, and 12 patients were initially treated at dose level 1. Two responses were observed in patients treated with the combination, and 6 additional patients experienced stable disease. However, combination therapy with ceritinib and trametinib presented greater challenges in terms of tolerability compared with ceritinib monotherapy, Eroglu notes. The observed toxicity profile, including dose-limiting toxicities of grade 3 rash and grade 2 glaucoma, prompted dose adjustments and interruptions for some patients.

Findings from the study provided more context for the safety and tolerability profile of ceritinib in combination with trametinib in patients with advanced melanoma. Further investigation and optimization of dosing strategies may be warranted to mitigate treatment-related AEs and enhance therapeutic outcomes, Eroglu concludes.