Dr Eroglu on Addressing Unmet Needs in Mutant 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 unmet needs that currently exist for patients with mutant melanoma, highlighting a phase 1/2 trial (NCT03501368) that evaluated ceritinib (Zykadia) alone and in combination with trametinib (Mekinist) for these patients.

In patients with advanced metastatic melanoma who have experienced progression after initial immunotherapy, there is a notable lack of effective treatment options, Eroglu begins. Although recently approved agents, such as lifileucel (Amtagvi), are promising for patients who have undergone primary therapy with checkpoint inhibitors or BRAF inhibitors, a significant number of patients cannot benefit from adoptive cellular therapies due to eligibility constraints, particularly those without a BRAF V600 mutation, she explains.

Previous studies have explored the use of MEK inhibitors in patients with BRAFwild-type or NRAS-mutant melanoma, which have indicated limited efficacy, Eroglu expands. Therefore, a phase 1/2 trial sought to build upon existing data by investigating the potential of TKIs in patients with BRAF wild-type melanoma, aiming to enhance treatment outcomes, she says. Ceritinib was identified as a candidate for repurposing in melanoma treatment, according to Eroglu. Research has demonstrated ceritinib's activity in both NRAS-mutant and wild-type melanomas, BRAF-mutant and wild-type cell lines, and subsequent animal models, Eroglu elucidates. Despite its original indication for ALK inhibition in lung cancer, ceritinib's efficacy in melanoma appears linked to its inhibition of kinases such as IGF1R, ACK1, and FAK, she notes.

Moreover, combining ceritinib with the MEK inhibitor trametinib has shown synergistic benefits in reducing tumor growth in melanoma xenografts and suppressing signaling pathways such as MAPK and mTOR, Eroglu continues. Notably, this combination exhibits enhanced effectiveness when administered after anti-PD-1 immunotherapy, as evidenced by animal model studies, she says. This research represents a strategic effort to address the pressing need for improved treatment options in patients with mutant melanoma who have exhausted initial immunotherapy options, Eroglu concludes.