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 

Previous studies have explored the use of MEK inhibitors in patients with 

-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 

 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 

-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.

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Zeynep Eroglu, MD, discusses a phase 1/2 trial that evaluated ceritinib alone and in combination with trametinib in patients with mutant melanoma.

Dr Eroglu on Ceritinib With or Withou 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.

Zeynep Eroglu, MD, discusses the efficacy and safety of ceritinib as monotherapy and in combination with trametinib in pretreated advanced melanoma. 

Dr Eroglu on Ceritinib With or Without Trametinib in Pretreated Advanced Melanoma

Dr Eroglu on Future Steps for Assessing Ceritinib Plus Trametinib in Metastatic 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 future steps in an ongoing study assessing the efficacy and safety of ceritinib (Zykadia), both as monotherapy and in combination with trametinib (Mekinist), in patients with metastatic melanoma. 

The objective Eroglu describers entails analytical scrutiny using methodologies such as flow cytometry and single-cell RNA sequencing to discern potential markers associated with favorable responses to ceritinib with or without trametinib, particularly in patients receiving immunotherapy as their preceding line of treatment. The overarching aim of this research is to delineate signaling pathways that may inform future therapeutic strategies, notwithstanding the specific drugs employed, by targeting markers identified in patients receiving immunotherapy as their most recent line of therapy, Eroglu says.

Eroglu notes that the challenges inherent in combining multiple TKIs underscore the importance of addressing overlapping toxicities, exemplified by the concomitant use of trametinib and ceritinib. This obstacle is not unique to the current study but resonates with findings from previous investigations, according to Eroglu. 

Prospective drug development endeavors aim to mitigate these challenges by identifying newer agents with improved toxicity profiles, Eroglu explains. The overarching goal of this approach is to facilitate the development of combination therapies characterized by reduced toxicity, thereby enabling dose escalation to achieve clinically efficacious levels, Eroglu says. This approach is pivotal given the continued relevance of targeted therapy in patients with metastatic melanoma following prior treatment with anti–PD-1 therapy and adoptive cellular therapy, Eroglu emphasizes.

Eroglu's research underscores the imperative need for elucidating potential markers of therapeutic response in elderly patients with metastatic melanoma, and particularly in those who have undergone immunotherapy as their preceding line of treatment. The identification of such markers holds promise for informing future therapeutic strategies aimed at addressing the unmet needs of this patient population, Eroglu notes. Moreover, Eroglu mentioned that efforts to overcome the challenges associated with combining TKIs underscore the ongoing commitment to refining treatment approaches and improving patient outcomes in metastatic melanoma.

Zeynep Eroglu, MD, discusses future steps for assessing ceritinib in combination with trametinib in patients with metastatic melanoma.

Zeynep Eroglu, MD, discusses the safety profile of ceritinib plus trametinib in pretreated metastatic melanoma.

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.

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 rationale for investigating patterns of outcomes in patients with metastatic melanoma harboring 

In a retrospective cohort analysis, investigators evaluated the association between baseline metastatic patterns and clinical outcomes in patients with 

-mutant metastatic melanoma. Combination immunotherapy is commonly used in metastatic melanoma, and BRAF/MEK inhibitors represent treatment options as targeted therapy, Eroglu says. This retrospective cohort analysis investigated real-world data from patients who were treated at a number of community centers across the United States, Eroglu adds.

Investigators also looked at changes regarding sites of distant metastases and the overall number of metastases to see how that correlated with outcomes for patients, Eroglu concludes.

Zeynep Eroglu, MD, discusses the rationale for investigating patterns of outcomes in patients with metastatic melanoma harboring BRAF mutations.


Dr. Erogolu on the Rationale for Investigating Patterns in BRAF+ Metastatic 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 utilization of circulating tumor DNA (ctDNA) in patients with melanoma.

Identifying a noninvasive biomarker, which are seen in other solid tumors, remains a challenge for patients with melanoma, Eroglu says. As a result, imaging or clinical exams are utilized to monitor patients for recurrence or progression while on treatment or following surgery, Eroglu explains. Time limits the frequency PET or CT scans that can be conducted on a given patient, making those methods less reliable for identifying disease recurrence or progression, Eroglu adds.

The hope is to use ctDNA is to detect relapse earlier or show how a patient may be responding to a treatment, like immunotherapy, without the burden of time between imaging scans, Eroglu continues. Addiontally, ctDNA could provide patients with melanoma a minimally invasive way to monitor and characterize disease status, Eroglue concludes.

Zeynep Eroglu, MD, discusses the utilization of circulating tumor DNA in patients with melanoma.


Zeynep Eroglu, MD

Articles

Dr Eroglu on Addressing Unmet Needs in Mutant Melanoma

Dr Eroglu on Ceritinib With or Without Trametinib in Pretreated Advanced Melanoma

Dr Eroglu on Future Steps for Assessing Ceritinib Plus Trametinib in Metastatic Melanoma

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

Dr. Erogolu on the Rationale for Investigating Patterns in BRAF+ Metastatic Melanoma

Dr. Eroglu on the Utilization of ctDNA in Melanoma