Dr Doonan on Treatment Strategies Following Progression on ICIs in Advanced Melanoma

"[Treatment following immune checkpoint inhibition (ICI)] continues to be an unmet need within the disease. We're fortunate that with up-front ICI in patients who are candidates for it, we effectively will only give that therapy to approximately 50% of patients or more…However, this also tells us that 30% to 40% or more of patients will [need subsequent treatment]."

Bently P. Doonan, MD, clinical assistant professor, Division of Hematology & Oncology, Department of Medicine, College of Medicine, the University of Florida, discusses current strategies for and associated challenges with the treatment of patients with advanced melanoma following disease progression on immune checkpoint inhibitors (ICIs).

Treatment options following checkpoint inhibition remain a significant unmet need in melanoma, Doonan begins. Although up-front checkpoint inhibition provides substantial benefits, only approximately 50% to 60% of eligible patients receive durable responses, leaving 30% to 40% of patients requiring subsequent therapy, he reports. Addressing these gaps—particularly for those lacking second-line options—is critical, Doonan emphasizes.

-mutated melanoma, molecularly targeted therapies such as the BRAF inhibitors such as vemurafenib (Zelboraf) and dabrafenib (Tafinlar), and the MEK inhibitors trametinib (Mekinist) and cobimetinib (Cotellic), remain a standard second-line option, Doonan continues. However, these mutations are present in only 40% to 50% of patients with advanced melanoma, leaving a substantial number of patients without clear alternatives. For those previously treated with ICI, options may include immune checkpoint rechallenge or escalation to dual-agent therapy, particularly in cases of recurrence after a robust initial response or stable remission, Doonan details. However, patients who develop resistance or do not respond to ICI require other strategies, he says.

, a tumor-infiltrating lymphocyte (TIL) therapy, Doonan states. This cellular therapy is approved as a third-line treatment for patients with 

 mutations and as a second-line option for the broader melanoma population.

However, for patients who are ineligible for TIL therapy or unable to access it, clinical trials and novel combination therapies are critical alternatives, he notes. For example, pembrolizumab (Keytruda) combined with lenvatinib (Lenvima) has shown promise in some cases, as has targeting less common molecular alterations, such as 

mutations by using drugs adapted from other cancer types, Doonan reports. Beyond these strategies, treatment options remain limited, underscoring the urgent need for continued research and therapeutic innovation in this space, Doonan concludes.

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Bently P. Doonan, MD, discusses treatment strategies for patients with advanced melanoma who have progressed on checkpoint inhibitors.


Bently P. Doonan, MD, assistant professor, Division of Hematology & Oncology, University of Florida (UF), UF Health, discusses the evaluation of targeted inhibition of IRAK-4 with emavusertib (CA-4948) in the treatment of metastatic brain melanoma.

A preclinical study presented at the 2023 AACR Annual Meeting used immunohistochemistry (IHC) to assess samples from patients with metastatic brain melanoma to define the distribution of myddosome signaling. The models were treated with emavusertib alone and in combination with an immune checkpoint inhibitor. Flow cytometry and IHC were also used to characterize the immune microenvironment.

Although the vast majority of drugs are unable to effectively penetrate the blood-brain barrier, especially in a therapeutic concentration, emavusertib was found to get into the brain, Doonan emphasized. Investigators wanted to investigate this agent in a solid tumor with an integral tumor microenvironment, leading to the focus on metastatic brain melanoma, Doonan says.

Previous literature showed that melanoma cells upregulate IRAK-4, Doonan notes, adding that this is done in response to inflammation. Although immunotherapy has an established role in the treatment of melanoma, approximately half of patients will not benefit from immunotherapy, partially due to inflammation associated with melanoma since inflammation could lead to the environment to become suppressive, Doonan explains.

Emavusertib blocks IRAK-4, affecting how cells utilize inflammation slowing their growth rate, Doonan notes. More importantly, emavusertib appeared to regulate the tumor microenvironment, which could improve the efficacy of standard immunotherapy with a checkpoint inhibitor, Doonan says. In aggressive, resistant mouse models for metastatic melanoma, including cell lines that do not traditionally respond to immunotherapy, there was improvement in the survival of these mice by adding emavusertib to a checkpoint inhibitor, Doonan concludes.

Bently P. Doonan, MD, discusses the evaluation of targeted inhibition of IRAK-4 with emavusertib in the treatment of metastatic brain melanoma.


Bently P. Doonan, MD

Articles

Dr Doonan on Treatment Strategies Following Progression on ICIs in Advanced Melanoma

Dr Doonan on the Evaluation of IRAK-4 Inhibition With Emavusertib in Metastatic Brain Melanoma