Dr Sznol on Biomarkers of Response in Metastatic Melanoma

“Tumor mutational burden is not a great biomarker in melanoma. PD-L1 is also not a great biomarker in melanoma, so it’s very hard to tell upfront who’s going to respond and who’s not [going] to [respond to] these immune therapies.”

Mario Sznol, MD, professor of clinical medical oncology at the Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Health System, discussed the ongoing challenge of identifying reliable biomarkers to guide immunotherapy decisions in melanoma.

The lack of robust biomarkers has made it difficult to predict which patients will derive durable benefit from immune checkpoint inhibitors, Sznol explained. Commonly explored biomarkers such as tumor mutational burden and PD-L1 expression have not demonstrated consistent clinical utility in melanoma, limiting their role in treatment selection, Sznol added.

Although there are several promising investigational markers, ranging from microbiome composition and HLA class I expression to tumor microenvironment metabolism, these variables remain difficult to integrate into a cohesive, clinically actionable framework, Sznol stated. Although research efforts continue to explore composite biomarker strategies, no standardized approach has been validated for routine use in practice.

Sznol also raised the effort to distinguish patients who may respond well to anti–PD-1 monotherapy from those who require combination immunotherapy, such as dual checkpoint blockade. This distinction is clinically meaningful, as monotherapy is generally associated with a more favorable toxicity profile. However, Sznol noted that the incremental toxicity of combination regimens, such as nivolumab (Opdivo) plus ipilimumab (Yervoy), may be less pronounced than often perceived, complicating decision-making.

Further complicating matters is the fact that patients who may be expected to respond well fail to do so, whereas others with aggressive, advanced disease, including brain and liver metastases, achieve surprisingly durable outcomes. These observations highlight the limitations of current clinical intuition and underscore the need for better predictive tools, Sznol added.

Ultimately, in advanced metastatic melanoma, there remains a lack of robust, clinically applicable biomarkers to guide therapy selection. Although investigational approaches continue to evolve, they have not translated into routine practice. Additionally, the complexity of treatment decision-making is further heightened by the expanding role of immunotherapy in adjuvant and neoadjuvant settings, broadening the landscape and reinforcing the need for more precise, individualized strategies, Sznol concluded.