Dr Weber on the Prognostic Utility of ctDNA Dynamics in Melanoma

Jeffrey S. Weber, MD, PhD, deputy director, codirector, the Melanoma Research Program, NYU Langone Perlmutter Cancer Center, Laura and Isaac Perlmutter Professor of Oncology, NYU Grossman School of Medicine, discusses the use of circulating-tumor DNA (ctDNA) dynamics when guiding treatment decision-making in melanoma, according to data from the phase 2b mRNA-4157-P201/KEYNOTE-942 trial (NCT03897881).

This randomized study compared the personalized mRNA-based neoantigen therapy mRNA-4157 (V940) in combination with pembrolizumab (Keytruda) vs pembrolizumab alone in patients with resected, high-risk melanoma.

Findings from the study were presented at the 2023 ESMO Congress, and showed that patients treated with mRNA-4157 and pembrolizumab experienced improved recurrence-free survival and distant metastasis-free survival compared with pembrolizumab alone, regardless of baseline ctDNA status. Notably, baseline ctDNA expression was identified as a potential negative prognostic factor for treatment outcomes in the study.

The crucial consideration for any biomarker lies in its impact on patient care, Weber begins. Generally, a test should not be conducted unless it will substantially influence disease management strategies, Weber states. If patients have negative baseline ctDNA that remains negative throughout treatment, they are more likely to respond well to therapy, he details. Accordingly, ctDNA serves as a predictive marker at baseline, providing valuable information about the patient's prognosis, Weber explains.

Although positive baseline ctDNA expression suggests poorer outcomes, the utility of ctDNA is limited by its potential to become positive during the course of treatment, Weber continues. The current utility of ctDNA is therefore primarily prognostic, he clarifies, stating that positive baseline expression may indicate poorer outcomes on treatment, and negative baseline expression is generally associated with positive outcomes.

Monitoring ctDNA over time can provide valuable insights, Weber adds. For instance, if ctDNA was initially negative and later increases, it could signal the need to switch therapy, he suggests. In scenarios where patients opt for a specific treatment, such as pembrolizumab alone, monitoring ctDNA becomes crucial. If ctDNA levels rise, it may prompt the addition of a vaccine or another drug to the current regimen, especially if studies on combining LAG3 antibodies with PD-1 antibodies show positive results, Weber says.

Ultimately, the influence of ctDNA on patient management is dynamic, requiring continuous monitoring and response adjustments based on its changing status over the course of treatment, Weber states. Further investigation is needed to better understand and leverage ctDNA monitoring to guide treatment decisions and disease management strategies in melanoma, he concludes.