Dr Tarhini on the Rationale for Studying Vidutolimod Plus Pembrolizumab in Melanoma

“There continues to be an important need for improving the efficacy [of standard therapies], as well as reducing systemic toxicity that may be associated with immune checkpoint blockade combination therapies. This was the main trigger for us to do this study."

Ahmad Tarhini, MD, PhD, a tenured senior member of the Departments of Cutaneous Oncology and Immunology, the director of Cutaneous Clinical and Translational Research, and the leader of the Neoadjuvant and Adjuvant Translational Science Program at the Moffitt Cancer Center and Research Institute; as well as a professor of oncologic sciences at the University of South Florida Morsani College of Medicine, discussed the rationale for the phase 2 ECOG-ACRIN EA6194 trial (NCT04708418) investigating neoadjuvant pembrolizumab (Keytruda) plus vidutolimod (formerly CMP-001) in patients with macroscopic, resectable stage III melanoma.

This randomized clinical trial enrolled patients with locoregionally advanced melanoma, including those with clinically detectable bulky disease who were at elevated risk of recurrence and mortality following definitive surgery, Tarhini began. Although significant therapeutic advances have been achieved for this population in recent years, there remains a clear need to enhance the efficacy of standard treatment approaches and simultaneously reduce systemic toxicities commonly associated with combination immune checkpoint blockade, he stated. These considerations provided the rationale for the initiation of this study, he added.

The investigation was further motivated by the novel mechanism of action of the experimental agent vidutolimod, a TLR9 agonist, according to Tarhini. TLR9 is an endosomal receptor expressed on B cells and plasmacytoid dendritic cells, he explained. Its activation induces the production of type I interferons, which in turn stimulate both innate and adaptive antitumor immune responses, he noted. This mechanism suggests the potential to augment antitumor activity and mitigate the toxicity profile observed with conventional checkpoint inhibitor combinations, he continued.

Prior studies examining the combination of vidutolimod with PD-1 blockade in the metastatic, PD-1–refractory setting have demonstrated the encouraging clinical activity of these types of combinations, Tarhini said. These findings prompted the evaluation of vidutolimod plus pembrolizumab in the neoadjuvant setting, where the therapeutic potential may be optimized, he reported. The hypothesis is that such a combination could improve efficacy outcomes with minimal systemic immune-related adverse effects, he concluded.