Neoadjuvant Vidutolimod Plus Pembrolizumab Elicits Responses and Is Safe in Stage III Melanoma

Ahmad Tarhini, MD, PhD

The neoadjuvant combination of pembrolizumab (Keytruda) with the TLR9 agonist vidutolimod (formerly CMP-001) generated higher pathologic complete response (pCR) rates vs pembrolizumab alone, as well as an acceptable safety profile, in patients with macroscopic, resectable stage III melanoma, according to Ahmad Tarhini, MD, PhD.

Findings from the phase 2 ECOG-ACRIN EA6194 trial (NCT04708418) demonstrated that among all enrolled patients, the pCR rate was 71% (95% CI, 51%-87%) among those who received the combination (n = 28) vs 48% (95% CI, 29%-67%) among those who received pembrolizumab alone (n = 29). The major pathologic response (MPR) rates in these respective arms were 79% (95% CI, 59%-92%) and 59% (95% CI, 39%-76%). Furthermore, at a median follow-up of 19 months (range, 2-36) for both arms, the 1-year event-free survival (EFS) rate was 89% (95% CI, 78%-100%) in the combination arm vs 75% (95% CI, 59%-91%) in the pembrolizumab monotherapy arm.

Any-grade and grade 3/4 treatment-related adverse effects (AEs) occurred in 100% and 29% of patients, respectively, who received vidutolimod plus pembrolizumab. The most common grade 3 AEs in this arm were cytokine release syndrome, hypertension, hypotension, diarrhea, wound dehiscence, injection site reaction, decreased lymphocyte count, metabolic acidosis, flank pain, and headache. One grade 4 AE (hyperglycemia) was reported.

“This quest for improving efficacy and simultaneously minimizing systemic toxicity could be practice changing,” Tarhini said in an interview with OncLive® during the 2025 ASCO Annual Meeting.

In the interview, Tarhini discussed the rationale for combining a PD-1 inhibitor with a TLR9 agonist, key efficacy and safety findings from the EA6194 trial, and how these data support the continued investigation of vidutolimod in patients with melanoma.

Tarhini is a tenured senior member of the Departments of Cutaneous Oncology and Immunology, in the Moffitt Cancer Center and Research Institute in Tampa, Florida, where he also serves as the director of Cutaneous Clinical and Translational Research and leader of the Neoadjuvant and Adjuvant Translational Science Program. He is also a professor of oncologic sciences at the University of South Florida Morsani College of Medicine.

OncLive: What was the clinical rationale for the EA6194 trial, and how was it intended to build upon findings from previous research?

Tarhini: This randomized clinical trial [enrolled] patients with locoregionally advanced melanoma, [including] patients with clinically detectable, bulky disease [who are] at high risk of recurrence and death after definitive surgery. There have been major advances recently, but 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, also taking into account the novel underlying mechanism of the experimental agent vidutolimod, which is a TLR9 agonist. TLR9 is an endosomal receptor that is expressed by B cells and plasmacytoid dendritic cells, and its activation leads to the induction of type 1 interferon, which leads to the stimulation of potent, innate, and adaptive antitumor immune responses. Recent testing of the combination of vidutolimod with PD-1 blockade in the metastatic PD-1–refractory setting showed promising data, and this intrigued us to test this combination in the neoadjuvant setting, where we feel it has what we’re looking for regarding improving efficacy, but also minimizing systemic, immune-mediated AEs, especially the high-risk effects.

What was the design of this trial?

The study was a randomized phase 2 study. The eligibility criteria included patients with clinically staged IIIB, IIIC, and IIID melanoma. These [patients] were allocated 1:1 into the control arm, which was anti–PD-1 monotherapy with pembrolizumab, or into the combination arm, which was an anti–PD-1 [agent] in combination with vidutolimod, which was given intratumorally weekly for up to 6 intratumoral doses [following 1 initial starting dose]. At approximately 9 to 11 weeks, these patients underwent definitive surgical management, and after recovery from surgery, all patients went on to receive systemic adjuvant therapy with anti–PD-1 monotherapy. The primary end point was pCR rate. Among the key secondary end points were MPR rate, which is either complete or near complete pathologic response; as well as other efficacy measures, including EFS, which considers disease progression, recurrence after surgery, or death because of disease or treatment.

What were the key efficacy findings from this study?

The study met its primary end point of improving pCR rate; this was 71% on the combination arm. The MPR rate [with the combination] was 79%, and the 1-year EFS rate was 89%. All these [outcomes] compared favorably [with those from] the control arm, as well as [with those from] historical controls.

What is important to note about the safety profile of vidutolimod plus pembrolizumab?

The safety profile was favorable, meaning there was no significant increase in grade 3/4 immune-mediated AEs in the combination arm compared with the monotherapy arm.

What are the clinical implications of these efficacy and safety findings?

The results were encouraging and therefore have justified moving forward with a definitive phase 3 clinical trial. In addition, we have banked extensive biospecimens in the context of the study from consenting patients, and currently, a comprehensive biomarker and mechanistic plan is ongoing, as funded by the National Cancer Institute and in collaboration with Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Center laboratories. The data are promising enough, and these can be validated in the context of the phase 3 clinical trial. In that regard, these findings may be practice changing following validation.

Reference

Tarhini A, Lee S, Davar D, et al. A phase II randomized study of neoadjuvant pembrolizumab (P) alone or in combination with vidutolimod (V) in high-risk resectable melanoma: ECOG-ACRIN EA6194. J Clin Oncol. 2025;43(suppl_17):LBA9505. doi:10.1200/JCO.2025.43.17_suppl.LBA9505