Vidutolimod combination yields encouraging responses in advanced melanoma

New early-phase clinical data supports the potential of vidutolimod in combination with pembrolizumab for treating PD-1–resistant advanced melanoma

Published on 3 August, 2025 in the Cancer journal, the final analysis of a phase 1b study evaluating the Toll-like receptor 9 (TLR9) agonist, vidutolimod, alone and in combination with pembrolizumab, has shown encouraging results for individuals living with programmed cell death 1 (PD-1)–resistant advanced melanoma.¹

Resistance to PD-1 blockade in melanoma is thought to be associated with a lack of CD8+ T cells in the tumour microenvironment.² Vidutolimod, a TLR9 agonist delivered intratumorally in a noninfectious virus-like particle, aims to stimulate both innate and adaptive anti-tumour immune responses by selectively activating plasmacytoid dendritic cells and promoting type I interferon secretion. This, in turn, is thought to enhance CD8+ T-cell responses against the tumour. It is hoped that combining this approach with the PD-1 inhibitor, pembrolizumab, may help overcome resistance in PD-1–refractory melanoma.¹^,³

This open-label, multicentre, phase 1b clinical trial (ClinicalTrials.gov identifier NCT02680184) included individuals with advanced cutaneous melanoma who had previously received or progressed on PD-1/PD-L1 inhibitors. Participants required at least one tumour suitable for direct injection, with eligible lesions measuring ≥0.5 cm in diameter. The study evaluated the safety and efficacy of intratumoral vidutolimod, given alone or with pembrolizumab. In part 1, patients (n=159) received various doses of vidutolimod plus pembrolizumab to assess safety and early signs of clinical benefit; part 2 evaluated vidutolimod monotherapy (n=40). Two formulations were tested: PS20-A (0.005%–0.01% polysorbate 20) and PS20-B (0.00167% polysorbate 20). Treatment was administered weekly for 7 weeks, then either every two or three weeks. Tumour responses were assessed at baseline, every 12 weeks and after treatment, with safety monitored throughout.

A total of 199 patients were enrolled across both parts of the study. The PS20-A formulation demonstrated greater clinical activity than PS20-B, with a best objective response rate (ORR) of 23.5% (95% CI, 15.5–33.1%) and 7.1% achieving complete response (CR) in the PS20-A plus pembrolizumab arm, compared with an ORR of 11.5% (95% CI, 4.7–22.2%) and 1.6% CR for those receiving PS20-B plus pembrolizumab. Vidutolimod monotherapy resulted in a 20.0% ORR (95% CI, 9.1–35.6%). Median duration of response was longest with PS20-A plus pembrolizumab (25.2 months), followed by PS20-B plus pembrolizumab (11.4 months) and vidutolimod monotherapy (5.6 months). Any-grade treatment-emergent adverse events (TEAEs) were reported in all patients, with grade ≥3 TEAEs reported in 55.3% of those receiving a combination therapy and 37.5% of those receiving monotherapy. No treatment-related deaths were noted.

Reporting on the findings the authors, Prof. Mohammed Milhem and colleagues, note that although the study had limitations typical of early-phase trials, including small sample size, lack of a control group and a limited follow-up, the observed durable antitumour activity and acceptable safety profile in this analysis supports the continued clinical development of vidutolimod to overcome PD-1 blockade resistance in advanced melanoma.

Vidutolimod is currently in phase 2 clinical development for melanoma and under investigation in randomized neoadjuvant trials in patients with high-risk, resectable stage III melanoma, including the ECOG‑ACRIN EA6194 trial.⁴

The full study results can be viewed here

References:

1. Milhem MM, Zakharia Y, Davar D, et al. Intratumoral vidutolimod as monotherapy or in combination with pembrolizumab in patients with programmed cell death 1 blockade-resistant melanoma: Final analysis from a phase 1b study. Cancer. 2025;131(15):e70022. DOI: 10.1002/cncr.70022..
2. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504. DOI:10.1093/annonc/mdw217
3. Cheng Y, Lemke-Miltner CD, Wongpattaraworakul W, et al. In situ immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy. J Immunother Cancer. 2020 Oct;8(2):e000940. DOI: 10.1136/jitc-2020-000940.
4. Tarhini AA, Lee SJ, 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.):Abstr.LBA9505.

Disclosure: This article was created by the touchDERMATOLOGY team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.

Citation: Vidutolimod combination yields encouraging responses in advanced melanoma. touchDERMATOLOGY.com. 06 August 2025.

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