News
Article
Author(s):
New clinical trial results reveal that intratumoral vidutolimod combined with pembrolizumab shows promise for treating advanced melanoma resistant to PD-1 therapy.
Image Credit: © dermnetnz.org
A recently concluded phase 1b clinical trial offers renewed hope for patients with advanced melanoma resistant to programmed cell death 1 (PD-1) blockade. The study evaluated intratumoral vidutolimod, a Toll-like receptor 9 (TLR9) agonist, administered either alone or in combination with pembrolizumab.1 A specific formulation (PS20-A) combined with pembrolizumab was well tolerated and showed improved efficacy.
“For PD-1 blockade–resistant melanoma, new immunotherapy combinations are needed to simultaneously target multiple cancer immune evasion mechanisms,” the authors wrote.
PD-1 resistance in melanoma is commonly associated with a non-inflamed tumor microenvironment lacking sufficient CD8+ T-cell infiltration.2 Vidutolimod aims to convert these tumors by activating plasmacytoid dendritic cells and inducing type I interferon responses. By directly injecting vidutolimod into tumors, the researchers sought to stimulate local and systemic antitumor immunity. Combining this with pembrolizumab, a PD-1 inhibitor, could potentially overcome immune resistance mechanisms.
This open-label, multicenter phase 1b trial (NCT02680184) consisted of two parts. Part 1 tested vidutolimod with pembrolizumab in 159 patients, and part 2 tested vidutolimod monotherapy in 40 patients. Two formulations of vidutolimod were assessed, PS20-A (0.005%–0.01% polysorbate 20) and PS20-B (0.00167%), at dose levels from 1 to 10 mg. The drug was injected intratumorally weekly for 7 weeks, followed by every 2 or 3 weeks thereafter. Included lesions had diameters of ≥0.5 cm.
There was a clinical focus on patients with metastatic and/or unresectable melanoma, including those who were previously treated with ipilimumab. Each had an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). All were enrolled between April 14, 2016, and April 26, 2021. Primary clinical endpoints revolved around safety and adverse events. Tumor assessments were evaluated at baseline screening, every 12 weeks, and then post-treatment.
The most clinically meaningful responses were observed with the PS20-A formulation. Over 7.1% of patients had a complete response with the best objective response rate of 23.5%. The median duration of response was 25.2 months with median overall survival of 16.3 months. Responses were seen in both injected and noninjected lesions, including in visceral metastases, suggesting systemic immune activation. Notably, 12 patients treated with PS20-A plus pembrolizumab had responses lasting over a year, with two maintaining responses beyond 36 months.
In contrast, the PS20-B formulation had a lower efficacy of 11.5%. The median duration of response was 11.4 months. According to the authors, this formulation is no longer in clinical development. When used as a monotherapy, vidutolimod showed an objective response rate of 20.0%. All responses were partial. The median duration of response was 5.6 months.
Any-grade treatment-emergent adverse events were common but manageable, occurring in 100.0% of patients. Grade ≥3 treatment-emergent adverse effects occurred in 55.3% (combination therapy) and 37.5% (monotherapy) of patients. The most frequently observed events were transient injection site reactions and flu-like symptoms such as chills, fever, fatigue, and nausea. Hypotension and hypertension were the most common severe (grade ≥3) events. In part 1, 3 patients (1.9%) had a treatment-emergent adverse event resulting in death. A patient with a past history of infected neoplasm died of sepsis, and 2 patients with baseline lung metastases died of respiratory failure. No treatment-related deaths occurred in part 2.
This study provides compelling early-phase evidence that intratumoral vidutolimod, especially in its PS20-A formulation, can generate durable clinical responses in patients with PD-1–resistant melanoma, in combination with pembrolizumab. Vidutolimod PS20-A is now being prioritized for further clinical development. Larger randomized trials with a control group and longer follow-up. are needed to validate these findings and establish the optimal treatment schedule.
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
Like what you’re reading? Subscribe to Dermatology Times for weekly updates on therapies, innovations, and real-world practice tips.