TLR9 Agonist Vidutolimod Shows Promise in Combination With Pembrolizumab in PD-1–Refractory Melanoma

The combination of intratumoral vidutolimod and intravenous pembrolizumab (Keytruda) demonstrated promising clinical activity in patients with PD-1 refractory melanoma. Furthermore, vidutolimod presented a manageable safety profile alone and in combination with pembrolizumab, according to findings from the final analysis of the phase 1b CMP-001-001 trial (NCT02680184) that were presented during the 2021 SITC Annual Meeting.

Additionally, tumor volume reductions in both injected and noninjected target lesions provided evidence of vidutolimod inducing a systemic antitumor response.

In patients administered vidutolimod polysorbate 20 at 0.01% (PS20 A) in combination with pembrolizumab (n = 98), the best objective response rate (ORR) was 23.5% (n = 23; 95% CI, 15.5%-33.1%) per RECIST v1.1 criteria. Additionally, durable responses were seen, with a median duration of response (DOR) of 25.2 months (95% CI, 8.7-not estimable [NE]) in responders. Solid tumor regression was seen in 27 patients (27.6%).

Furthermore, vidutolimod demonstrated single-agent activity in a subset of patients treated without pembrolizumab (n = 40). Data showed this group had a best ORR of 20.0% (95% CI, 9.1%-35.6%) per RECIST v1.1 criteria. When including postprogression responders, this group experienced a 22.5% ORR (95% CI, 10.8%-38.5%). However, patients in this subset had a median DOR of just 5.6 months (95% CI, 3.1-NE).

“The substantially shorter duration of response to vidutolimod alone provides a strong rationale for the development of vidutolimod in combination with PD-1 blockade,” lead study author John M. Kirkwood, MD, professor of medicine, dermatology, and clinical and translational science at the University of Pittsburgh School of Medicine and the Clinical and Translational Science Institute at the University of Pittsburgh, said in a poster presentation of the data. “Vidutolimod alone and in combination with pembrolizumab had a very manageable safety profile.”

Vidutolimod is a first-in-class, immunostimulatory, noninfectious virus-like particle (VLP) containing a CpG-A TLR9 agonist. Standard treatment for advanced melanoma is PD-1 blockade alone or in combination with CTLA-4 blockade. Previous results from the dose-escalation portion of this study showed an ORR of 25% (n = 11) in patients receiving vidutolimod plus pembrolizumab. The goal of the remainder of the study was to determine the recommended phase 2 dose of the two agents, plus the safety of vidutolimod monotherapy.

To qualify for the trial, patients were required to have histologically confirmed metastatic or unresectable cutaneous melanoma and at least 1 lesion amenable to intratumoral injection. Patients also needed a history of current or previous anti–PD-1/PD-L1 treatment. Past treatments with other TLR9 agonists, oncolytic viruses, or innate immune activators were not excluded.

CMP-001-001 was a 2-part, open-label, multicenter trial evaluating vidutolimod alone and in combination with pembrolizumab. Part 1 of the study explored dose escalation and expansion with vidutolimod and pembrolizumab, where patients (n = 159) were divided into two treatment groups. The first group (n = 98) received vidutolimod PS20 A and pembrolizumab, and the second group (n = 61) received vidutolimod polysorbate 20 at 0.00167% (PS20 B) and pembrolizumab.

The subset of patients receiving vidutolimod PS20 A were placed on two different treatment courses. One group (n = 61) received vidutolimod PS20 A and pembrolizumab weekly for 7 weeks, then once every 3 weeks until discontinuation. The other subset received vidutolimod PS20 A and pembrolizumab weekly for 2 weeks, then once every 3 weeks until discontinuation. This group was evaluated only in the part 1 dose-escalation phase.

Based on the results of the trial, 10mg of vidutolimod PS20 A was labeled as the recommended phase 2 dose (RP2D).

To determine the safety profile of the combination of vidutolimod alone and in combination with pembrolizumab, researchers examined the patient groups from part 1 and part 2 of the trial. For part 1, the median follow up was 14.8 months, and 156 patients (98.1%) reported at least 1 treatment-related adverse effect (TRAE). Furthermore, 55 patients (34.6%) experienced at least 1 grade 3 TRAE, and 4 patients (2.5%) experienced at least 1 grade 4 TRAE. In part 2, 38 patients (95.0%) experienced at least 1 TRAE. Furthermore, 9 patients (22.5%) reported at least 1 grade 3 TRAE.

The most common TRAE reported was chills in 119 patients (74.8%) in part 1 and 24 patients (60.0%) in part 2. Additionally, pyrexia was reported in 98 patients (61.6%) and 20 patients (50.0%) in part 1 and part 2, respectively.

Kirkwood mentioned the phase 2 CMP-001-010 trial (NCT04698187) and the phase 2/3 CMP-001-011 trial (NCT04695977) as further studies evaluating this agent in combination with a PD-1 inhibitor.

“Clinical studies to confirm the efficacy of vidutolimod with PD-1 blockade in patients with previously untreated, advanced melanoma, as well as those with PD-1 refractory melanoma are ongoing,” Kirkwood said.

Reference

1. Kirkwood JM, Zakharia Y, Davar D, et al. Final analysis: phase 1b study investigating intratumoral injection of toll-like receptor 9 agonist vidutolimod ± pembrolizumab in patients with PD-1 blockade–refractory melanoma. J Immunother Cancer. 2021;9. doi: 10.1136/jitc-2021-SITC2021.950