A randomized phase II clinical trial on intratumoral autologous CD1c (BDCA-1) ⁺ /CD141 (BDCA-3) ⁺ myeloid dendritic cells (myDC) plus ipilimumab (IPI) and synthetic adjuvant AS01B combined with low-dose intravenous (IV) nivolumab (NIVO) in advanced pretreated melanoma patients.

Abstract

e21514 Background: Many advanced melanoma patients (pts) will not obtain a durable response on immune checkpoint- (ICI) and BRAF/MEK-inhibitors (in case of a BRAFV600 mutation). Dendritic cells are crucial for ICI effectiveness and are often excluded from the tumor microenvironment in refractory melanoma. In a previous phase I clinical trial (NCT03707808), low-dose IV NIVO (10 mg) combined with intratumoral (IT) injections of autologous CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC, IPI and synthetic adjuvant AS01B was proven feasible with a promising efficacy signal (DCR 50%) (Tijtgat et al, JITC 2024). We aimed to evaluate the added value of the myDC in a randomized trial. Methods: In this single-center, prospective, two-stage phase II clinical trial, advanced melanoma pts with injectable metastases progressive on standard-of-care life prolonging treatments were randomized 1:1 to receive weekly IT IPI and AS01B with (arm A) or without (arm B) a single IT injection of autologous myDC, and bi-weekly low-dose NIVO IV. At progression (PD), pts in arm B could cross-over to receive the single IT autologous myDC injection with continued study treatment. A sample size of 9 pts in each arm was determined according to a Simon’s two-stage study design. The 1-year PFS rate (1y PFS) served as primary endpoint. Key secondary endpoints were safety, ORR (per RECIST v1.1), PFS and OS. Results: At this interim analysis, 16 pts (8 in each arm) were enrolled (10 male, median (med) age 69, AJCC stage IIIB: 1, IIIC: 5; M1a: 6, M1c: 3, M1d: 1) between Jan ‘24 and DBL (20 Jan '26). There were no significant differences in treatment disposition between both study arms (med 6.5x IT (range 1-22) and 4x IV NIVO (range 1-12)). 13 pts were evaluable for response. The ORR was 28% in arm A (2 CR: 30 wks and 73+ wks), and 17% in arm B (1 CR: 48+ wks). 4 out of 5 pts crossed over at PD to receive myDC. After cross-over, there was one stable disease. After a median follow-up of 38 wks (range 2-101), 11 pts progressed (6 in arm A, 5 in arm B), and 6 had died (4 in arm A, 2 in arm B). Estimation of the 1y PFS is immature, requiring additional follow-up. Med PFS was 14 wks (95% CI 11-16) in arm A and 17 wks (95% CI 11-22) in arm B. All pts experienced at least one treatment-related adverse event (TRAE); most commonly low-grade fatigue (44%) and injection site reaction (56%) with equal frequency in both arms. 5 pts interrupted treatment temporary (4) or definitive (1) due to TRAE. No grade ≥4 TRAE occurred. Conclusions: Weekly IT IPI+AS01B and bi-weekly low-dose NIVO IV, with or without a single IT injection of myDC, is safe and results in durable tumor responses in a meaningful subset of advanced pretreated melanoma pts. Additional follow-up is needed to estimate the added value of IT myDC in this investigational IT immunotherapy regimen. Clinical trial information: EUDRACT 2017-003280-35.