A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Chemo-immunotherapy Combination Using Motolimod with Pegylated Liposomal Doxorubicin in Recurrent or Persistent Ovarian Cancer: A Gynecologic Oncology Group Partners Study
Mené sur des patientes atteintes d'un carcinome épithélial de l'ovaire récidivant, d'un cancer des trompes de Fallope ou d'un carcinome péritonéal primitif, cet essai de phase II évalue l'efficacité, du point de vue de la survie globale et de la survie sans progression, et la toxicité d'un traitement combinant motolimod, un agoniste du récepteur TLR8, et doxorubicine liposomale pégylée
Background: A Phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod—a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses—combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. Patients and Methods: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1:1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6–12 months) and GOG performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression. Results: The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank 1-sided p=0.923, HR=1.22) or progression-free survival (PFS; log rank 1 sided p=0.943, HR=1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared to those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS. Conclusions: The addition of motolimod to PLD did not improve clinical outcomes compared to placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches https://academic.oup.com/annonc/article-abstract/doi/10.1093/annonc/mdx049/3038392/A-Phase-2-Randomized-Double-Blind-Placebo?redirectedFrom=fulltext.