Haymaker et al. reported the first results of using intratumoral tilsotolimod (TLR9 agonist) in combination with ipilimumab in ILLUMINATE-204 – a phase 1/2 clinical trial in patients with advanced melanoma refractory to anti-PD-1 therapy. Out of 64 patients, 48.4% experienced grade 3/4 adverse events. The ORR was 22.4% (n=49) with tumor reduction in injected and non-injected lesions. Injection of tilsotolimod induced rapid type-1 interferon responses, macrophage infiltration, and local DC maturation. The presence of DCs at baseline, and T cell proliferation and clonal expansion at local and distant lesions correlated with clinical response.
Contributed by Shishir Pant
ABSTRACT: Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase 1/2 trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1-resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase 2 dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in non-injected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local interferon-alpha gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase 3 clinical trial with this combination (NCT03445533) is ongoing.
Author Info: (1) Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center. (2) Hematology and Medical Oncology, Ochsner Health System. (3) Interventional Radiology &
Author Info: (1) Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center. (2) Hematology and Medical Oncology, Ochsner Health System. (3) Interventional Radiology & Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center. (4) Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center. (5) Cancer Medicine, The University of Texas MD Anderson Cancer Center. (6) Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center. (7) The University of Texas MD Anderson Cancer Center. (8) The University of Texas MD Anderson Cancer Center. (9) Huntsman Cancer Institute. (10) Department of Medicine, Vanderbilt-Ingram Cancer Center. (11) University of Arizona Cancer Center. (12) Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. (13) Idera Pharmaceuticals, Inc. (14) Idera Pharmaceuticals, Inc. (15) Department of Biostatistics, The University of Texas MD Anderson Cancer Center. (16) Pathology and Dermatology, University of California, San Francisco. (17) Oncology Research, Nektar Therapeutics (United States). (18) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center. (19) Gabrail Cancer Center. (20) University of Massachusetts Medical School. (21) University of Kansas Medical Center. (22) Medicine, Roswell Park Comprehensive Cancer Center. (23) Cutaneous Oncology, Moffitt Cancer Center. (24) Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center. (25) Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center adiab@mdanderson.org.
