Tilsotolimod Exploits the TLR9 Pathway to Promote Antigen Presentation and Type 1 IFN Signaling in Solid Tumors: A Multicenter International Phase I/II Trial (ILLUMINATE-101).

PURPOSE: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors. PATIENTS AND METHODS: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunologic assessment. Blood samples and tumor biopsies of injected and noninjected lesions were obtained at baseline and 24 hours after treatment for immune analyses. RESULTS: Thirty-eight and 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLT) or grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD), whereas 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease. CONCLUSIONS: Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment. See related commentary by Punekar and Weber, p. 5007.

Checkpoint inhibitors: Better outcomes among advanced cutaneous head and neck melanoma patients.

OBJECTIVE: The aim of this study was to investigate if the treatment outcomes of checkpoint inhibitors (CPI) in patients with advanced-stage skin head and neck melanoma (HNM) differs from outcomes in patients with non-HNM. DESIGN: A retrospective cohort study of patients with unresectable AJCC stage III and stage IV, who received CPI between 2010 and 2017. PARTICIPANTS: Overall, 122 unresectable AJCC stage III and metastatic stage IV melanoma adult patients were treated with CPI during the study period (consecutive patients). The HNM group of patients was comparable with limbs and trunk melanoma group except different distant metastatic (M1a/b/c/d) pattern (p = 0.025). MAIN OUTCOMES: Comparison of overall survival and clinical response to CPI in patients with advanced-stage skin melanoma of the head and neck with non-HNM. RESULTS: We analyzed 38 patients with melanoma arising in the head and neck skin regions, 33 with melanoma of limbs and 51 with trunk melanoma. Most of the head and neck patients were men (89.5%), the average age of melanoma diagnosis was 61.4±16.7 years (range 16.4-85.6). More than a third of HNM group of patients (36.8%) were 70 years and older. Overall response rate (ORR) to CPI was 50% (CR 31.6% and PR 18.4%) in the head and neck study group of patients, compared to an ORR of 36.3% and 23.5% in melanoma of the limbs and of the trunk, respectively (p = 0.03). The median overall survival of HNM group of patients was 60.2±6.3 months, CI 95% [47.7-72.7], 63% were alive at 30 months, reaching a plateau. Whereas, the median survival time of limbs and trunk melanoma were 51.2 and 53.4 months, which did not reach significance. CONCLUSIONS AND RELEVANCE: Response rate to CPI is significantly improved in patients with melanoma of the head and neck and they have a trend towards improved, long standing, overall survival.