Phase 1/2 study of TSN222, a novel dual action tumor immune agonist (DATIA), in patients with advanced malignancies.

Abstract

e14572 Background: TSN222 is a novel stimulator of interferon genes (STING) agonist capable of being metabolized into a DNA synthesis inhibitor in vivo. This dual action affords sequential stimulation of the innate immune system and release of apoptotic DNA to further activate the STING pathway, and neoantigens to assist the emerging T-cell responses in the tumor microenvironment. TSN222 demonstrated potent antitumor effects via intratumoral (i.t.) injection on a variety of preclinical tumor models across solid tumors and lymphomas. Methods: This first-in-human phase 1/2 study was to determine the maximum tolerated dose (MTD), recommended tolerated phase 2 dose, pharmacokinetic (PK) profile, and preliminary antitumor activity of TSN222 in patients with advanced malignancies. In the phase 1 part, prespecified 7 sequential dose levels from 100 to 6400 μg of TSN222 were to be evaluated, using a "3+3" design for dose escalation. Patients received TSN222 via i.t. injection on Days 1, 8 and 15 of every 28-day cycle until disease progression or unacceptable toxicity. Here we report the data from the ongoing phase 1 part. Results: As of Jan 17, 2025, 16 patients were treated with 100-1600 μg of TSN222, including 5 patients with sarcoma (2 with liposarcoma, 1 each with myxoid fibrosarcoma, epithelioid sarcoma and perivascular epithelioid cell tumor), 4 melanoma and 1 each of 7 other tumors. Median age was about 56 years (range 35-70). Median lines of prior systemic therapy were 4 (range 1-8). No dose-limiting toxicity was observed and MTD not reached. The most common (≥ 10%) treatment related adverse events (TRAEs) were injection site pain (18.8%) and pyrexia (12.5%), with the rest TRAEs occurring in 1 patient each (6.3%), and all TRAEs were of grade 1-2. Among 9 patients assessed per RECIST 1.1, 2 patients with sarcoma had partial response (PR) and are still on treatment with TSN222 at 800 μg for 7.5 and 3.3 months, respectively; 5 had stable disease and 2 had disease progression. Paired biopsies of a PR patient demonstrated that TSN222 significantly induced STING activation, increased CD4 and CD8 positive T cells infiltration and programmed death-ligand 1 (PD-L1) expression in the tumor microenvironment compared to baseline. The plasma T max of TSN222 and its cytotoxic metabolite was around 0.25 and 1 hour, and half-life was 0.8 and 7 hours, respectively. Both C max and AUC displayed dose-proportional increases, without obvious accumulation after multiple dosing. Conclusions: TSN222 was well tolerated with favorable PK profile and promising antitumor activity in patients with heavily pretreated advanced tumors. In addition to monotherapy, the differentiated safety profile of TSN222 supports the exploration of diverse combination therapies in clinical trials. Current data also informs the tolerance and efficacy potential of TSN222 as a promising payload for antibody drug conjugates (ADCs) development. Clinical trial information: NCT05842785 .