Early safety and efficacy from a phase I clinical study of TWP-101, a novel CD137 agonist antibody, in patients with advanced melanoma and urothelial carcinoma.

9530 Background: CD137 plays the roles as a potent co-stimulator of both adaptive and innate immune cells, being an attractive target for cancer immunotherapy. TWP-101 is a fully humanized agonistic anti-CD137 monoclonal IgG4 antibody, targeting a novel epitope of CD137 with a unique mechanism of actions as a CD137 agonist but not CD137 ligand antagonist. The phase I study of TWP-101 in patient (pt)s with advanced melanoma and urothelial carcinoma was initiated (NCT04871334). Methods: Enrolled pts were advanced melanoma refractory to standard therapy. Dose-escalation includes accelerated titration (0.01 and 0.03mg/kg) and conventional Fibonacci 3+3 dose levels (0.1, 0.3, 1.0 and 3.0 mg/kg). TWP-101 was administered intravenously every Q2W until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The primary objectives were to define the safety profile, to determine the maximum tolerated dose and RP2D of TWP-101. Secondary objectives were to evaluate pharmacokinetics (PK), immunogenicity and preliminary clinical efficacy. Exploratory objectives were to determine pharmacodynamics (PD) biomarkers. Results: From Feb 2021 to Mar 2022,13 melanoma pts (median age 54 years, range 39-73; 6 men, 7 women; median 2 prior lines of therapy, range 1-6; 12 with prior immunotherapy) were treated. The following five dose levels had been evaluated from 0.01 to 1.0 mg/kg. 3mg/kg dose escalation is ongoing, no MTD has been reached. The median treatment time was 16 wks. (range 2-59). On cutoff date of October 31, 2022, 13 pts discontinued treatment due to progression disease (n = 12) and protocol deviation (n = 1). No DLTs were observed. 9 pts (69.2%) experienced treatment-related adverse events (TRAE). The most common TRAEs (≥10%) were neutropenia (23.1%), leukopenia (15.4%), hypertriglyceridemia (15.4%), anemia (15.4%), hyponatremia (15.4%). 1 pt experienced grade 3-4 TRAEs: hyponatremia, Asthenia and reduced appetite. In all TRAEs, one grade 1 decreased free triiodothyronine and one grade 2 pyrexia were possibly related, and all other TRAEs, including 2 treatment-related SAEs (1 grade 4 hyponatremia and 1 grade 2 subarachnoid hemorrhage), were identified as possibly unrelated. Deaths were due to progression disease (n = 3). Preliminary PK analysis showed dose-proportional kinetics. For 12 evaluable pts, 2 pts achieved PR (16.7%), 5 pts was SD. DCR was 58.3%. Median PFS was 16 wks. (range 16-60), PFS of 2 PR pts was 24 and 60 wks. Conclusions: TWP-101 demonstrated a good safety profile without hepatotoxicity frequently observed with other studied CD137 antibodies. Both favorable tolerability and preliminary antitumor activity warrant further evaluation in pts with advanced melanoma and urothelial carcinoma. Clinical trial information: NCT04871334 .