A phase 1 study of AGEN2373, a novel CD137 agonist antibody designed to avoid hepatoxicity, in patients with advanced solid tumors.
Authors: Barve Minal A. , Tolcher Anthony W. , Carvajal Richard D. , Izar Benjamin , El-Khoueiry Anthony B. , Hanna Diana L. , Tarhini Ahmad A. , Whitman Eric D. , Bhatia Shailender , Davar Diwakar , Lutzky Jose , Taylor Matthew H. , Tello Monique , Rosenthal Katherine , Danielyan Anna , Yip Wai Ki , Song James , Savitsky David , Chand Dhan , Grossman Joseph Elan 
Published: June 2023

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Background: We present results from the completely enrolled monotherapy arm of the first-in-human dose escalation study of AGEN2373, a novel CD137 agonist antibody engineered to maximize efficacy by circumventing the dose-limiting hepatotoxicity reported for prior CD137 agonists (NCT04121676). AGEN2373 binds to a unique epitope of CD137 on effector T and NK cells in the tumor and tumor-draining lymph nodes, promoting co-engagement of activating Fcγ receptors. CD137 (4-1BB) is a tumor necrosis factor receptor superfamily protein and co-stimulatory receptor that promotes anti-tumor activity of adaptive and innate immune cells, making it an attractive target for immunotherapy. Methods: 46 patients (pts) received AGEN2373 IV every 2 weeks (Q2W), Q3W, or Q4W at doses between 0.03 and 10 mg/kg in a 3+3 design. Key endpoints included safety, tolerability, PK, preliminary efficacy, and PD markers. Imaging was Q8W. Results: Pts were enrolled between Oct 2019 and May 2022 with a median follow-up of 7.2 months. The median age was 64 (range 33-82). The most common tumor types were colorectal cancer, 13 pts (28%) and sarcoma, 8 (17%). Median prior therapies were 4 (range 1-14) including 48% with prior immunotherapy. There were no dose-limiting toxicities (DLTs) and no treatment-related hepatitis. 37% of pts had treatment-related AEs (TRAEs). TRAEs >10% were limited to fatigue (17%) and nausea (15%). There were no G3, 4 or 5 TRAEs. Pharmacokinetic parameters including half-life, clearance, and volume of distribution were consistent with a human IgG1 Fc backbone. Induction of soluble CD137 was dose dependent with 2 mg/kg as the lowest saturating dose and minimum predicted efficacious dose. In 19 pts treated at 2 mg/kg or higher who had at least one post-baseline scan, the overall response rate (ORR) was 11% (n=2); 37% had SD (n=7) resulting in a disease control rate (DCR) (CR, PR or SD) of 47%. Notable responses include: a pt with vulvar SCC who had progressed rapidly on pembrolizumab and had a confirmed partial response (cPR) while remaining on AGEN2373 x 2 mg/kg q2w for ~40 wks, and a pt with ampullary carcinoma with 4 prior regimens had a cPR on AGEN2373 x 6 mg/kg q3w with complete resolution of the pancreatic lesion. A pt with CRPC had a 38% tumor reduction in liver target lesions (confirmed) on AGEN2373 x 10mg/kg q3w but was non-evaluable due to palliative radiation to bone metastases. Conclusions: AGEN2373 showed objective responses as monotherapy in heavily pretreated pts with solid tumors and was well-tolerated with no evidence of hepatotoxicity. This distinguishes AGEN2373 from previous CD137-targeted agents that reported dose-limiting hepatotoxicity. Combination therapy with botensilimab, a novel Fc-enhanced CTLA-4 antagonist, is being studied in pts with PD(L)-1 pretreated melanoma. Clinical trial information: NCT04121676 .