Abstract CT227: Interim results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody®) monotherapy and in combination with toripalimab (an anti-PD-1 antibody) in patients (pts) with advanced/metastatic solid tumors
Authors: Ariyapperuma Mihitha , Park John J. , Khattak Adnan , Richardson Gary , Hamid Anis , Morris Michelle , Tolcher Anthony W. , Goh Boon Cher , Lam Justina , Chmielowski Bartosz , She Kristine , Zhang Yanyan , Li Ai , Zheng Songmao , Liu Guizhong , Zhu Lvyu , Wang Hongyan , Cui Xiaoxing , Luo Peter , Zha Jiping 
Published: April 2023

Abstract
Background: ADG126 is an anti-CTLA-4 fully human IgG1 SAFEbody® with a masking peptide blocking the antigen binding site. ADG126 is designed to be preferentially activated in the tumor microenvironment (TME), with the goal of limiting on-target off-tumor toxicities and promoting prolonged exposure to active drug in the TME. Activated ADG126 binds to a unique and conserved epitope of CTLA-4 with species cross-reactivity. Nonclinical studies have demonstrated that activated ADG126 potentiates T cell activation and depletes immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC) specifically in the TME. We present interim results from our ongoing Phase 1b/2 study (ADG126-1001, NCT04645069) on dose escalation and expansion of ADG126 monotherapy as well as dose escalation of ADG126 + toripalimab (Tori).
Method: Pts with advanced solid tumors received ADG126 monotherapy (0.1, 0.3, 1, 3, 10, and 20 mg/kg) Q3W IV or ADG126 (6 or 10 mg/kg) + Tori (240mg) Q3W IV. Primary endpoints are safety and tolerability. Secondary endpoints are PK, anti-drug antibody (ADA), as well as ORR, DCR, DOR and PFS per RECIST 1.1.
Result: As of Dec. 26, 2022, 30 pts have received ADG126 monotherapy. The median number of treatment cycles was 2 (range: 1-24). The median age was 63.5 (39-84) years. 43% of pts had ≥ 3 prior lines of therapies, and 47% had been previously treated with anti-PD-(L)1 and/or anti-CTLA-4 therapies. ADG126 was well-tolerated with no dose-limiting toxicities (DLTs) observed, nor was the MTD reached. Only Grade (G) 1-2 TRAEs were reported; TRAEs ≥10% included diarrhea (17%), fatigue (17%), pruritus (13%), and rash (10%). Among 27 evaluable pts, DCR = 37%. One pt with ovarian serous carcinoma had a major CA125 response (90% reduction) and her disease was stable with ongoing treatment of ADG126 1 mg/kg at Cycle 24 (~16 months). In addition, 14 pts have received ADG126 + Tori in the dose escalation cohorts. The median age was 60 (36-85) years; 50% had ≥ 3 prior lines of therapies, and 43% received prior anti-PD-1 therapies. Both dose levels were well tolerated with no DLT. TRAEs (&gt; 10%) included diarrhea (21%), fatigue (14%), pruritus (14%), rash (14%) and nausea (14%). After multiple cycles at 6 or 10 mg/kg Q3W, G3 TRAEs were observed in 21% (3/14) pts, including elevated liver function test/hepatitis, elevated lipase and diarrhea, which are immune-related, and sepsis. No G4/5 TRAEs have been reported. Among 12 evaluable pts, DCR = 58%, including 2 partial responses. Early efficacy signals were observed with continuous tumor shrinkage and stabilization in IO-resistant and cold tumors.
Conclusion: The anti-CTLA-4 SAFEbody ADG126 shows favorable safety profiles in monotherapy up to 20 mg/kg and in combination with Tori up to 10 mg/kg. Furthermore, promising anti-tumor activity in heavily pre-treated patients was observed in the dose escalation phase. By enabling higher dose levels in combination with anti-PD-1 therapy, ADG126 may unleash the full therapeutic potential for proven and novel indications.
Citation Format: Mihitha Ariyapperuma, John J. Park, Adnan Khattak, Gary Richardson, Anis Hamid, Michelle Morris, Anthony W. Tolcher, Boon Cher Goh, Justina Lam, Bartosz Chmielowski, Kristine She, Yanyan Zhang, Ai Li, Songmao Zheng, Guizhong Liu, Lvyu Zhu, Hongyan Wang, Xiaoxing Cui, Peter Luo, Jiping Zha. Interim results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody®) monotherapy and in combination with toripalimab (an anti-PD-1 antibody) in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT227.