Abstract CT233: Initial results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody®) in combination with pembrolizumab (an anti-PD-1 antibody) in patients with advanced/metastatic solid tumors
Authors: Li Daneng , Sharma Sunil , She Kristine , Li Wenda , Li Ai , Zheng Songmao , Liu Guizhong , Ndukwo Ogon , Hu-Lowe Dana , Chisamore Michael , Luo Peter , Zha Jiping , Patel Manish R. 
Published: April 2023

Abstract
Background: ADG126 is a fully human anti-CTLA-4 IgG1 SAFEbody® that has a cleavable masking peptide at the antigen binding site. This design enables ADG126 to be preferentially activated in the tumor microenvironment (TME) to afford prolonged on-tumor drug exposure and limited off-tumor toxicity. The activated ADG126 binds to a unique and highly conserved epitope of CTLA-4, enabling seamless translational studies. ADG126 is activated efficiently in vitro and in vivo, which primes T cells via partial blockade of CTLA-4 interaction with its ligands. ADG126 depletes immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC) specifically in the TME, and it synergizes with anti-PD-1 antibody to induce potent anti-tumor efficacy. In a Phase 1b/2 study, ADG126 monotherapy demonstrated a favorable safety profile and clinical activity in heavily pre-treated patients (pts). Here we present preliminary results from dose escalation of ADG126 in combination with pembrolizumab (Pembro) in pts with advanced/metastatic solid tumors (NCT05405595).
Method: This is a Phase 1b/2, open-label, multicenter dose escalation and dose expansion study to evaluate the safety, tolerability, PK and preliminary efficacy of ADG126/Pembro combination regimen. Pts received ADG126 (6 or 10 mg/kg, Q3W or Q6W, IV) plus Pembro (200mg, Q3W, IV). Primary endpoints are safety and tolerability. Secondary endpoints are PK, ADA, ORR, DCR, DOR and PFS per RECIST 1.1.
Results: As of Jan 20, 2023, 11 pts have been treated with ADG126/Pembro combination in dose escalation cohorts. The median age was 61 yo (26-75); 82% pts had at least 3 prior therapies, 18% pts received prior IO therapies. A majority of pts (82%) have what are considered immunologically “cold” tumors (MSS CRC, PDAC, ovarian cancer, etc.). ADG126 was dosed at 6 mg/kg Q3W (5 pts), 10 mg/kg Q3W (3 pts) and 10 mg/kg Q6W (3 pts); Pembro was dosed at 200 mg Q3W. Both 6 and 10 mg/kg dose levels on either Q3W or Q6W were well tolerated with no DLT, and no Grade 3 and higher treatment-related adverse events (TRAEs) were reported. Clinical efficacy has been observed in 10 evaluable pts of different tumor types, including 1 confirmed partial response (PR) and 1 stable disease (SD) at 10 mg/kg (5 evaluable pts), and 1 SD at 6 mg/kg (5 evaluable pts). Additional safety and efficacy data with repeat dosing will be presented.
Conclusions: The anti-CTLA-4 SAFEbody ADG126 in combination with Pembro is well-tolerated up to 10 mg/kg Q3W or Q6W in the dose escalation cohorts with repeat dosing. The safety profile of this combination appears to be more favorable than other anti-CTLA-4/anti-PD-1 combination therapies reported to date, with no ≥ G3 TRAEs in the dose escalation phase. Clinical efficacy, including one confirmed PR, have been observed in multiple tumor types. Taken together, ADG126/Pembro combination may unleash the full therapeutic benefit of anti-CTLA-4/anti-PD-1 combination in advanced cancer pts beyond immune-sensitive tumor types.
Citation Format: Daneng Li, Sunil Sharma, Kristine She, Wenda Li, Ai Li, Songmao Zheng, Guizhong Liu, Ogon Ndukwo, Dana Hu-Lowe, Michael Chisamore, Peter Luo, Jiping Zha, Manish R. Patel. Initial results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody®) in combination with pembrolizumab (an anti-PD-1 antibody) in patients 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 CT233.