Safety and efficacy of ADG126 (an anti-CTLA-4 masking antibody) in combination with pembrolizumab: Updated results of phase 1b/2 study in advanced MSS CRC.

Abstract

3579 Background: ADG126 is an anti-CTLA-4 IgG1 masked antibody that is preferentially activated in the tumor upon cleavage of masking peptides in the tumor microenvironment. Cleaved ADG126 binds to a unique epitope on CTLA-4, blocks CTLA-4 function, primes T cells and depletes Tregs. ADG126 in combination with pembrolizumab (Pembro) has been evaluated in a Phase 1b/2 clinical trial (NCT05405595) and we have reported outcome in 3L MSS CRC patients (Pts) free of liver metastasis (NLM). 1-4 We update results from additional dose expansion (EXP) in Pts of advanced MSS CRC. Methods: This is a Phase 1b/2, open-label, multicenter dose escalation and expansion study. Primary endpoints were safety and tolerability, and early signal of efficacy. Secondary endpoints were PK, ADA, ORR, DCR, DOR, PFS and OS. Results: As of Jan.15, 2025, a total of 54 MSS CRC Pts were treated with ADG126/Pembro (200 mg Q3W) in EXP phase across 3 dose levels of ADG126 (Table 1). 18% Pts had ≥ 3 prior therapies and none had prior IO therapy. There was no Grade 4/5 TRAE, and MTD was not reached. Grade 3 TRAEs were dose-dependent: 38% (5/13), 20% (6/30) and 0% (0/11) for 20 mg/kg LD 1 , 10 mg/kg Q3W and 10 mg/kg Q6W cohorts, respectively. The discontinuation rate remains low for the EXP cohorts (6%). The ORR, CBR, mPFS and 12-mon OS of MSS CRC Pts without liver and peritoneal metastasis (NLPM) are listed in Table 1. ORR increased as a function of ADG126 dose. Although 10 mg/kg Q6W/Pembro did not yield PR, all 6 EE Pts remain on study (1 on treatment) at 18-mon of follow-up. Correlation between dose level/regimen, ORR, CBR and mPFS between 10 mg/kg Q6W and Q3W cohorts has been observed. mOS is not reached for 10 mg/kg Q3W NLPM after 15.5-mon follow up. Longer term efficacy data from 20 mg/kg LD cohort will be reported. Conclusions: Dose-dependent ORR has been observed for ADG126/Pembro IO doublet across multiple dose levels/regimens of ADG126 (10 mg/kg Q6W to 20 mg/kg LD) that is associated with well-tolerated to acceptable safety profile, which is enabled by a relatively large therapeutic window. The overall performance of ADG126/Pembro IO doublet warrants further clinical development including combination with SOCs targeting earlier lines/broader populations, such as MSS CRC with liver metastasis. Clinical trial information: NCT05405595 . Key efficacy results from MSS CRC patients. ADG126 Dose/Pembrolizumab (200 mg, Q3W) 10 mg/kg Q6W 10 mg/kg Q3W 20 mg/kg LD 1 Total # Safety Evaluable 11 30 13 54 Efficacy Evaluable (NLPM) 10 (6) 29 (22) 12 (12) 51 (40) MSS CRC NLPM≥≥>= Objective Response Rate (ORR) 0 PR = 23% (5/22) 2 (CI: 8-45) PR = 33% (4/12) 3 (CI: 10-65) NA 6-mon CBR% 33% 55% (CI: 32-76%) NM NA mPFS (mon) 5.9 6.7 (CI: 4.6-9.0) NM NA 12-mon OS 100% 75.1 (CI: 50-89%) NM NA 1 20 mg/kg LD: ADG126 20 mg/kg x1 cycle followed by 10 mg/kg Q3W. 2 Including 1 unconfirmed PR. 3 All confirmed. CI: 95% confidence interval (report for n >=12 Pts cohort). NM: data not mature. NA: not applicable.