ADG126 Exhibits Clinical Meaningful Efficacy in MSS CRC

The combination of ADG126 and pembrolizumab (Keytruda) delivered a durable clinical benefit with a meaningful overall response rate (ORR) of 29% in patients with metastatic microsatellite stable colorectal cancer (MSS CRC). Patients demonstrated a median duration of response (DOR) of 8 months, and an interim median overall survival (OS) of 19.4 months after 18 months of follow-up, according to updated results of a phase 1b/2 trial (NCT05405595) presented during the European Society for Medical Oncology Targeted Anticancer Therapies (ESMO TAT) Asia Congress 2025.^1,2

The dose-expansion study investigated 4 regimens: 10 mg/kg every 3 weeks plus pembrolizumab (n = 30; cohort A), 20 mg/kg loading dose followed by 10 mg/ kg every 3 weeks (n = 14; cohort B), 20 mg/kg every 6 weeks plus pembrolizumab (n = 7; cohort C), and 10 mg/kg every 6 weeks (n = 11; cohort D). In total, 62 heavily pretreated patients with MSS CRC were evaluated by the April 2025 cutoff.

The primary end points were safety, tolerability, maximum tolerated dose, and recommended phase 2 dose. Secondary end points were pharmacokinetics, pharmacodynamics, and antitumor activity.

ADG126 is a novel anti–CTLA-4 agent incorporating protease-cleavable masking technology that enables tumor-specific activation. The antibody demonstrates 10-fold higher antibody-dependent cellular cytotoxicity than ipilimumab (Yervoy) without requiring Fc domain engineering, enhancing regulatory T-cell depletion in the tumor microenvironment.

Efficacy data from cohorts A and D showed an ORR of 17% (95% CI, 6.0%–36.0%) and 0% (95% CI, 0.0%–31.0%), respectively. The combined ORR for cohorts B and C was 29% (95% CI, 11.0%–52.0%). The disease control rate for cohort A was 76% (95% CI, 56.0%–90.0%) and for cohort D, 70.0% (95% CI, 35.0%–93.0%). In cohorts B and C, the disease control rate was 81.0% (95% CI, 58.0%–95.0%).

Median progression-free survival (PFS) was 4.8 months (95% CI, 2.6-6.7) in cohort A and 4.5 months (95% CI, 1.4–7.1) in cohort D. PFS was not reached for the combined cohorts B and C (95% CI, 2.7–not available [NA]). The PFS rate for cohort A was 39.5% (95% CI, 21.8%–56.7%) and 40% (95% CI, 12.3%–67.0%) for cohort D. In combined cohorts B and C, the PFS rate was 50.4% (95% CI, 20.7%–74.2%).

Among confirmed partial responses, the median DOR was 8 months (95% CI, 4.2–NA). Survival data showed a median OS of 19.4 months in the 10 mg/kg cohort after 17.8 months of follow-up.

“These findings significantly exceeded the 10.8- and 12.1-month benchmarks from FRESCO [NCT02314819] and FRESCO-2 [NCT04322539] trials, respectively, in patients without liver metastases [NLM],” Sun-Young Kim, MD, PhD, assistant professor in oncology, Department of Oncology, Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, said during a presentation of the data.^3,4

Patient Characteristics

The overall median age of patients was 58 years (range, 26-75). Most patients were female (53%), and 66% were Asian. Thirty-two percent of patients had 3 or more prior lines of therapy, and all patients (100%) were NLM, with 24% exhibiting peritoneal involvement.

Safety

Investigators reported that no dose-limiting toxicities or grade 4/5 treatment-related adverse events (TRAEs) were observed with an overall discontinuation rate of 4%. Patients in cohort A demonstrated a 10% discontinuation rate.

Grade 3 TRAEs occurred in 20% of patients in cohort A compared with 17% in cohort C. The most common TRAEs included pruritus (43%), hypothyroidism (20%), and adrenal insufficiency (17%). In cohorts B and C, adverse events were manageable with infrequent use of infliximab (Remicade), and the every-6-week schedule showed lower rates of grade 3 events than the loading dose regimen.

These findings suggest that ADG126 plus pembrolizumab could represent a meaningful advancement for patients with MSS CRC, particularly in those without liver metastases. The combination offers higher response rates than historical anti–CTLA-4 therapies, a near doubling of survival compared with fruquintinib (Fruzaqla) benchmarks, and manageable toxicity. The results warrant further investigation in randomized controlled trials.

REFERENCES:

1. Kim SY, Li D, Patel M. A phase Ib/II update of ADG126 (an anti-CTLA-4 masking antibody) across different dosing regimens in combination with pembrolizumab in advanced/ metastatic MSS CRC. Presented at: ESMO TAT Asia Congress 2025; July 18-20, 2025; Hong Kong SAR, China. Abstract 39O.

2. Kim SY, Li D, Patel M, et al. A phase Ib/II update of ADG126 (an anti-CTLA-4 masking antibody) across different dosing regimens in combination with pembrolizumab in advanced/ metastatic MSS CRC. Ann Oncol. 2025;10(suppl 6):1-7. doi:10.1016/esmoop/esmoop105384

3. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855

4. Dasari A, Lonardi S, Garcia-Carbonero R, et al; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53. doi:10.1016/S01406736(23)00772-9