(UroToday.com) The 2026 ASCO GU Annual Symposium featured a trials-in-progress session highlighting ongoing studies in advanced urothelial carcinoma. Dr. Timothy Yap presented the design of the ongoing NECTINIUM-2 study (NCT07020117), a first-in-human phase 1b trial evaluating the Nectin-4–targeted radiopharmaceutical [225Ac]Ac-AKY-1189 in patients with locally advanced or metastatic solid tumors, including urothelial carcinoma.
Nectin-4 is a clinically validated therapeutic target in metastatic urothelial cancer and is overexpressed across several additional solid tumor types, suggesting broad therapeutic potential. AKY-1189 is a high-affinity and selective Nectin-4–targeted miniprotein that demonstrates rapid plasma clearance and favorable biodistribution in normal tissues in humans when conjugated to gallium-68. Preclinical work has demonstrated that [225Ac]Ac-AKY-1189 can induce tumor regression and disease stabilization in models of urothelial carcinoma following a single administration. The antitumor activity of this radiopharmaceutical appears target-dependent and is observed at doses that are well tolerated in preclinical systems. Collectively, these data support further clinical evaluation of [225Ac]Ac-AKY-1189 as a potential therapeutic strategy in patients with advanced solid tumors.
NECTINIUM-2 (NCT07020117) is designed as a first-in-human, phase 1b, multi-center, open-label study composed of two parts: dose escalation followed by dose expansion. Eligible patients are adults (≥18 years) with histologically or cytologically confirmed locally advanced or metastatic solid tumors and at least one measurable lesion according to RECIST v1.1. Additional key eligibility criteria include:
- ECOG performance status of 0–1
- Adequate end-organ function
- Documented disease progression following prior systemic chemotherapy in the metastatic setting
- Evidence of tumor uptake on [64Cu]Cu-AKY-1189 PET/CT imaging.
Key exclusion criteria include:
- Prior exposure to radiopharmaceutical therapy
- Receipt of investigational treatment within the preceding four weeks
- Receipt of systemic anticancer therapy or external beam radiotherapy within the prior three weeks.
Part 1 of the study consists of a dose-escalation phase evaluating ascending doses of [225Ac]Ac-AKY-1189 administered for up to six treatment cycles in approximately 30 patients with locally advanced or metastatic urothelial cancer. The primary objective of this portion of the study is to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD), as well as to establish the recommended phase 2 dose (RP2D).
Following identification of the RP2D, Part 2 of the study will assess the clinical activity of [225Ac]Ac-AKY-1189 in three expansion cohorts of patients with Nectin-4–positive solid tumors. These expansion cohorts are intended to further characterize the safety profile and preliminary efficacy of the radiopharmaceutical across tumor types that express Nectin-4.
The NECTINIUM-2 trial has initiated enrollment in the United States and represents an early clinical effort to evaluate targeted alpha-particle radiopharmaceutical therapy directed at Nectin-4 in patients with advanced malignancies. The results of this study will inform the feasibility, safety, and potential clinical activity of this approach and may help define a new therapeutic strategy for patients with advanced urothelial carcinoma and other Nectin-4–expressing cancers.
Presented by: Timothy A. Yap, MBBS, PhD, FRCP, Medical Oncologist, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA
Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center, Tucson, AZ – @rksayyid on X during the 2026 ASCO GU Annual Symposium, San Francisco, CA, February 26th–28th, 2026