Preliminary results from a first-in-human phase 1 dose escalation trial of ADRX-0706, a next generation Nectin-4 ADC, in subjects with advanced solid tumors.
Year: 2025
Type: conference-abstract
Abstract: 3018 Background: ADRX-0706 is a Nectin-4 targeting ADC designed to provide an increased therapeutic window through stable conjugation of a novel microtubule inhibitor payload (AP052) to an IgG1 monoclonal antibody at a drug-to-antibody ratio of 8. Preliminary safety, anti-tumor activity, pharmacokinetic (PK) and Nectin-4 expression results are presented from the dose escalation part of the ongoing Phase 1 trial (NCT06036121). Methods: Eligible subjects with select advanced solid tumors (urothelial [UC], cervical [CC], breast [BC], head and neck [HNSCC], ovarian [OC], non-small cell lung [NSCLC], and pancreatic [PC]) were enrolled in cohorts of escalating dose levels (1-16 mg/kg, Q3W, IV) using a BOIN design with backfill. Nectin-4 expression was evaluated retrospectively. Primary and secondary endpoints included dose-limiting toxicities [DLTs], adverse events [AEs], laboratory value changes, PK, immunogenicity, and response per RECIST v1.1. Results: As of the 13Dec24 data cutoff, 53 subjects with a median age of 59 years and median of 4 (1-14) prior therapies were enrolled. One DLT (G3 stomatitis) occurred at the highest dose of 16 mg/kg. The most common treatment related AEs (TRAE ≥15%) were arthralgia (32%), fatigue (21%), rash (19%), anemia (17%), and nausea (15%). The majority of TRAEs were G1-2 in severity and manageable, including only 3 (5.7%) subjects with peripheral neuropathy and 2 (3.8%) with liver enzyme increase. The most common ≥G3 TRAE was neutropenia (11%). ADC exposure increased in a dose-proportional manner with minimal deconjugation and the ADC half-life was 15 days. There were 5 subjects who achieved objective response across different tumor types (UC, NSCLC, CC) and 9 with stable disease per RECIST among 30 response-evaluable subjects treated at doses ≥8 mg/kg (ORR 16.7%, DCR 46.7%), including 2 triple negative BC (TNBC) subjects with 27% and 29% decrease in tumor size who remain on treatment. ADRX-0706 demonstrated Nectin-4 expression-dependent anti-tumor activity with all responses observed in tumors with H-score ≥100, including a confirmed complete response (CR) in a CC subject (H-score 250). Two responses were observed after prior progression on other Nectin-4 targeting MMAE drugs and three responses remain ongoing with subjects on treatment for 9+ to 23+ weeks. Based on these data, 10 mg/kg Q3W was selected as the Phase 1b dose. Conclusions: ADRX-0706 demonstrated a preliminary safety profile differentiated from MMAE-conjugates and with manageable toxicities. The antibody-like PK profile together with minimal deconjugation supports Q3W dosing. Encouraging anti-tumor activity was observed in multiple heavily pretreated tumors with moderate-high Nectin-4 expression. Enrollment in Phase 1b cohorts of UC, CC, and TNBC is ongoing. Clinical trial information: NCT06036121 .
Source: Journal of Clinical Oncology
Institutions: University of California, Los Angeles, UCLA Jonsson Comprehensive Cancer Center, The University of Texas MD Anderson Cancer Center, University of Southern California, USC Norris Comprehensive Cancer Center, South Texas Accelerated Research Therapeutics, Sarah Cannon, Wuhan Union Hospital, Peking University Third Hospital, Fujian Provincial Cancer Hospital, Tongji University, Shanghai East Hospital
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4410814460