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.

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 .