BC3195, a novel ADC targeting cadherin-3 (CDH3): Updated results of a first-in-human phase I study in patients with advanced solid malignancies.

3019 Background: Cadherin-3 (CDH3), a calcium-dependent cell-cell adhesion glycoprotein, is overexpressed on lung, breast, head and neck and other malignancies, and associated with cancer invasiveness and poor prognosis. BC3195 is known as the only antibody drug conjugate (ADC) in clinical stage, targeting CDH3 with cleavable linker and payload of monomethyl auristatin E (MMAE). Methods: A phase I, open-label, first in human study whose objectives were to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of BC3195 is being performed in patients (pts) with advanced solid malignancies. BC3195 is administered as 1-hr IV infusion every 3 weeks (Q3W) or every week (QW). An evaluation of seven dose levels (DLs) is planned: 0.3, 0.6, 1.2, 1.8, 2.1, 2.4 mg/kg Q3W and 1.2 mg/kg QW with a BOIN design guiding dose escalation. Results: As of the data cut-off-date (Dec 26 th , 2024), 56 pts have been enrolled. The number of pts in each DL is shown in the table. Twenty-five (44.6%) pts had received ≥3 prior lines of treatment. Stomatitis (71.4%), rash (60.7%) and anemia (53.6%) were the main adverse events (AEs). Stomatitis and rash typically occurred in the first cycle and were manageable. Twenty-one pts (37.5%) experienced Grade≥3 treatment related adverse events (TRAEs). Among the 50 pts who were evaluable for tumor response, 5 pts in 2.4 mg/kg Q3W had partial response (PR). Of the 20 NSCLC pts treated in 2.4 mg/kg, 4 pts had confirmed PR (cPR), and 14 pts had stable disease (SD) as their best response; the objective response rate (ORR) was 50% (4/8) in previously-treated EGFR-mutant NSCLC pts, and mPFS was 168 days (Table). PK results demonstrated that exposure of the ADC, total antibody (TA) and MMAE increased in a non-linear manner at dose up to 2.4 mg/kg. Median T max values for ADC and TA were 1 h, and median T max for free MMAE was 25-169 h. In addition, elimination t 1/2 values averaged 54 h, 78 h and 63 h for the ADC, TA, and MMAE at 2.4 mg/kg, respectively. Conclusions: BC3195 has a manageable safety profile and favorable PK characteristics and demonstrated impressive preliminary antitumor activity in heavily-pretreated pts with NSCLC, of which most had EGFR-mutations (ORR=50%). Dose optimization and expansion are ongoing. Clinical trial information: NCT05957471 . Safety and efficacy data of study BC3195-101 (safety analysis set). Efficacyand Safety 0.3 mg/kgQ3W(N = 3) 0.6 mg/kgQ3W(N = 3) 1.2 mg/kgQ3W(N = 3) 1.8 mg/kgQ3W(N = 9) 2.1 mg/kgQ3W(N = 6) 2.4 mg/kg Q3W (N =31) All*(N=56) All tumor types(N = 31) EGFR-mut NSCLC(N = 8) ORR, n (%) 0 0 0 0 0 5 (16.1) 4 (50.0) 5 (8.9) DCR, n (%) 1 (33.3) 2 (66.7) 1 (33.3) 3 (33.3) 2 (33.3) 22 (71.0) 7 (87.5) 32 (57.1) mPFS, days 40 82 40 40 39 130 168 91 Grade≥3 TRAE n (%) 0 0 0 2 (22.2) 1 (16.7) 17 (54.8) 3 (37.5) 21 (37.5) *The subject in 1.2 mg/kg QW dose level is not presented in a dedicated column in this table.