Abstract CT068: A phase 1/2, open-label, multicenter, first-in-human study to evaluate the safety, pharmacokinetics, and anti-tumor activity of YH32367 in patients (pts) with HER2+ locally advanced/metastatic (a/m) solid tumors

Abstract Background: YH32367, a HER2 x 4-1BB bispecific antibody engineered to amplify tumor-localized super-agonist activity of 4-1BB while minimizing off-target toxicity, showed potent preclinical anti-tumor and long-term immune memory effects. We report dose escalation results of a 2-part Phase 1/2 study. Methods: Pts with HER2+ (IHC3+ or IHC2+/ISH+) locally a/m solid tumors refractory/intolerant to standard therapy received intravenous YH32367 on Day 1 of 21-day cycles across 8 dose levels (0.3-30 mg/kg). Primary endpoint was treatment emergent adverse events (TEAEs) up to Day 21; secondary endpoints included pharmacokinetics (PK), objective response rate (ORR), disease control rate (DCR), and duration of response (DoR). Results: At data cutoff (May 24, 2024), 32 pts enrolled across 8 dose levels (63% male; median age, 60 yrs; most common tumors, biliary tract [BTC; n=14 {44%}] and gastric [n=9 {28%}]; median [range] prior treatment lines, 2 [0-7]; prior trastuzumab-based regimen, 1 [0-3]). No dose-limiting toxicities were observed; maximum-tolerated dose was not reached. Overall, 10/32 (31%) pts had treatment-related AEs (TRAEs; 1 [3%] grade ≥3; Table), most commonly pyrexia (5 [16%]) and chills (4 [13%]); 1 TRAE led to death (0.75 mg/kg). PK exposure increased slightly greater than dose-proportionally, attributable to target-mediated drug disposition. Serum s4-1BB levels showed a dose-dependent increase after YH32367 administration. Confirmed partial response was achieved in 7/31 pts overall (ORR, 23%; DCR, 55%; median [95% CI] DoR, not reached [NR; 4.2-NR]; Table), and in 4/13 pts with BTC (ORR, 31%; DCR, 62%; DoR, NR [8.3-NR]). Conclusions: YH32367, at doses ≤30 mg/kg, showed favorable safety, promising clinical benefit, and non-linear PK in previously treated pts with HER2+ a/m solid tumors, supporting further development in the dose optimization phase. Citation Format: Do-Youn Oh, SunYoung Rha, Jin Seok Ahn, Ganessan Kichenadasse, Jennifer Man, Yukyung Kim, Mikyung Kim, NaMi Lee, Yeji Lim, Jiah Kang, Mi-Jung Kwon, Eunjung Lee, Young Bong Park, Minji Choi, Sung-Bae Kim. A phase 1/2, open-label, multicenter, first-in-human study to evaluate the safety, pharmacokinetics, and anti-tumor activity of YH32367 in patients (pts) with HER2+ locally advanced/metastatic (a/m) solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT068.