Abstract CT098: Phase I study of GQ1005, a new generation HER2-ADC, in patients with HER2-expressing and HER2 mutated advanced solid tumors

Abstract Background: GQ1005 is a new generation antibody-drug conjugate, targeting HER2-expressing tumor cells with Topoisomerase I inhibitors (DXd) as its payload via a stable and cleavable linker. In preclinical studies, GQ1005 demonstrated comparable antitumor activity compared to Enhertu in multiple tumor cell line xenograft models with no noticeable toxicity, indicating higher therapeutic index. GLP toxicity studies demonstrated that GQ1005 was well tolerated, with the highest non-severe toxic dose determined to be 60mg/kg. This report presents the preliminary findings of an ongoing phase I study, which aims to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of GQ1005 in patients with advanced solid tumors expressing HER2 or harboring HER2 mutations. Methods: GQ1005 was administrated intravenously every 3 weeks. An accelerated titration design was employed for the initial 2mg/kg dose, followed by Bayesian Optimal Interval Design for subsequent dose levels of 4, 6, 7.2, and 8.4 mg/kg. The primary objective of this study was to evaluate the safety, tolerability, and to determine the MTD or RP2D. Results: As of Oct. 13th, 2023, 46 (30 in dose-escalation and 16 in dose-expansion phase) subjects with HER2-expressing/mutated advanced solid tumors, predominantly in breast cancer (18), and lung cancer (18) , were enrolled into the study. Patients received a median of 3 (range, 1-11) prior lines of treatment, and 86.4% of pts previously received anti-HER2 therapies before. During dose escalation, No DLT was observed in all doses, MTD was not reached up to 8.4 mg/kg. Treatment-related adverse events (TRAEs) occurred in 44 (95.7%) subjects. The most common TRAEs were grade 1 or 2, including nausea (52.2%), vomiting (39.2%), aspartate aminotransferase (AST) increased (39.1%), alanine aminotransferase (ALT) increased (23.9%), anemia (23.9%), anorexia (21.7%), fatigue (19.6%), leukopenia (15.2%), infusion-related reactions (15.2%) , decreased lymphocyte count (15.2%) and dizziness (15.2%). Grade ≥3 TRAEs only occurred in 4 subjects (8.7%), including anemia, decreased lymphocyte count and γ-glutamyltransferase (GGT) increased. Interstitial lung disease was observed in 6 pts received highest dose level and most of them have recovered. No drug-related deaths. The pharmacokinetics analysis showed the concentration of GQ1005 and TAb generally peaked rapidly and declined in a roughly biphasic manner. Among 38 evaluable subjects, 1 pt achieved complete response, 18 cases achieved confirmed partial response, and 11 had stable disease, the objective response rate was 50% (19/38), the disease control rate was 78.9% (30/38) , and the 6-month PFS rate was 43.0% in all patients. Conclusions: GQ1005 demonstrated a promising antitumor activity in HER2-expressing/mutated advanced solid tumors patients previously heavily treated, and showed a good tolerance and manageable safety profile. The dose expansion study is on-going at 7.2 mg/kg to establish the RP2D in four cohorts. (NCT06154343; sponsored by GeneQuantum Healthcare (Suzhou) Co., Ltd.) Citation Format: Caicun Zhou, Bo Yang, Ting Deng, Biyun Wang, Jian Zhang, Yuping Sun, Linlin Wang, Hongwei Yang, Jingfen Wang, Wei Li, Qi Song, Yuchong Yang. Phase I study of GQ1005, a new generation HER2-ADC, in patients with HER2-expressing and HER2 mutated advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT098.