Safety and preliminary efficacy of GQ1001, a next generation HER2-targeting ADC, combined with pyrotinib in pretreated patients with HER2-positive metastatic breast cancer: A phase 1b clinical trial.

person Biyun Wang Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China info_outline Biyun Wang, Chengcheng Gong, Leiping Wang, Xichun Hu, Ting Li, Zhonghua Tao, Mingchuan Zhao, Yannan Zhao

Authors person Biyun Wang Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China info_outline Biyun Wang, Chengcheng Gong, Leiping Wang, Xichun Hu, Ting Li, Zhonghua Tao, Mingchuan Zhao, Yannan Zhao Organizations Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Abstract Disclosures Research Funding GeneQuantum Healthcare (Suzhou) Co., Ltd Background: GQ1001 is a novel HER2-targeted antibody-drug conjugate (ADC) that was generated by conjugating trastuzumab to DM1 via a unique open-ring containing linker and the enzymatic site-specific conjugation technology, which significantly improves homogeneity and stability of the study drug [1]. Preclinical studies showed robust anti-tumor activities in multiple HER2+ PDX and CDX models, and excellent pharmacokinetics and safety profiles in rats and cynomolgus monkeys. Phase 1a study (NCT04450732) showed superior tolerability and promising antitumor efficacy in heavily pretreated HER2-positive advanced solid tumors [2]. In vivo study also demonstrated a synergistic anti-tumor efficacy of GQ1001 combined with pyrotinib, an irreversible pan-HER2 receptor tyrosine kinase inhibitor (TKI) [1]. Thus, a phase 1b study (NCT05575804) was designed to investigate the safety and preliminary efficacy of the combination of GQ1001 and pyrotinib in pretreated patients with HER2-positive metastatic breast cancer. Methods: In the “3+3” dose-escalation phase, the dose of GQ1001 was 6.0 mg/kg, 7.2 mg/kg and 8.4 mg/kg intravenously in a 21-day cycle, and pyrotinib was taken orally in a fixed dose of 320 mg once daily in 28-day cycles. The dose escalation or de-escalation was based on the incidence of specified dose-limiting toxicities (DLTs) in the initial dose group. DLTs were observed for the first 21 days. Results: A total of 15 HER2-positive metastatic breast cancer patients received GQ1001 and pyrotinib treatment. All patients (15/15) had failed on previous trastuzumab (or its biosimilars) containing therapy and 33.3% of the patients (5/15) had been treated with pertuzumab. By Dec. 31, 2023, dose escalation has been completed with no DLT reported. Maximal tolerable dose was not reached up to 8.4 mg/kg, the highest dose tested. Most patients (13/15; 73.3%) experienced grade 3-4 treatment-related adverse event, including diarrhea (66.7%), anemia (13.3%), alanine aminotransferase increase (6.7%), thrombocytopenia (6.7%), and urticaria (6.7%). At the data cut off date (Dec. 31, 2023), nine patients were still on going, with the longest treatment duration of 348 days. The objective response rate (ORR) was 66.7% (10/15) in all patients enrolled, and 71.4% (10/14) in patients who had received tumor evaluation. At 6.0 mg/kg, 7.2 mg/kg and 8.4 mg/kg dose level, the ORR was 75% (3/4), 100% (5/5), 33.3% (2/6), respectively. Conclusions: GQ1001 in combination with pyrotinib demonstrated manageable safety profile and promising preliminary antitumor activity among pretreated patients with HER2-positive metastatic breast cancer. [1] HUANG L, et al. Cancer Research, 2023, 83(7_Supplement): 2702-. [2] LEMECH C, et al. Cancer Research, 2023, 83(8_Supplement): CT178-CT. Clinical trial information: NCT05575804.