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.

e13020 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 (7Supplement): 2702-. 2 LEMECH C, et al. Cancer Research, 2023, 83 (8Supplement): CT178-CT. Clinical trial information: NCT05575804.