Abstract CT053: BAT8001, a potent anti-HER2 antibody drug conjugate with a novel uncleavable linker to reduce toxicity for patients with HER2-positive tumor

T-DM1, an antibody drug conjugate (ADC), has been approved by FDA for patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane. DM1 is released because it is connected to the linker of T-DM1 by a thio-ether bond, which can be broken via retro-Michael addition. To improve the antibody-drug stability, we created an anti-HER2 ADC (BAT8001) which used a novel uncleavable linker to connect trastuzumab and a payload of maytansine derivative. BAT8001 exhibits similar level of potency against proliferation of HER2-overexpressed cells as T-DM1 and demonstrates strong inhibition activity on tumor growth in both cell-line and patient-derived xenograft models. Pharmacokinetics (PK) study in monkey reveals BAT8001 has similar level of exposure, half-life, and Cmax as T-DM1. BAT8001 Ph1 clinical trial in patients with HER2+ late-stage breast cancer recently was completed. The clinical study used standard “3+3” multiple-dose escalation method, evaluated BAT8001 safety, PK and explored the efficacy. Twenty-nine subjects were randomized and 27 subjects received the treatment with escalated dose 1.2mg/kg, 2.4mg/kg,3.6mg/kg, 4.8mg/kg and 6.0mg/kg. Two subjects died during the screening time without treatment due to disease progression. Nineteen (79.2%) subjects completed at least 4-cycle treatment. The PK parameter (Cmax and AUC(0-t)) values demonstrated dose-dependent linear relationship. In the safety evaluation, the incidences of AE and AE with CTCAE >=3 increased when dose escalated. The platelet count decrease and AST elevation were found to be the most common and severe AEs. Three subjects had serious adverse events (SAE) of bone destruction which were considered to be not investigated-drug related by the PI. Among those 3 subjects, 2 subjects withdrew from the study due to the SAE and 1 subject continued the treatment. The preliminary efficacy assessment after 10 months treatment found that 1 (3.7%) patient exhibited the complete response (CR), 5 (18.5%) patients exhibited the partial responses (PR), and 5(18.5%) patients exhibited the stable diseases. Based on the information above, the dose of 3.6mg/kg achieved target drug exposure and was found to be the effective and well-tolerated, which was selected to be the dose in the confirmatory clinical trial. Currently, a Phase 3, multicenter, randomized, open-label, controlled trial evaluating the efficacy and safety of BAT8001 has been initiated in patients with HER2+ metastatic breast cancer who previously received trastuzumab separately or in combination with taxanes. The trial is designed to compare BAT8001 versus lapatinib combined with capecitabine which is 2nd-line standard of care for metastatic breast cancer patients in China. This Phase 3 trial plans to recruit approximately 410 patients and by Jan 2019 more than 130 patients have received the treatment of BAT8001. The BAT8001 benefit-risk profile continues to support further development and the clinical results will be revealed by early 2020. Citation Format: Shusen Wang, Fei Xu, Ruoxi Hong, Wen Xia, Jin-Chen Yu, Weijia Tang, Jin Wei, ShuQiang Song, Zhaohe Wang, Li Zhang, Shengfeng Li. BAT8001, a potent anti-HER2 antibody drug conjugate with a novel uncleavable linker to reduce toxicity for patients with HER2-positive tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT053.