Results of a phase 1/2 study of MHB036C: A potential best-in-class TROP2 antibody-drug conjugate (ADC) incorporating a potent DNA topoisomerase I inhibitor in locally advanced or metastatic solid tumors.

person Shun Lu Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China info_outline Shun Lu, Qingyuan Zhang, Xiangjiao Meng, Yuping Sun, Hui Hua Xiong, Dongqing Lv, Xiaojia Wang, Lin Wu, Xiaorong Dong, Yuanyuan Ji, Yinghua Ji, Liang Han, Kaijian Lei, Ou Jiang, Yanqiu Zhao, Zhen Zhang, Junwei Shi, Guoqing Cao

Authors person Shun Lu Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China info_outline Shun Lu, Qingyuan Zhang, Xiangjiao Meng, Yuping Sun, Hui Hua Xiong, Dongqing Lv, Xiaojia Wang, Lin Wu, Xiaorong Dong, Yuanyuan Ji, Yinghua Ji, Liang Han, Kaijian Lei, Ou Jiang, Yanqiu Zhao, Zhen Zhang, Junwei Shi, Guoqing Cao Organizations Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China, Harbin Medical University Cancer Hospital, Harbin, China, Shandong Cancer Hospital, Jinan, China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, Taizhou Hospital of Zhejiang Province, Taizhou, China, Zheijang Cancer Hospital, Hangzhou, China, Hunan Cancer Hospital, Changsha, China, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, Anyang Tumor Hospital, Anyang, China, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China, Xuzhou Central Hospital, Xuzhou, China, Department of Oncology, the Second People's Hospital of Yibin, Yibin, China, The Second People's Hospital of Neijiang, Neijiang, China, Henan Cancer Hospital, Zhengzhou, China, Nanyang First People's Hospital, Nanyang, China, Minghui Pharmaceutical (Hangzhou) Ltd., Hangzhou, China Abstract Disclosures Research Funding No funding sources reported Background: MHB036C, an investigational ADC, comprises a humanized anti-TROP2 monoclonal antibody engineered to minimize potential toxicities mediated by non-specific uptake, and a highly potent DNA topoisomerase I inhibitor (5~10 times more potent than DXd) conjugated via a stable cleavable linker. In preclinical studies, MHB036C demonstrated superior tumor killing activities (5~10 times more potent than the DS-1062a analog) and a favorable safety profile with no unique toxicities as compared to other TROP2 ADCs and no occurrences of interstitial lung disease (ILD). We here present the safety and efficacy results from a first-in-human phase 1/2 study of MHB036C. Methods: Patients with locally advanced or metastatic solid tumors were enrolled in dose-escalation (D-Esc) and dose-expansion (D-Exp) segments. The D-esc study, utilizing an accelerated titration followed by the traditional 3+3 design, assessed MHB036C at doses ranging from 0.25-2.25 mg/kg administered intravenously (IV) every 3 weeks. Results: At data cutoff (Dec 31, 2023), 26 pts were enrolled and received at least one dose of MHB036C (D-Esc, n=11, D-Exp, n=15). Two pts experienced dose-limiting toxicities (Grade 3 stomatitis) at 2.25 mg/kg. The MTD was determined to be 1.5 mg/kg. The most common TRAEs overall in ≥25% of pts were stomatitis, anemia, decreased appetite, vomiting, white blood cell (WBC) count decreased, fatigue, nausea, and neutrophil count decreased. The most common Grade ≥3 TRAEs (occurred in ≥5% of pts) were stomatitis (34.6%), WBC count decreased (11.5%), neutrophil count decreased (7.7%), and anemia (7.7%). No ILD was reported. Of 21 response-evaluable pts, 7 experienced partial responses. In the subset of 12 NSCLC pts treated with doses ranging from 1.3 to 2.25 mg/kg, the ORR was 33.3% (4/12) and the DCR was 83.3%. In the subset of 5 HER2-negative breast cancer pts encompassing 4 TNBC pts and 1 HR+/HER2- breast cancer patient, the ORR was 60.0% (3/5). Conclusions: MHB036C demonstrated a manageable safety profile without either major hematologic side effects or ILDs and encouraging efficacy in NSCLC and HER2- breast cancer, representing a potential best-in-class TROP2 ADC. The dose optimization and expansion study is ongoing to establish the RP2D for MHB036C. Clinical trial information: CTR20231246.

Clinical