Trastuzumab Rezetecan in Human Epidermal Growth Factor Receptor 2–Expressing Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma and Colorectal Cancer: A Multicenter, Open-Label, Phase I Trial

Author(s): Tianshu Liu, MD¹; Suxia Luo, MD²; Xianglin Yuan, MD³; Dong Liu, MD⁴; Zhaofei Zhou, BS⁵; Xin Wang, MD⁶; Yanhong Deng, MD⁷; Jun Chen, MD⁸; Mulin Liu, MD⁹; Huan Zhou, MD¹⁰; Xiubao Ren, MD¹¹; Wensheng Qiu, MD¹²; Yu Cao, MD¹³; Shirong Cai, MD¹⁴; Yugang Dong, MD¹⁵; Yanqiao Zhang, MD¹⁶; Wei Wang, MM¹⁷; Jun Liang, MD¹⁸; Pingsheng Xu, MD¹⁹; Heli Liu, MD²⁰; Kaijing Zhao, PhD²¹; Yang Fan, MM²¹; Ning Dou, PhD²¹; Chuanpei Huang, MD²¹; Jin Li, MD²²;

Source: DOI: 10.1200/JCO-25-00716

Dr. Anjan Patel's Thoughts

Encouraging phase I signal for this HER2-targeted Antibody-drug conjugate (ADC) in heavily pretreated GI cancers, 45% overall response rate (ORR) and 16.3mo median overall survival (OS) in HER2-positive gastric compares favorably with T-DXd benchmarks, and the 40.5% objective response rate (ORR) with 22.7mo OS in HER2-positive colorectal cancer (CRC) is notable. The 2% ILD rate looks meaningfully better than T-DXd’s reported range, which could be a real differentiator. Hematologic toxicity is substantial but manageable. Small China-only phase I, but worth watching closely as this advances.

PURPOSE

Antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) could be a promising strategy for HER2-expressing gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJ) and colorectal cancer (CRC). We conducted a phase I trial to assess trastuzumab rezetecan, a novel HER2-targeted ADC, in HER2-expressing advanced GC/GEJ and CRC.

METHODS

Patients with HER2-expressing advanced GC/GEJ and CRC whose disease progressed on and/or had no available/applicable standard treatment were enrolled. Patients were intravenously given trastuzumab rezetecan 3.2, 4.8, 6.4, and 8.0 mg/kg (once every 3 weeks) in an i3+3 dose-escalation scheme, followed by pharmacokinetics expansion selected doses and then clinical expansion. The primary end points were dose-limiting toxicity (DLT) and safety.

RESULTS

Between March 30, 2021, and August 1, 2023, 100 patients were enrolled (57 with GC/GEJ and 43 with CRC). One DLT occurred in the 8.0 mg/kg dose cohort. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 66 (66.0%) patients. Only 5 (5.0%) patients discontinued treatment because of TRAEs. In HER2-positive GC/GEJ (n = 40), trastuzumab rezetecan achieved an objective response rate (ORR) of 45.0%, a median progression-free survival (PFS) of 9.0 months (95% CI, 7.0 to 11.3), and a median overall survival (OS) of 16.3 months (95% CI, 12.4 to not reached [NR]). In GC/GEJ with HER2 immunohistochemical 2+ and in situ hybridization–negative (n = 12), trastuzumab rezetecan had an ORR of 25.0%, a median PFS of 12.2 months (95% CI, 2.8 to 14.0), and an immature median OS. In HER2-positive CRC (n = 37), trastuzumab rezetecan had an ORR of 40.5%, a median PFS of 9.5 months (95% CI, 7.3 to 11.2), and a median OS of 22.7 months (95% CI, 17.5 to NR).

CONCLUSION

Trastuzumab rezetecan showed tolerable safety and preliminary efficacy in HER2-expressing advanced GC/GEJ and CRC.

Author Affiliations

¹Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; ²Phase I Clinical Research Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; ³Department of Digestive Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ⁴Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ⁵Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China; ⁶Department of GCP, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China; ⁷Oncology Internal Medicine First District, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; ⁸Oncology Department, The First Affiliated Hospital of Nanchang University, Nanchang, China; ⁹Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China; ¹⁰Phase I Clinical Trial Lab, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China; ¹¹Biotherapy Department, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China; ¹²Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China; ¹³Phase I Clinical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China; ¹⁴Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; ¹⁵Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; ¹⁶Gastroenterology Ward 2, Harbin Medical University Cancer Hospital, Harbin, China; ¹⁷Gastroenterology and Urology Department II, Hunan Cancer Hospital, Changsha, China; ¹⁸Medical Oncology, Peking University International Hospital, Beijing, China; ¹⁹Phase I Clinical Research Laboratory, Xiangya Hospital Central South University, Changsha, China; ²⁰Gastroenterology, Xiangya Hospital Central South University, Changsha, China; ²¹Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co, Ltd, Shanghai, China; ²²Department of Oncology, Shanghai East Hospital, Shanghai, China

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