Dan Liu1, Chunguang Ma2, Ping Lu3, Jifang Gong4, Dingwei Ye2, Siyang Wang5, Peijian Peng5, Yuxian Bai6, Yuqin Song7, Jianhua Chen8, Ou Jiang9, Guojun Zhang10, Yi Ba11, Li Chen12, Jianji Pan13, Qi Li14, Liling Zhang15, Shanzhi Gu16, Xianli Yin17, Bangwei Cao18, Weiqing Han19, Haiying Dong20, Jianming Guo21, Huilai Zhang11, Hang Su22, Yongsheng Jiang23, Weiwei Ouyang24, Lulin Ma25, Yan Sun26, Feng Zhang27, Jun Lv28, Yabing Guo29, Chongyuan Xu29, Junyuan Qi30, Li Wang31, Xiang Wang32, Zhen Liu33, Lin Shen34. 1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Early Drug Development Center, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, China. 2. Fudan University Shanghai Cancer Center, 270 Dong 'an Road, Xuhui District, Shanghai, 200032, China. 3. The First Affiliated Hospital of Xinxiang Medical School, 88 Jiankang Road, Weihui, 453100, China. 4. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology/Early Drug Development Center, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, China. 5. The Fifth Affiliated Hospital Sun Yat-Sen University, 52 Meihua East Road, Xiangzhou District, Zhuhai, 519000, China. 6. Harbin Medical University Cancer Hospital, 150 Haping Road, Nangang District, Harbin, 150081, China. 7. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), The Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China. 8. Thoracic Medicine Department I, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, China. 9. The Second General Hospital of Neijiang City, 224 Xinjiang Road, Dongxing District, Neijiang, 641100, China. 10. The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, China. 11. Tianjin Medical University Cancer Institute & Hospital, Huanhu West Road, Tiyuan North, Hexi District, Tianjin, 300060, China. 12. The First Affiliated Hospital of Nanchang University, 17 Yongwai Main Street, Donghu District, Nanchang, 330006, China. 13. Fujian Provincial Cancer Hospital, 420 Fuma Road, Jin'an District, Fuzhou, 350014, China. 14. Shanghai General Hospital, 85 Wujin Road, Hongkou District, Shanghai, 200080, China. 15. Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, No.1277 Jiefang Avenue, Wuhan, 430022, China. 16. Department of Interventional Radiology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, China. 17. Department of Gastroenterology and Urology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, China. 18. Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, Xicheng District, Beijing, 100050, China. 19. Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, China. 20. Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, No.158 Shangtang Road, Xiacheng District, Hangzhou, 310014, China. 21. Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Xuhui District, Shanghai, 200032, China. 22. The Fifth Medical Center of PLA General Hospital, No.8 Fengtai East Street, Fengtai District, Beijing, 100071, China. 23. Tongji Hospital, Tongji Medical College Huazhong University of Science &Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, China. 24. Guizhou Cancer Hospital, No. 1 Beijing West Road, Yunyan District, Guiyang, 550004, China. 25. Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100083, China. 26. Department of Oncological Radiotherapy, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, China. 27. The First Affiliated Hospital of Bengbu Medical School, No 287 Changhuai Road, Longzihu District, Bengbu, 233000, China. 28. Beijing Youan Hospital, Capital Medical University, 8 West Toutiao, Youanmenwai, Fengtai District, Beijing, 100069, China. 29. Nanfang Hospital, The First Affiliated Hospital of Southern Medical School, 1838 Guangzhou Avenue North, Baiyun District, Guangzhou, 510515, China. 30. Institute of Hematology & Blood Diseases Hospital, No. 288 Nanjing Road, Heping District, Tianjin, 300051, China. 31. Jiangsu Province Hospital, No. 300 Guangzhou Road, Gulou District, Nanjing, 210005, China. 32. Shanghai General Hospital, No. 100 Haining Road, Hongkou District, Shanghai, 200080, China. 33. Guangzhou Gloria Biosciences Co., Ltd., Yuhua Road, Shunyi District, Beijing, 101318, China. 34. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology/Early Drug Development Center, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, China. Electronic address: linshenpku@163.com.
Abstract
BACKGROUND: GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. AIM: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. METHODS: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. RESULTS: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. CONCLUSION: GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.
BACKGROUND:GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. AIM: This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. METHODS: In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. RESULTS: Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. CONCLUSION:GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.