Dose escalation and expansion (phase Ia/Ib) study of GLS-010, a recombinant fully human antiprogrammed death-1 monoclonal antibody for advanced solid tumors or lymphoma. (May 2021)

• Record Type: Journal Article
• Authors: Liu, Dan; Ma, Chunguang; Lu, Ping; Gong, Jifang; Ye, Dingwei; Wang, Siyang; Peng, Peijian; Bai, Yuxian; Song, Yuqin; Chen, Jianhua; Jiang, Ou; Zhang, Guojun; Ba, Yi; Chen, Li; Pan, Jianji; Li, Qi; Zhang, Liling; Gu, Shanzhi; Yin, Xianli; Cao, Bangwei; Han, Weiqing; Dong, Haiying; Guo, Jianming; Zhang, Huilai; Su, Hang; Jiang, Yongsheng; Ouyang, Weiwei; Ma, Lulin; Sun, Yan; Zhang, Feng; Lv, Jun; Guo, Yabing; Xu, Chongyuan; Qi, Junyuan; Wang, Li; Wang, Xiang; Liu, Zhen; Shen, Lin;
• Is Part Of: European journal of cancer. Volume 148(2021)
• Page Start: 1
• Page End: 13
• Publication Date: 2021-05
• Subjects: Programmed death-1 monoclonal antibody -- Phase Ia/Ib study -- Solid tumors -- Safety -- Efficacy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2021.01.020
• Languages: English
• ISSNs: 0959-8049

Abstract

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. Highlights: The PK, PD, and immunogenicity characteristics of GLS-010 were described. DLT and MTD of GLS-010 were not found. The RP2D was 240 mg Q2w. Anemia, leukopenia, and elevated alanine aminotransaminase/aspartate aminotransferase/bilirubin were commonly reported TEAEs. GLS-010 showed considerable efficacy (ORR 23.6%), especially in Hodgkin lymphoma.