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

• Published in: European journal of cancer (1990) 2021-05, Vol.148, p.1-13
• Main 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
• Format: Article
• Language: English
• Subjects: Adverse events; Alanine; Anemia; Anticancer properties; Antitumor activity; Bilirubin; Dosage; Efficacy; Hypothyroidism; Immunohistochemistry; Leukopenia; Lymphoma; Monoclonal antibodies; Mutation; Patients; PD-1 protein; PD-L1 protein; Pharmacodynamics; Pharmacokinetics; Pharmacology; Phase Ia/Ib study; Programmed death-1 monoclonal antibody; Safety; Solid tumors; Toxicity; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2021.01.020

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. 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. 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. 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. GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy. •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.