Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients
Bixia Tang, Xieqiao Yan, Xinan Sheng, Lu Si, Chuanliang Cui, Yan Kong, Lili Mao, Bin Lian, Xue Bai, Xuan Wang, Siming Li, Li Zhou, Jiayi Yu, Jie Dai, Kai Wang, Jinwei Hu, Lihou Dong, Haifeng Song, Hai Wu, Hui Feng, Sheng Yao, Zhihong Chi, Jun Guo, Bixia Tang, Xieqiao Yan, Xinan Sheng, Lu Si, Chuanliang Cui, Yan Kong, Lili Mao, Bin Lian, Xue Bai, Xuan Wang, Siming Li, Li Zhou, Jiayi Yu, Jie Dai, Kai Wang, Jinwei Hu, Lihou Dong, Haifeng Song, Hai Wu, Hui Feng, Sheng Yao, Zhihong Chi, Jun Guo
Abstract
Background: JS001, a humanized IgG4 monoclonal antibody against the programmed death-1 (PD-1) receptor, blocks the interaction of PD-1 with its ligands and promotes T cell activation in preclinical studies. This phase I study is designed to evaluate the safety, tolerability, and clinical activity of JS001 in advanced melanoma or urologic cancer patients who are refractory to standard systemic therapy.
Patients and methods: In the dose escalation cohorts, subjects initially received a single-dose, intravenous infusion of JS001, and were followed for 28 days followed by multi-dose infusions every 2 weeks. In the dose expansion cohorts, subjects received multi-dose infusions every 2 weeks. Clinical response was evaluated after each 8-week treatment cycle according to RECIST v1.1 criteria.
Results: Thirty-six subjects diagnosed with advanced melanoma (n = 22), urothelial cancer (UC) (n = 8), or renal cell cancer (RCC) (n = 6) were enrolled. Melanoma subjects included 14 acral and 4 mucosal subtypes. JS001 was well tolerated, and no dose-limiting toxicity was observed. By the safety data cutoff date, 100% of subjects had treatment-related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 36%. Among all 36 subjects, 1 confirmed complete response (acral melanoma), 7 confirmed partial responses (2 acral melanoma, 1 mucosal melanoma, 2 UC, and 2 RCC), and 10 stable disease were observed, for an objective response rate of 22.2% (95% CI, 10.1 to 39.2), and a disease control rate of 50.0% (95% CI, 32.9 to 67.1). Clinical responses were correlated with PD-L1 expression on tumor cells, the presence of tumor infiltrating lymphocytes (TIL), baseline tumor volume, ECOG performance status, serum LDH levels, high percentage of activated CD8+ T cells and CD3- CD16+ CD54+ NK cells in the peripheral blood as well as tumor mutational burden (TMB).
Conclusion: JS001 was well tolerated and demonstrated promising anti-tumor activity in UC and RCC as well as in previously underexplored acral and mucosal melanoma subtypes. Subjects with an immune-active profile in the tumor microenvironment or in peripheral blood responded favorably to JS001 treatment. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on acral and mucosal melanoma subtypes, representative of the regional disease epidemiology.
Trial registration: Clinical Trial ID: NCT02836795 , registered July 19, 2016, retrospectively registered.
Keywords: JS001; Melanoma; Monoclonal antibody; PD-1; Renal cell carcinoma; Urothelial cancer.
Conflict of interest statement
Ethics approval and consent to participateThe study was approved by regulatory and independent ethics committees at Beijing Cancer Hospital and done in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All patients provided written informed consent before study entry.
Consent for publicationAll patients provided written informed consent for publication.
Competing interestsThe authors declare that they have no competing interests.
Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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