Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients

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 participate

The 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 publication

All patients provided written informed consent for publication.

Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Antitumor activity of JS001. Clinical response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by investigators every 8 weeks. a The percentage of sum of diameters of target lesions over baseline measurement during JS001 treatment is shown for each subject over time in the spider plot. Responses were durable in most patients, as the median duration of response was 5.6 months (range from 1.8 to 17.7+ months). b Waterfall plot of best percentage reduction in tumor burden from baseline is shown. Prior lines of treatment were marked by color for each subject. Seven out of 8 responding subjects had received at least two prior systemic treatments

Fig. 2

Survival after JS001 treatment. a Progression-free survival (PFS) of subjects by histology. b Overall survival (OS) of subjects by histology. Percentages of survival patients are shown at indicated time points. Numbers of patients at risk at indicated time points are shown below the x-axis

Fig. 3

Pharmacodynamic readouts of JS001. a PD-1 receptor occupancy (RO) was determined as the percentage of receptor bound JS001 to total PD-1 on activated lymphocytes (CD3+ CD45RA−) from the peripheral blood by flow cytometry analysis. RO of responders (CR + PR + SD) and non-responders (PD) are shown. b The frequency of activated CD8+ T cells (CD3+ CD8+ CD45RA−) over time are shown in clinical responders and non-responders

Fig. 4

Correlation of PD-L1 expression by IHC staining in tumor biopsy with clinical efficacy. a High (> 50%) (n = 7), medium (1–50%) (n = 9), and low (< 1%) (n = 12) PD-L1 expression subgroups determined by anti-PD-L1 (SP142) IHC staining on tumor cells are compared for clinical response. b PFS of subjects by PD-L1 expression. PD-L1+ subjects showed significant PFS benefit than PD-L1− subjects, HR = 0.36 (95% CI 0.14–0.93), p = 0.034. c OS of subjects by PD-L1 expression. Percentages of survival patients are shown at indicated time points. Numbers of patients at risk at indicated time points are shown below the x-axis

Fig. 5

Correlation of biomarkers or subgroups with clinical efficacy. Subgroups by age, gender, PD-L1 expression on tumor cells, the presence of CD8+ TILs, ECOG performance score, LDH serum levels, baseline tumor burden, and prior lines of treatment are compared for clinical response to JS001 treatment. PD-L1-positive status was defined as the presence of membrane staining of any intensity in ≥ 1% of tumor cells by SP142 IHC staining. Upper limit of normal (ULN) for LDH serum level is 250 U/L. Baseline tumor burden was represented by sum of diameters of target lesion(s) per RECISTv1.1, and 100 mm was used as a cutoff

Fig. 6

Correlation of TMB with objective response and overall survival upon JS001 treatment. Genomic profiling was performed by next-generation sequencing with a 450 cancer-related gene panel on both FFPE tumor and paired peripheral blood samples from 23 available subjects. The TMB was calculated by summing up somatic mutations within the coding regions examined the NGS panel. a Correlation of TMB with clinical response. Six mutations per Mb was used as a cutoff. b Correlation of TMB, PD-L1 status, and clinical response

Fig. 7

Genomic profiling of enrolled subjects. Genomic profiling was performed by next-generation sequencing with a 450 cancer-related gene panel on both FFPE tumor and paired peripheral blood samples from 23 available subjects. Genomic alterations including SNV, short and long INDELs, CNV, and gene rearrangement and fusions were assessed