JS001, an anti-PD-1 mAb for advanced triple negative breast cancer patients after multi-line systemic therapy in a phase I trial

Abstract

Background: Triple negative breast cancer (TNBC), as defined by ER, PR and HER2 negative expression in tumor, has limited treatment options beyond conventional chemotherapy. JS001, a humanized IgG4 antibody for PD-1, has demonstrated acceptable safety profile and preliminary anti-tumor activity in solid tumors.

Methods: This phase I open-label study is designed to evaluate the safety, tolerability, and antitumor activity of JS001 in advanced TNBC patients who are refractory to standard systemic therapy. The study has a 3+3 dose escalation design with planned cohorts at 1, 3, and 10 mg/kg Q2W followed by a dose expansion cohort at 3 mg/kg. (Clinical Trial ID: NCT02838823).

Results: From August 04, 2016 to October 26, 2017, 20 heavily-pretreated advanced TNBC patients were enrolled into three dose cohorts (6 in 1 mg/kg, 8 in 3 mg/kg and 6 in 10 mg/kg). As of August 30, 2018, no DLT was observed and no MTD was reached. No AEs were grade 4 or 5. The most common treatment related AEs were all grade 1/2. Treatment related grade 3 AEs (15%) included 1 hyponatremia, 1 rash and 1 bronchospasm (infusion related reaction). Among 20 evaluable subjects, the ORR was 5%. One patient in 10 mg/kg group obtained PR, who was PD-L1 strong positive (>50%) in tumor biopsy, with treatment duration of 12.8 months as of data cutoff. As of follow-up on July 15, 2019, the patient continued PR with treatment duration of 24 months and still ongoing. Six patients achieved SD, for a DCR of 35%. The median PFS of all subjects was 1.8 months (95% CI, 1.4 to 4.6). 45% subjects are PD-L1 positive (≥1% cutoff), among whom a 11.1% ORR and a 22.2% DCR were observed.

Conclusions: JS001 exhibited a favorable safety profile in advanced TNBC patients who are refractory to multi-line systemic therapy. JS001 also showed a moderate response in these TNBC patients who had limited treatment options.

Keywords: JS001; advanced breast cancer; anti-PD-1 mAb; triple negative.

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

2019 Annals of Translational Medicine. All rights reserved.

Figures

Figure 1

Tumour response to JS001 (n=20). (A) Change from baseline of target lesions over time. (B) The time on treatment for each patient and duration of response. Length of bars equals time from treatment initiation to last imaging assessment.

Figure 2

Kaplan-Meier curves of progression-free survival (PFS) in JS001 treated patients with advanced TNBC. (A) Analysis of three dose cohorts and total patients. (B) Analysis of PD-L1 positive vs. negative expression patients.

Figure 3

The advanced TNBC patient obtained partial response (PR) who received JS001 at a dose of 10 mg/kg, with treatment duration of 55.9 weeks (12.8 months) as of data cutoff. As of follow-up on July 15, 2019, the patient continued PR with treatment duration of 24 months and still ongoing. (A) CT scan show the pleural metastasis (red arrow) at pretreatment, 24 weeks (PR), 32 weeks (PR confirmation) and 56 weeks (last imaging assessment) respectively. (B) PD-L1 strong positive (>50%) in tumor biopsy (10×) using a prototype immunohistochemistry assay. (C) Whole exome sequencing (WES) revealed some significant copy number variants (CNV) were detected and tumor mutation burden (TMB) at 4.7 mut/Mb.