Preliminary Results from a Multicenter, Single-Arm, Phase 2 Study of CS1001, an Anti-Programmed Death-Ligand 1 (PD-L1) Human Monoclonal Antibody (mAb), in Patients (pts) with Relapsed or Refractory Extranodal Natural Killer/T Cell Lymphoma (rr-ENKTL)
Authors: Huang Hui-qiang , Tao Rong , Zou Liqun , Cen Hong , Guo Ye , Huang Yunhong , Qian Wenbin , Zhang Liling , Zhou Hui , Yang Yu , Yang Haiyan , Zhu Dan , Fang Teng , Dai Hangjun , Wang Yueling , Yang Jianxin 
Published: November 2019

Background
ENKTL is a subtype of mature T cell and NK cell lymphoma, with a higher incidence in Asia than in Europe and North America. Pts with rr-ENKTL have a poor prognosis after failing an L-asparaginase-based regimen, and lack effective treatment. Epstein-Barr virus (EBV) infection is one of the mechanisms and characteristics of ENKTL, which induces immune tolerance of tumor by upgrading PD-L1 expression in tumor cells. Blocking the PD-1 pathway could, therefore, be an effective treatment for ENKTL. A Phase 2 trial is being conducted to evaluate CS1001, a first full-length, fully human immunoglobulin G4 (IgG4) mAb directed against PD-L1, in pts with rr-ENKTL.
Method
This is a multicenter, single-arm, Phase 2 clinical trial to evaluate CS1001 monotherapy in rr-ENKTL. Pts aged 18-75 years with rr-ENKTL after failing prior asparaginase-based chemotherapy or chemoradiotherapy were eligible if they had ECOG performance status (PS) ≤ 1, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion. All the pts will receive CS1001 1200 mg intravenously every 3 weeks for up to 2 years, until disease progression, intolerance, etc. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per Lugano 2014 criteria. Key secondary endpoints included ORR by investigators, complete and partial response rate, time to response, duration of response (DoR) and progression-free survival, overall survival and safety. Adverse events (AEs) were summarized according to NCI CTCAE v4.03.
Result
As of June 17, 2019, 29 pts (male: 16, 55.2%; median age: 44 years, range 30-74) were enrolled. Twenty (20, 69.0%) pts entering the study had an ECOG PS of 1. Twenty-two (22, 75.9%) pts had Stage IV of disease at screening. Eight (8, 27.6%) pts received 2 lines of prior systemic therapy and 6 (20.7%) pts received ≥3 lines of prior systemic therapy. The median duration of follow-up was 5.55 (range, 0.69-12.19) months. Among the 22 efficacy-evaluable pts, the investigator-assessed ORR was 40.9%. A total of 7 (31.8%) pts achieved complete response (CR), and 2 (9.1%) pts had partial response (PR); 1 additional pt achieved PR after pseudo-progression. The DoR ranged from 0.03+ to 8.61+ months; median DoR was not achieved. All CR pts were still in remission. The IRRC assessments were not available at the time of data cut-off.
The median duration of treatment was 11.7 (range, 2.9 to 53.0) weeks. Fifteen (15, 51.7%) pts remained on treatment and 14 (48.3%) had discontinued from study treatment (12 due to progressive disease, 2 due to AEs). The majority of pts (25, 86.2%) had treatment-emergent AEs (TEAEs), of whom 21 (72.4%) pts reported treatment-related AEs (TRAEs). The most frequently reported (≥10%) TRAEs were pyrexia (6, 20.7%), blood thyroid stimulating hormone increased (4, 13.8%), white blood cell count decreased (4, 13.8%), and rash (3, 10.3%). Three (3, 10.3%) pts reported Grade (G) ≥3 TRAEs. Two (2) G5 AEs (death and haemophagocytic lymphohistiocytosis) were reported in 2 pts; none was assessed as related to CS1001 by the investigators. Serious AEs were observed in 5 (17.2%) pts, and 1 of them (sinus node dysfunction) was assessed as related to CS1001 by the investigator. Immune-related AEs (irAEs) were reported in 5 pts, including a G3 rash and the remaining irAEs were G1. TEAEs that led to permanent treatment discontinuation occurred in 2 (6.9%) pts, which included haemophagocytic lymphohistiocytosis (G5) and facial nerve disorder (G2). No death or permanent discontinuation due to AEs were assessed as related to the study drug.
After data cut-off date, 3 additional pts reached response assessment time point, of which 2 pts achieved CR, resulting in ORR of 44% (11/25) and a CR rate of 36% (9/25). The updated data will be reported at the ASH conference.
Conclusion
In this study, CS1001 was shown to be active with a high CR rate and durable response, and was generally well-tolerated in pts with rr-ENKTL. The preliminary safety and efficacy profile of CS1001 support further exploration and development of CS1001 in rr-ENKTL pts.

Disclosures
No relevant conflicts of interest to declare.