BeiGene Announces Phase 1 Long-Term Exposure Data and Results from Structural and Mechanistic Analyses on Tislelizumab at the AACR Annual Meeting
“We believe that these two presentations further support the broad development program for tislelizumab as a potentially differentiated anti-PD1 antibody,” said
Long-Term Exposure to Tislelizumab, an Investigational Anti-PD-1 Antibody, in a First-in-Human Phase 1 Study
Phase 1 Poster Data (Poster number CT084, board number 8)
The multi-center, open-label Phase 1 trial (ClinicalTrials.gov Identifier: NCT02407990) of tislelizumab as monotherapy in advanced solid tumors is being conducted in
With a median follow-up of 27.2 months, the objective response rate (ORR) among patients with LTE was 68 percent. Four patients achieved complete response (CR), including patients with cutaneous squamous cell carcinoma, endometrial, bladder and esophageal cancers (n=1 each). All four patients were PD-L1 positive. Partial responses (PR) and stable disease (SD) were observed in both PD-L1 positive and PD-L1 negative tumors. The median duration of response (DoR) was 21.1 months in those with LTE.
LTE to tislelizumab was generally well-tolerated when given for more than 12 months. As of the data cutoff, 52 of 65 patients (80%) experienced one or more treatment-related adverse event (TRAE), most of which were mild to moderate in severity. Rash was the only TRAE reported in more than 15% of patients, and no rash event of grade 3 or higher occurred. TRAEs of grade 3 or higher were arthritis, diarrhea, fatigue, granuloma, hyperglycemia, increased alanine aminotransferase, rash papular, and lichenoid keratosis (n=1 each).
Serious TRAEs occurred in three patients, including pyrexia (n=2) and arthritis (n=1) and all resolved. Three patients experienced AEs that eventually led to discontinuation. There were no fatal AEs.
The Molecular Binding Mechanism of Tislelizumab, an Investigational Anti-PD-1 Antibody, is Differentiated from Pembrolizumab and Nivolumab
Preclinical Poster Data (Poster number 2383, board number 7)
In this non-clinical study, the co-crystal structure of the PD-1 extracellular domain with the antigen-binding fragment (Fab) of tislelizumab was solved to reveal the molecular binding mechanism, and structure-guided mutagenesis and surface plasmon resonance studies were performed to compare the binding of tislelizumab, pembrolizumab and nivolumab to PD-1.
Tislelizumab was shown to form extensive interactions with PD-1 with three complementarity-determining regions (CDR) of VL domain and two CDRs of VH domain. The dissociation rate of tislelizumab from wild type PD-1 was about 100-fold and 50-fold slower than that of pembrolizumab and nivolumab, respectively.
Tislelizumab was shown to have a different binding orientation to PD-1 compared to pembrolizumab and nivolumab. The binding surface on PD-1 for tislelizumab partially overlaps with that for pembrolizumab but differs significantly from that for nivolumab. The amino acids Gln75, Thr76, Asp77 and Arg86 in PD-1 were identified to be critical epitopes for tislelizumab binding but not pembrolizumab or nivolumab, as mutations of these epitopes showed relatively little effect on binding of PD-1 to pembrolizumab and nivolumab as compared to tislelizumab.
Tislelizumab was demonstrated to be differentiated from pembrolizumab and nivolumab by a distinctive binding orientation, the unique epitopes, and binding kinetics to PD-1.
Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug candidate produced from BeiGene’s immuno-oncology biologic program, and is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.
Clinical trials of tislelizumab include a global Phase 3 clinical trial in patients with second-line non-small cell lung cancer (NSCLC); a global Phase 3 clinical trial in first-line patients with hepatocellular carcinoma (HCC); a global Phase 3 clinical trial in second-line patients with esophageal squamous carcinoma (ESCC); a global Phase 3 clinical trial in first-line patients with gastric cancer (GC); a global Phase 3 clinical trial in first-line patients with ESCC; a global Phase 3 trial in patients with Stage III NSCLC; a global Phase 2 clinical trial in second- or third-line patients with HCC; a global Phase 1 clinical trial in patients with relapsed/refractory (R/R) NK/T-cell lymphomas; and a global Phase 1 clinical trial in patients with solid tumors. In
The new drug application (NDA) in
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding the encouraging clinical data from clinical trials of tislelizumab, the mechanism of action of tislelizumab, and BeiGene’s advancement of, and anticipated clinical development, regulatory milestones and commercialization of tislelizumab. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including
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