BeiGene Announces Clinical Data on Tislelizumab and Pamiparib Presented at the European Society for Medical Oncology (ESMO) Congress 2019
“We are excited to present the pivotal data for tislelizumab in the second indication in
First Report of Efficacy and Safety from a Phase 2 Trial of Tislelizumab for the Treatment of Locally Advanced or Metastatic Urothelial Carcinoma in Asian Patients
This multi-center, open-label Phase 2 trial (NCT04004221) of tislelizumab is being conducted in patients in
- Of the 104 patients evaluable for response, the confirmed ORR was 23.1%, with 8 complete responses (CRs) and 16 partial responses (PRs) per IRC assessment. Additional results included:
° Median duration of response (DoR) was not reached. Of the 24 responders, 19 (79%) had maintained response as of the data cutoff; and
° Median progression-free survival (PFS) and overall survival (OS) were 2.1 and 9.8 months, respectively;
- Tislelizumab was generally well-tolerated. There were 105 patients with >1 treatment-related adverse event (TRAE); the most common TRAEs of any grade were anemia (26.5%), decreased appetite (18.6%), pyrexia (16.8%), aspartate aminotransferase increased (15%), and pruritus (15%);
- Thirty-nine patients experienced grade >3 TRAEs related to the study drug. The most common grade >3 TRAEs were anemia (7.1%), urinary tract infection (4.4%), decreased appetite (3.5%), and hyponatremia (3.5%);
- Twelve (11%) patients experienced adverse events (AEs) related to the study drug that resulted in treatment discontinuation. Serious AEs related to study treatment were reported in 11 (9.7%) patients;
- Immune-related treatment-emergent adverse events (TEAEs) occurred in 64% of patients. Common immune-related TEAEs included immune-mediated skin adverse reaction (34%), immune-mediated hepatitis (24%), thyroid disorders (13%), and immune-mediated nephritis and renal dysfunction (12%); and
- Four (3.5%) patients experienced AEs with fatal outcome, including hepatic failure (n=2), respiratory arrest (n=1), and renal impairment (n=1). The events of hepatic failure and respiratory arrest were reported as possibly related to the study drug by the investigator. The event of renal impairment was reported as possibly unrelated to the study drug.
Updated Results of Pamiparib in Combination with Low-Dose Temozolomide in Patients with Locally Advanced or Metastatic Solid Tumors
This open-label, multi-center Phase 1b dose-escalation/expansion trial (NCT03150810) of pamiparib plus low-dose temozolomide (TMZ) was designed to evaluate the safety, tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity of the combination in patients with locally advanced and metastatic tumors. Patients received full-dose pamiparib in combination with escalating doses of TMZ, administered in both pulse and continuous dosing schedules.
The recommended Phase 2 dose and schedule of the combination was determined to be 60 mg of pamiparib taken orally twice daily for 28 days, with TMZ at 60 mg orally once daily during days one through seven.
- The combination was shown to be generally well-tolerated; 112 patients had >1 TEAE; the most common TEAEs occurring in 20% or more patients of any grade were anemia (57.5%), nausea (54.0%), fatigue (48.7%), decreased appetite (34.5%), neutropenia (32.7%), thrombocytopenia (31.9%), vomiting (29.2%), and decreased platelet count (23.0%);
- Sixty-three patients experienced grade >3 TEAEs related to the study drug. The most common grade >3 TEAEs were cytopenias (anemia, neutropenia, and thrombocytopenia), all of which were manageable and reversible. Related grade 4 AEs included thrombocytopenia (11.5%), neutropenia (9.7%), decreased neutrophil counts (8.8%), decreased platelet counts (7.1%), and decreased white blood cells (2.7%);
- Three (2.7%) patients experienced AEs related to the study drug that resulted in treatment discontinuation. Serious AEs related to study treatment were reported in 11 (9.7%) patients;
- Four (3.5%) patients experienced AEs with fatal outcome, all of which were considered by investigators to be unrelated to the study drug;
- As of the data cutoff 57 of 66 patients enrolled in the dose-escalation phase were evaluable for response; 52 patients had measurable disease and were evaluated by either RECIST v1.1 or
Prostate Cancer Working Group2 criteria. Results included:
° ORR was 19.3% (11 PRs); 8 of 11 responses were confirmed. In addition, an unconfirmed
PSAresponse was observed in one patient with prostate cancer;
° Disease control rate (DCR) was 64.9% (95% CI, 51.1–77.1);
° Median DoR was 6.4 months (95% CI, 2.1–7.7);
° Median treatment duration was 3.7 months (range 0.2–18.1); and
° In a biomarker analysis, 62.5% (5/8) of patients assessed as homologous recombination deficiency (HRD+) showed a response;
- There were 19 evaluable patients, with < two prior lines of chemotherapy, enrolled in the extensive-stage small cell lung cancer (ES SCLC) expansion cohort. ORR was 31.6%; with one CR and five PRs. The DCR was 78.9%, with 3.6 months median treatment duration (1.0–5.7) and five patients remained on treatment; and
- There were 15 evaluable patients enrolled in the gastric/gastroesophageal junction (G/GEJ) cancer expansion cohort. ORR was 0%; The DCR was 33.3%, with 1.9 months median treatment duration (0.3–5.8) and two patients remained on treatment.
Safety, Antitumor Activity, and Pharmacokinetics of Pamiparib in Patients with Advanced Solid Tumors: Updated Phase 1 Dose-Escalation/Expansion Results
The multi-center, open-label Phase 1A/1B trial (NCT02361723) of pamiparib is being conducted in
- Of the 101 patients, the most common (occurring in 20% or more patients) TEAEs of any grade were nausea (69.3%), fatigue (48.5%), anemia (35.6%), diarrhea (33.7%), vomiting (31.7%), decreased appetite (22.8%), and constipation (21.8%);
- The most common grade 3 or higher TEAE occurring in 5% or more patients were anemia (24.8%) and alanine aminotransferase (ALT) increase (5%);
- TEAEs led to treatment discontinuation in 6.9% of patients. Five (5%) patients experienced TEAEs with a fatal outcome, all of which were considered by investigators to be unrelated to the study drug;
- As of the data cutoff, 58 patients with ovarian and associated cancer were evaluable for efficacy per RECIST v1.1 criteria. Of these patients, 23 (39.7%) achieved a confirmed objective response, with four CRs (6.9%) and 19 PRs (32.8%). Additional results included:
° The clinical benefit rate was 53.4%;
° The median duration of response was 14.9 months (11–17.9);
° The ORR was higher (61.3%) in 31 patients with germline or somatic BRCA mutation (g/s BRCAmut+) as compared to 14.8% in 27 patients who were BRCA wild-type or unknown (BRCAwt or BRCAunk) status;
° There were 22 patients with platinum sensitivity, 23 patients were platinum-resistant, and 12 patients were platinum-refractory. The ORR was 77.3% for platinum-sensitive patients, 17.4% for platinum-resistant and 8.3% for platinum-refractory patients;
° In patients who were platinum-sensitive with BRCAmut+ the ORR was 83.3% (15/18); in patients who were BRCAwt or BRCAunk the ORR was 50% (2/4); and
° In patients who were platinum-resistant with BRCAmut+ the ORR was 20% (2/10); and in patients who were BRCAwt or BRCAunk the ORR was 15.4% (2/13);
- Pharmacokinetic data showed that the plasma exposure of pamiparib increased nearly proportionally with increase in dose with a terminal half-life of approximately 13 hours, and supported administration of pamiparib, with or without food.
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 biologics 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.
Ongoing clinical trials of tislelizumab include a Phase 3 clinical trial in patients with second-line or third-line non-small cell lung cancer (NSCLC); a Phase 3 clinical trial in first-line patients with hepatocellular carcinoma (HCC); a Phase 3 clinical trial in second-line patients with esophageal squamous carcinoma (ESCC); a Phase 3 clinical trial in first-line patients with gastric cancer (GC); a Phase 3 clinical trial in first-line patients with ESCC; and a Phase 2 clinical trial in second- or third-line patients with HCC. The aforementioned trials are enrolling patients in multiple countries, including
In addition to a pivotal Phase 2 clinical trial in patients with relapsed or refractory (R/R) classical Hodgkin’s lymphoma (cHL) and a pivotal Phase 2 clinical trial in patients with locally advanced or metastatic urothelial cancer,
New drug applications (NDA) for tislelizumab in patients with R/R cHL and in patients with previously treated locally advanced or metastatic UC have been accepted and granted priority review by the
Pamiparib (BGB-290) is an investigational inhibitor of PARP1 and PARP2 which has demonstrated pharmacological properties such as brain penetration and PARP-DNA complex trapping in preclinical models. Discovered by
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 data from ongoing clinical trials of tislelizumab and pamiparib, the mechanism of action of tislelizumab, BeiGene’s advancement of, and anticipated clinical development, regulatory milestones and commercialization of tislelizumab and pamiparib. 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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