On December 13, 2019 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, and Mirati Therapeutics (NASDAQ:MRTX), a clinical-stage targeted oncology company, reported preliminary data from an ongoing Phase 1b trial of investigational anti-PD-1 antibody tislelizumab in combination with investigational tyrosine kinase inhibitor sitravatinib in patients with platinum-resistant ovarian cancer, which demonstrated antitumor activity and was generally well tolerated (Press release, BeiGene, DEC 13, 2019, View Source [SID1234552364]). Results from the Phase 1b clinical trial were presented at the 2019 European Society for Medical Oncology Immuno-Oncology (ESMO I-O) Congress on December 13, 2019 in Geneva, Switzerland.
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"Tislelizumab and sitravatinib have both demonstrated antitumor activity as single agents, so we’re encouraged by the early evidence showing the potential for these two agents to work together to treat advanced solid tumors, including platinum-resistant ovarian cancer," said Yong (Ben) Ben, M.D., Chief Medical Officer, Immuno-Oncology at BeiGene. "We continue to make progress in the collaboration with Mirati Therapeutics and we look forward to continued enrollment in the trial and further clinical data on the combination of tislelizumab and sitravatinib, a compound that has a unique tyrosine kinase inhibition profile."
"We were eager to enter into this collaboration with BeiGene because we believe sitravatinib, a spectrum-selective receptor tyrosine kinase inhibitor, may help increase the activity of anti-PD-1 antibodies such as tislelizumab in patients whose solid tumors exhibit resistance," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer, Mirati Therapeutics, Inc. "The initial results from this Phase 1b trial suggest further development of this combination for the treatment of advanced solid tumors, including platinum-resistant ovarian cancer, is warranted."
Summary of Preliminary Results from the Phase 1b Trial in Platinum-Resistant Ovarian Cancer
Abstract 94O
This open-label, multi-center Phase 1b trial (NCT03666143) of tislelizumab in combination with sitravatinib consists of nine disease-specific cohorts in patients with advanced solid tumors. The results presented at ESMO (Free ESMO Whitepaper) I-O were from cohort E in 20 patients with recurrent platinum-resistant ovarian cancer who did not have prior exposure to anti-PD-1/PD-L1 agents. Patients were treated with tislelizumab at 200 mg IV every three weeks and sitravatinib at 120mg orally once daily. At the data cutoff of July 17, 2019, 17 patients were evaluable and preliminary results included:
Seven patients achieved a partial response (PR), including four confirmed PRs; the overall response rate (ORR) was 23.5% (4/17, 95% CI: 6.8%, 49.9%); eight patients achieved stable disease (SD);
The median duration of response (DoR) was not reached (95% CI: 12.29 weeks, not reached);
The median progression-free response (PFS) was 18 weeks (95% CI: 12.29 weeks, not reached), and the PFS rate at 3 months and 6 months was 88.2% (95% CI: 60.6%, 96.9%) and 35.3% (95% CI: 9.0%, 63.8%), respectively;
All 20 patients in this cohort experienced treatment-emergent adverse events (TEAEs) of any grade;
Fifteen patients (75%) experienced at least one grade ≥ 3 TEAE, with the most common being hypertension (25%) and fatigue (10%);
Immune-related TEAEs were hypothyroidism (20%), diarrhea (15%), and rash (15%);
Six patients (30%) discontinued the study treatment due to TEAEs; and
Two patients experienced TEAEs leading to death, abdominal pain and respiratory failure, both of which were considered unrelated to treatment by the study investigator.
BeiGene and Mirati entered into an exclusive license agreement for the development, manufacturing and commercialization of Mirati’s sitravatinib in Asia (excluding Japan), Australia, and New Zealand in January 2018. Clinical trials for tislelizumab and sitravatinib are ongoing in patients with non-small cell lung cancer, renal cell carcinoma, melanoma, hepatocellular cancer and gastric cancer.
About Tislelizumab
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.
Select 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 the United States, Europe, and China.
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, BeiGene is conducting a Phase 3 clinical trial in first-line patients with non-squamous NSCLC; a Phase 3 clinical trial in first-line patients with squamous NSCLC; a Phase 3 clinical trial in patients with first-line nasopharyngeal cancer (NPC); a Phase 3 clinical trial in first-line patients with urothelial carcinoma (UC); a Phase 3 clinical trial in patients with localized ESCC; and a Phase 2 trial in patients with MSI-H or dMMR solid tumors. These studies have been enrolling patients primarily in China.
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 China National Medical Products Administration (NMPA, formerly known as CFDA). BeiGene has full development and commercial rights to tislelizumab worldwide.
About Sitravatinib
Sitravatinib is an investigational spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being evaluated in combinations of anti-PD-1 checkpoint inhibitors, in patients whose cancers have progressed despite treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation. Sitravatinib is being evaluated in multiple clinical trials to treat patients who are refractory to prior immune checkpoint inhibitor therapy, including the ongoing potentially registration-enabling Phase 3 trial of sitravatinib in combination with a checkpoint inhibitor in non-small cell lung cancer (NSCLC). In addition, sitravatinib combinations with checkpoint inhibitors are being evaluated in selected checkpoint inhibitor naïve patients.
Sitravatinib is also being evaluated as a single-agent in a Phase 1b expansion clinical trial emphasizing enrollment of patients whose tumors harbor specific mutations in the CBL protein. When CBL is inactivated by mutation, multiple RTKs, including TAM, VEGFR2 and KIT, are dysregulated and may act as oncogenic tumor drivers in NSCLC and melanoma.