On December 3, 2018 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases, reported results presented by collaborators at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. One study presents details of a next-generation CAR T technology that increases T cell persistence and decreases T cell exhaustion (Press release, Atara Biotherapeutics, DEC 3, 2018, View Source [SID1234531881]). Another important study presents positive Phase 2 clinical results in patients with EBV+ PTLD involving the CNS. PTLD patient treatment patterns and health outcomes are described in additional ASH (Free ASH Whitepaper) presentations.

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"Our highlighted ASH (Free ASH Whitepaper) presentations this year demonstrate the promise of Atara’s next-generation CAR T and off-the-shelf, allogeneic T-cell immunotherapy pipeline," said Dietmar Berger, M.D., Ph.D., Global Head of Research and Development of Atara Biotherapeutics. "Cutting-edge CAR T discoveries by our Moffitt Cancer Center collaborators may have wide applications including as a component of our CAR T programs in acute myeloid leukemia (AML) and B-cell malignancies. Our collaborating investigators at Memorial Sloan Kettering also showed promising Phase 2 clinical results for patients with EBV+ PTLD involving the CNS, a difficult-to-treat and often lethal complication of bone marrow and organ transplantation. We are encouraged by these robust results and the broad potential of our CAR T technologies and T cell immunotherapy platform."

60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting Summary:

Abstract 966: Mutation of the CD28 Costimulatory Domain Confers Increased CAR T Cell Persistence and Decreased Exhaustion
Session: 703. Adoptive Immunotherapy: Preclinical Studies to Improve Safety and Efficacy of CAR-T Cells
Oral Presentation Date and Time: Monday, December 3, 2018 at 5:45 pm PST
Location: Marriott Marquis San Diego Marina, San Diego Ballroom B
Authors: Justin C Boucher, Gongbo Li, Bishwas Shrestha, Maria L Cabral, Dylan Morrissey, Lawrence Guan, Marco L Davila
Affiliations:Moffitt Cancer Center

Abstract 4590: Adoptive Therapy with EBV-Specific T Cells for Treatment of CNS EBV Post-Transplant Lymphoproliferative Disease Arising after Hematopoietic Stem Cell Transplant or Solid Organ Transplant
Session: 723. Clinical Allogeneic and Autologous Transplantation: Late Complications and Approaches to Disease Recurrence: Poster III
Poster Presentation Date & Time: Monday, December 3, 2018 from 6:00 pm – 8:00 pm PST
Location:San Diego Convention Center, Hall GH
Authors: Susan Prockop, MD, Stephanie Suser, Ekaterina Doubrovina, MD, PhD, Hugo R. Castro-Malaspina, MD, Esperanza B. Papadopoulos, MD, James W. Young, MD, Victoria Szenes, PNP, Alison Slocum, MA, Karim Baroudy, MS and Richard J. O’Reilly, MD
Affiliations: Memorial Sloan Kettering Cancer Center
Overview:

This poster presentation evaluated EBV-specific T-cells generated from primary and third party (tab-cel) donors.
Patients with EBV+ PTLD involving the CNS following allogeneic hematopoietic stem cell transplant (HCT) or solid organ transplant (SOT) who failed prior rituximab from the Phase 2 studies 95-024 (NCT00002663) and 11-130 (NCT01498484) were included in the analysis.
Abstract 4777: Treatment Patterns for Patients with Post-Transplant Lymphoproliferative Disorder Who Fail Rituximab after Allogeneic Hematopoietic Stem Cell Transplantation: Findings from a Systematic Literature Review
Session: 902. Health Services Research—Malignant Diseases: Poster III
Poster Presentation Date & Time: Monday, December 3, 2018 from 6:00 pm – 8:00 pm PST
Location:San Diego Convention Center, Hall GH
Authors: Hairong Xu, MD, PhD, Crystal Watson, MS, Shan Ashton Garib, MA, Anna Forsythe, PharmD, MSc, MBA and Arie Barlev, PharmD
Affiliations:Atara Biotherapeutics, Purple Squirrel Economics

Abstract 3556: Estimating Long-Term Survival in a Cohort of Allogeneic Hematopoietic Stem Cell Transplant Patients
Session: 902. Health Services Research—Malignant Diseases: Poster II
Poster Presentation Date & Time: Sunday, December 2, 2018 from 6:00 pm – 8:00 pm PST
Location:San Diego Convention Center, Hall GH
Authors: Stephen Palmer, MSc, Casey Quinn, PhD, MPhil, Crystal Watson, MS and Arie Barlev, PharmD
Affiliations:Centre for Health Economics, University of York, PRMA Consulting Ltd., Atara Biotherapeutics

Abstract 4596: Dual-Sensitized T-Cells Responding to EBV Blcl and Either CMVpp65 or WT-1 Peptide Pools Have Distinct or Shared HLA Restrictions That May Depend on the Presenting HLA Alleles
Session: 723. Clinical Allogeneic and Autologous Transplantation
Poster Presentation Date & Time: Monday, December 3, 2018 from 6:00 pm – 8:00 pm PST
Location: San Diego Convention Center, Hall GH
Authors: Ekaterina Doubrovina, MD, PhD, Aisha N. Hasan, MD, Susan Prockop, MD, Karim Baroudy, MS, and Richard O’Reilly, MD
Affiliations: Memorial Sloan Kettering Cancer Center

Abstract 5839: A Systematic Literature Review of Real-World Evidence in Post-Transplant Lymphoproliferative Disorder
Authors: Hairong Xu, MD, PhD, Anna Forsythe, PharmD, MSc, MBA, Arie Barlev, PharmD, Nazia Rashid, PharmD and Crystal Watson, MS
Affiliations:Atara Biotherapeutics, Purple Squirrel Economics

Abstract 5841: Younger Patients Are Impacted By Post-Transplant Lymphoproliferative Disorder: Findings from a Systematic Literature Review of Real-World Evidence
Authors: Crystal Watson, MS, Hairong Xu, MD, PhD, Anna Forsythe, PharmD, MSc, MBA, Shan Ashton Garib, MA and Arie Barlev, PharmD
Affiliations:Atara Biotherapeutics, Purple Squirrel Economics

Abstract 5840: Risk of Patients Developing Post-Transplant Lymphoproliferative Disorder within the First Year after an Allogeneic Hemopoietic Stem Cell Transplant, 2011 to 2016: A US Claims Database Analysis
Authors: Arie Barlev, PharmD, Hairong Xu, MD, PhD, Nicole Fulcher, MA, Crystal Watson, MS, Ila Sruti, MPH and Akshay Sudhindra, MD
Affiliations:Atara Biotherapeutics, IBM Watson Health

About EBV+ PTLD
Since its discovery as the first human oncovirus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of lymphoproliferative disorders, including lymphomas, and other cancers. EBV is widespread in all human populations and persists as a lifelong, asymptomatic infection. In immunocompromised patients, such as those undergoing allogeneic hematopoietic cell transplants (HCT) or solid organ transplants (SOT), EBV-associated post-transplant lymphoproliferative disorder (EBV+ PTLD) represents a life-threatening condition. The expected median survival for patients with EBV+ PTLD following HCT who have failed rituximab first line therapy is 16-56 days. In EBV+ PTLD following SOT, patients failing rituximab are considered to have increased risk for chemotherapy-induced treatment-related mortality compared to other lymphoma patients. One- and two-year survival in patients with high-risk EBV+ PTLD following SOT is estimated to be 36% and 0%, respectively.

About tab-cel (tabelecleucel)
Atara’s most advanced T-cell immunotherapy in development, tab-cel, is a potential treatment for patients with Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorder (EBV+ PTLD) who have failed rituximab, as well as other EBV-associated hematologic and solid tumors, including nasopharyngeal carcinoma (NPC). In February 2015, the FDA granted tab-cel Breakthrough Therapy Designation for EBV+ PTLD following allogeneic hematopoietic cell transplant (HCT), and in October 2016, tab-cel was accepted into the EMA Priority Medicines (PRIME) regulatory pathway for the same indication, providing enhanced regulatory support. In addition, tab-cel has orphan status in the U.S. and EU. Tab-cel is in Phase 3 clinical development for the treatment of EBV+ PTLD following an allogeneic hematopoietic cell transplant (MATCH study) or solid organ transplant (ALLELE study), and Atara recently initiated a Phase 1/2 study in NPC.

On December 3, 2018 Geron Corporation (Nasdaq: GERN) reported that results from IMbark, a Phase 2 clinical trial of imetelstat treatment in Intermediate-2 or High-risk myelofibrosis (MF) patients who are relapsed or refractory to a Janus Kinase (JAK) inhibitor, were presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California (Press release, Geron, DEC 3, 2018, View Source [SID1234531880]). The oral presentation was made on December 3, 2018 by John Mascarenhas, M.D., Associate Professor of Medicine in the Myeloproliferative Disorders Program of the Tisch Cancer Institute, Division of Hematology/Oncology at the Icahn School of Medicine at Mount Sinai, and an IMbark clinical investigator.

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"The IMbark results suggest a meaningful survival outcome in this poor-prognosis, relapsed/refractory MF patient population where there are currently no approved treatments," said John A. Scarlett, M.D., Geron’s President and Chief Executive Officer. "We plan to explore potential late-stage development opportunities for imetelstat in MF through discussions with experts in MF and regulatory authorities and expect to provide a decision regarding future development of imetelstat in this patient population by the end of the third quarter of 2019."

Clinical Data Presentation

Title: Imetelstat is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels (Abstract #685)

IMbark is a Phase 2 clinical trial that evaluated two starting dose levels of imetelstat (either 4.7 mg/kg or 9.4 mg/kg administered by intravenous infusion every three weeks) in more than 100 patients with Intermediate-2 or High-risk MF who have relapsed after or are refractory to prior treatment with a JAK inhibitor. The oral presentation highlighted efficacy and safety data from the primary analysis, as well as overall survival data with a clinical cutoff of October 22, 2018 and a median follow up of approximately 27 months.

The co-primary efficacy endpoints for the trial are spleen response rate, defined as the proportion of patients who achieve a ≥35% reduction in spleen volume assessed by imaging; and symptom response rate, defined as the proportion of patients who achieve a ≥50% reduction in Total Symptom Score, at 24 weeks. Key secondary endpoints are safety and overall survival.

For the 9.4 mg/kg dosing arm (n=59), the spleen response rate was 10% (6/59) and the symptom response rate was 32% (19/59). In addition, improvement in bone marrow fibrosis was observed in 25% (15/59) of patients.

The new data presented at ASH (Free ASH Whitepaper) indicate that median overall survival (OS) for the 9.4 mg/kg dosing arm was 29.9 months, which suggests a meaningful survival outcome with imetelstat treatment in this poor-prognosis patient population, all of whom met rigorous criteria for having failed or not responded to JAK inhibitor treatment prior to enrollment in the trial. Other observational studies of similar patient populations published in medical literature have reported median OS ranged from approximately 12-14 months.

The safety profile reported for imetelstat-treated patients in IMbark was consistent with prior clinical trials of imetelstat in hematologic malignancies, and no new safety signals were identified. Cytopenias, particularly neutropenia and thrombocytopenia, were the most frequently reported adverse events which were predictable, manageable and reversible.

The slides from the oral presentation at ASH (Free ASH Whitepaper) are available on Geron’s website at www.geron.com/r-d/publications.

Future Plan for Imetelstat in Relapsed/Refractory MF

Based on the data from IMbark, Geron plans to discuss the potential future development of imetelstat in MF with MF experts and regulatory authorities. Such discussions will consider how the IMbark results compare with other therapies currently available to MF patients and enable a better understanding of the potential significance of the IMbark results to patients and physicians. The Company expects to outline a decision regarding potential future MF development by the end of the third quarter of 2019.

Analyst and Investor Event

On December 10, 2018, Geron will host a webcasted event for analysts and investors. At the event, Dr. John Mascarenhas will reprise the oral presentation made at the ASH (Free ASH Whitepaper) Annual Meeting, as well as describe the unmet medical need in relapsed/refractory MF. A live audio webcast of the event will be available on Geron’s website, www.geron.com/investors/events. If you are unable to listen to the live presentation, an archived webcast of the event will be available on the Company’s website for 30 days.

About Imetelstat

Imetelstat is a novel, first-in-class telomerase inhibitor exclusively owned by Geron and being developed in hematologic myeloid malignancies. Early clinical data suggest imetelstat may have disease-modifying activity through the suppression of malignant progenitor cell clone proliferation, which allows potential recovery of normal hematopoiesis. Ongoing clinical studies of imetelstat include a Phase 2/3 trial called IMerge in lower risk myelodysplastic syndromes (MDS) and a Phase 2 trial called IMbark in Intermediate-2 to High-risk myelofibrosis. Imetelstat received Fast Track designation from the United States Food and Drug Administration for the treatment of patients with transfusion-dependent anemia due to lower risk MDS who are non-del(5q) and refractory or resistant to an erythroid stimulating agent.

On December 3, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported results from the Phase 3 iLLUMINATE (PCYC-1130) trial, evaluating the chemotherapy-free, anti-CD20 combination of IMBRUVICA (ibrutinib) plus obinutuzumab (Gazyva) in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, DEC 3, 2018, View Source [SID1234531878]). At a median follow-up of 31 months, study results showed IMBRUVICA plus obinutuzumab significantly prolonged progression-free survival (PFS) (median not reached [NR] vs. 19 months) with a 77 percent reduction in risk of progression or death versus chlorambucil plus obinutuzumab, the current National Comprehensive Cancer Network guidelines Category 1 treatment regimen (hazard ratio [HR] 0.23; 95% confidence interval [CI]: 0.15-0.37; P<0.0001).

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The data were presented today in an oral session at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (abstract #691) and were simultaneously published in The Lancet Oncology. Based on these data, a supplemental New Drug Application (sNDA) was recently accepted for Priority Review by the U.S. Food and Drug Administration (FDA) to expand the use of IMBRUVICA in combination with obinutuzumab in previously untreated CLL/SLL. IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"iLLUMINATE represents one of three IMBRUVICA Phase 3 studies in chronic lymphocytic leukemia being presented at this year’s ASH (Free ASH Whitepaper). Results from the iLLUMINATE study support the use of IMBRUVICA as a chemotherapy-free, anti-CD20 combination treatment option versus the current National Comprehensive Cancer Network guidelines Category 1 treatment of chlorambucil plus obinutuzumab," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "These latest findings, in addition to seven-year long-term data and a Late-Breaker at this year’s ASH (Free ASH Whitepaper), add to the robust amount of data supporting the use of IMBRUVICA as backbone therapy in CLL and SLL."

CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).1 While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year.2,3 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.4 Both CLL and SLL are predominately diseases of the elderly, with a median age at diagnosis ranging from 65-70 years.5

"For years, we had to rely on chemotherapy as the only treatment option for patients with previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma," said Carol Moreno, M.D., Ph.D., Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and lead study investigator of iLLUMINATE. "We’re pleased to share results from iLLUMINATE that help show that it is possible to provide efficacious treatment for patients with CLL and SLL without the use of chemotherapy."

About Abstract #691: Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab as First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE

Oral presentation: Monday, December 3 at 10:30 a.m. PST

In the Phase 3 iLLUMINATE (PCYC-1130) study, newly diagnosed CLL patients were randomized to receive IMBRUVICA 420 milligrams (mg) once daily continuously in combination with obinutuzumab 1000 mg intravenously over six cycles (n=113); or chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle plus obinutuzumab 1000 mg intravenously over six cycles (n=116). The primary endpoint was PFS, as assessed by an Independent Review Committee (IRC). The study also evaluated: PFS for patients with high-risk features (unmutated IGHV, del11q, del17p or TP53 mutation); rate of undetectable minimal residual disease (MRD); overall response rate (ORR); overall survival (OS); and safety.

At a median follow-up of 31.3 months, ibrutinib plus obinutuzumab significantly prolonged the IRC-assessed PFS compared to chlorambucil plus obinutuzumab, with a 77 percent reduction in risk of progression or death (median NR vs. 19 months; hazard ratio [HR] 0.23; 95% CI: 0.15-0.37; P<0.0001). At 30 months, the IRC-assessed PFS rates were 79 percent and 31 percent with ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab, respectively. The investigator-assessed PFS was also significantly improved with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab (median NR vs. 21.9 months; HR 0.26; 95% CI: 0.16-0.42; P<0.0001).

The PFS in the IMBRUVICA plus obinutuzumab arm in the high-risk population, including those with unmutated IGHV, del11q, del17p, or TP53 mutation was assessed, with an 85 percent reduction in risk of progression or death (median not reached vs. 14.7 months; HR 0.15; 95% CI: 0.09-0.27; P<0.0001). In addition, IRC-assessed ORR was higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (88% vs. 73%); complete response (CR)/complete response with incomplete blood recovery (CRi) rates were also higher with 19 percent versus eight percent, respectively. The investigator-assessed ORR was also higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (91% vs. 81%); CR/CRi rates were also higher with 41 percent versus 16 percent, respectively. Depth of remission as reflected by undetectable MRD in blood and/or bone marrow was greater in patients with ibrutinib plus obinutuzumab, with 35 percent of patients showing undetectable MRD compared to 25 percent of patients with chlorambucil plus obinutuzumab. OS rates at 31 months were 86 percent for the ibrutinib arm compared to 85 percent for the chlorambucil arm.

Most common Grade 3 or higher adverse events (AEs) in the ibrutinib plus obinutuzumab arm versus chlorambucil plus obinutuzumab arm were neutropenia (43% vs. 63%), thrombocytopenia (35% vs. 25%), diarrhea (34% vs. 10%), cough (27% vs. 12%), infusion-related reactions (25% vs. 58%), arthralgia (22% vs. 10%), pyrexia (19% vs. 26%), anemia (17% vs. 25%), and nausea (12% vs. 30%). Ibrutinib plus obinutuzumab also seemed to decrease the risk of infusion reactions related to the use of obinutuzumab.

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2018, please visit: View Source

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by inhibiting a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.6 IMBRUVICA blocks signals that tell malignant B-cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).7

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
In August 2018, IMBRUVICA plus rituximab was approved for adult patients with WM.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.8 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, more than 135,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,011 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,011 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustments may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

On December 3, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported its updated efficacy and safety data from the untreated acute myeloid leukemia (AML) arm from the ongoing Phase 1 dose-escalation and expansion study evaluating single agent ivosidenib in patients with hematologic malignancies and an isocitrate dehydrogenase-1 (IDH1) mutation (Press release, Agios Pharmaceuticals, DEC 3, 2018, View Source [SID1234531872]). The data were featured in an oral presentation at the 60thAmerican Society of Hematology Annual Meeting in San Diego.

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"Ivosidenib induced deep, durable remissions in newly diagnosed AML patients who are older, have high rates of secondary AML and prior hypomethylating agent exposure," said Gail Roboz, M.D., Weill Cornell Medical College and an investigator in the study. "Ivosidenib had a favorable safety profile characterized by a low rate of febrile neutropenia and infections. In addition, transfusion independence was observed across response categories, including in patients who did not achieve complete remission."

"We believe these data are encouraging and represent compelling evidence for the potential of single agent ivosidenib as a new treatment option for newly diagnosed AML patients who are ineligible for standard therapies," said Chris Bowden, M.D., chief medical officer at Agios. "There is tremendous need for targeted treatment options for these patients who are typically older and have comorbid conditions, and we are on track to submit a supplemental new drug application for ivosidenib for this patient population under the FDA Real Time Oncology Review pilot program by the end of January 2019."

Untreated AML Data Presentation
As of the May 11, 2018 data cutoff, a total of 258 patients with advanced hematologic malignances and an IDH1 mutation were treated in the Phase 1 study, including 34 patients with untreated AML (nine from dose-escalation and 25 from expansion) who received 500 mg of ivosidenib daily. Enrollment to the study is closed.

Among the untreated AML patients, 20.6% had de novo AML and 79.4% had secondary AML (sAML).
The median age for these patients was 76.5 years (64-87) and 41.2% had received a prior hypomethylating agent.
The median treatment duration for the untreated AML patients was 4.3 months (0.3-35.1).
Safety Data
As of the data cut-off, a safety analysis conducted for the 34 untreated AML patients showed that ivosidenib demonstrates a safety profile that is consistent with previously reported data for all 258 patients. The most common adverse events (AEs) of any grade >25% regardless of causality were diarrhea (52.9%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%) and edema peripheral (26.5%). Adverse events of interest were the following:

8.8% reported Grade ≥3 ECG QT prolongation. Ivosidenib was dose reduced in two patients and held in four patients (for any grade of ECG QT prolongation).
17.6% reported IDH-differentiation syndrome (IDH-DS) of any grade, which was managed with corticosteroids and diuretics. Three patients had their dose temporarily held, and no patients required dose reductions.
3% reported Grade ≥3 leukocytosis.
No AEs of interest lead to any permanent treatment discontinuations or deaths.
Efficacy Data
Data from 33 untreated AML patients with an IDH1 mutation confirmed by the Abbott RealTime IDH1 assay demonstrated an overall response rate (ORR) of 57.6% (19 of 33 patients) [95% CI 39.2, 74.5] and a combined complete remission (CR) and CR with partial hematologic recovery (CRh) rate of 42.4% [95% CI 25.5, 60.8] which is the primary endpoint of the study.

The CR rate was 30.3% (10 of 33 patients) [95% CI 15.6, 48.7] and the CRh rate was 12.1% (4 of 33 patients) [95% CI 3.4, 28.2]. CRh is defined as <5% of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (ANC >500/microliter and platelets >50,000/microliter).
Median time to first response was 1.9 months (range 0.9, 3.6) for all patients who responded and median time to CR/CRh was 2.8 months (range 1.9, 12.9).
Median durations of CR, CR+CRh, and ORR were not estimable (lower bound of 95% CI 4.2, 6.5 and 6.5 months, respectively); the estimated 12-month durations of response were 77.8%, 66.7% and 59.5%, respectively.
Transfusion independence, defined as an absence of transfusions for at least 56 consecutive days on treatment, was observed across all response categories.
Of the patients who achieved a CR or CRh and were transfusion dependent at baseline, all became independent of platelet and RBC transfusions during any 56-day post baseline period.
Achievement of transfusion independence was also seen among some non-CR/CRh responders and non-responders.
IDH1 mutation clearance, defined as a reduction in mIDH1 variant allele frequency to below the limit of detection of 0.02–0.04% (2-4 x10-4), was observed in 64% (9/14) of patients with untreated AML who achieved CR or CRh, including 50% (5/10) of patients with CR and 100% (4/4) of patients with CRh.
MDS Data Presentation
Updated safety and efficacy data based on May 11, 2018 data cutoff were also presented on December 1, 2018 for 12 myelodysplastic syndrome (MDS) patients from the dose-escalation (n=3) and expansion (n=9) portions of the Phase 1 study whose starting dose was 500 mg daily. The median age was 72.5 years (52-78).

The most common AEs of any grade occurring in ≥20% of patients were back pain and fatigue (n=4, 33.3% each) and anemia, decreased appetite, diarrhea, dyspnea, hypokalemia, pruritus, and rash (n=3, 25% each). Most AEs were grade 1–2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment.
Grade 2 IDH differentiation syndrome (IDH-DS) was observed in 1 of 12 patients.
Of the 12 patients with MDS, five achieved CR (41.7%) [95% CI (15.2%, 72.3%)], one achieved a partial response (PR) (8.3%) and five achieved marrow CR (mCR) (41.7%), resulting in an ORR of 91.7% [95% CI (61.5%, 99.8%)].
The median durations of CR was not estimable at the time of the data cutoff; the median duration of response was 21.4 months with 95% CI [2.3, NE]. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively.
Among the five patients who were transfusion dependent at baseline, four became transfusion independent for at least 56 days on treatment.
TIBSOVO (ivosidenib) is not approved for the treatment of patients with newly diagnosed AML or MDS by any regulatory authority.

About TIBSOVO (ivosidenib)

TIBSOVO (ivosidenib) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. For more information, visit TIBSOVO.com.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 34 patients who experienced differentiation syndrome, 27 (79%) recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade were fatigue (39%), leukocytosis (38%), arthralgia (36%), diarrhea (34%), dyspnea (33%), edema (32%), nausea (31%), mucositis (28%), electrocardiogram QT prolonged (26%), rash (26%), pyrexia (23%), cough (22%), and constipation (20%).
The most frequently reported ≥Grade 3 adverse reactions (≥5%) were electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), tumor lysis syndrome (6%), and differentiation syndrome (5%).
Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and the median age of diagnosis is 68. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 27 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.

About Myelodysplastic Syndrome (MDS)
MDS comprises a diverse group of bone marrow disorders in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The National Cancer Institute estimates that more than 10,000 people are diagnosed with MDS in the U.S. each year. Failure of the bone marrow to produce mature healthy cells is a gradual process, and reduced blood cell and/or reduced platelet counts may be accompanied by the loss of the body’s ability to fight infections and control bleeding. For roughly 30 percent of the patients diagnosed with MDS, this bone marrow failure will progress to AML. Chemotherapy and supportive blood products are used to treat MDS.

On December 3, 2018 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, reported the presentation of clinical data from the pivotal Phase 2 trial of its investigational anti-PD-1 antibody, tislelizumab, in Chinese patients with relapsed/refractory (R/R) classical Hodgkin’s lymphoma (cHL) (Press release, BeiGene, DEC 3, 2018, View Source;p=RssLanding&cat=news&id=2379122 [SID1234531870]). These data were presented in an oral session at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), taking place December 1-4, 2018 in San Diego, CA, and are included in BeiGene’s new drug application (NDA) in China for tislelizumab for the treatment of patients with R/R cHL.

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"We set out to address the needs of patients with R/R cHL who have failed to achieve a response or progressed after autologous stem cell transplant (ASCT), or who are not candidates for ASCT, as these patients, unfortunately, have very poor outcomes," said Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. "We are excited to report strong results including high complete response (CR) rates from the first registration study for this potentially differentiated anti-PD-1 agent."

Tislelizumab was discovered by BeiGene scientists, and is being developed globally and in China as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid and hematologic cancers with 11 Phase 3 or potentially registration-enabling studies ongoing or planned to initiate in the near term. The NDA for tislelizumab in China in patients with R/R cHL has been accepted by the China National Medical Products Administration (NMPA, formerly known as CFDA) and granted priority review status.

"In this study, tislelizumab demonstrated an overall response rate (ORR) of 86 percent, including a CR rate of 61 percent. Tislelizumab was also generally well-tolerated by patients with R/R cHL. We are excited by its clinical activity and believe that tislelizumab represents a potential new immunotherapy option for patients in China and elsewhere in the world," said Yuqin Song, M.D., Ph.D., Associate Professor of Medical Oncology, Deputy Director of the Lymphoma Department at Peking University Cancer Hospital in China, and the presenting author of the study.

Summary of Clinical Results

This single arm, open-label, multi-center, pivotal Phase 2 trial of tislelizumab as a monotherapy in Chinese patients with R/R cHL (ClinicalTrials.gov Identifier: NCT03209973) enrolled 70 patients who failed to achieve a response or progressed after ASCT, or received at least 2 prior lines of systemic therapy for cHL and were not an ASCT candidate. Patients were treated with tislelizumab, dosed at 200 mg intravenously every three weeks. The primary endpoint of the trial is ORR assessed by independent review committee (IRC) using PET-based imaging according to the Lugano Classification 2014.

As of May 25, 2018, 70 patients with R/R cHL were evaluable for efficacy and 53 patients (75.7%) remained on study treatment. Thirteen patients received prior ASCT, and the remaining 57 patients were ineligible for prior ASCT, including 53 for failure to achieve an objective response to salvage chemotherapy, two for inadequate stem cell collection or unable to collect stem cells, and two for co-morbidities. The patients had a median of three prior lines of systemic therapy with a range of 2 to 11. The median study follow-up was 7.85 months (3.4-12.7). Results included:

The ORR by IRC was 85.7 percent (60/70); the CR rate was 61.4 percent (43/70) and the partial response (PR) rate was 24.4 percent (17/70). Among patients who had received prior ASCT, 92.3 percent (12/13) achieved an objective response, with nine patients (69.2%) achieving a CR;

The median duration of response (DOR) had not yet been reached. The estimated event-free rates at 9 months were 84 percent;

Progression-free survival (PFS) data were preliminary and 6-month PFS was estimated at 80 percent. The median PFS had not yet been reached;

The majority of adverse events (AEs) were grade 1 or 2 in severity. The most frequently reported treatment emergent adverse events (TEAEs) of any grade were pyrexia (52.9%), hypothyroidism (30.0%), weight increased (28.6%), upper respiratory tract infection (27.1%), cough (17.1%), white blood cell count decreased (14.3%), and pruritus (14.3%);

Grade ≥3 TEAEs occurred in 21.4% of patients. The most frequently reported Grade 3 or higher TEAEs were upper respiratory tract infection (2.9%), pneumonitis (2.9%), and productive cough (2.9%);

Four patients (5.7%) discontinued study drug due to TEAEs, including pneumonitis (n=2), focal segmental glomerulosclerosis (n=1), and organizing pneumonia (n=1); there were no cases of TEAE leading to death; and

Immune-related AEs reported in more than five percent of patients included thyroid disorder (18.6%), pneumonitis (5.7%), and skin adverse reactions (5.7%).
Investor Webcast:
Date and Time: Monday, December 3, 2018 at 20:00 PST (Tuesday, December 4 at 12:00 China Standard Time)
Webcast: A live webcast and replay of the event will be available on BeiGene’s investor website, View Source

About Classical Hodgkin’s Lymphoma
Hodgkin’s lymphoma is one of the two major types of lymphoma that begin in the lymph nodes and tissues of the lymphatic system. All other lymphomas are classified as non-Hodgkin’s lymphomas. Classical Hodgkin’s lymphoma, the most common form representing about 95 percent of the patients with Hodgkin’s lymphoma, is characterized by the presence of very large cells called Reed-Sternberg cells. There were approximately 2,100 diagnosed cases of Hodgkin’s lymphoma in China in 2012.i Although the cancer can occur in both children and adults, it is most commonly diagnosed in young adults between the ages of 15 and 35 and in older adults over age 50.

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.

Discovered by BeiGene scientists, tislelizumab 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. The new drug application (NDA) for tislelizumab in China for patients with R/R cHL has been accepted by the China National Medical Products Administration (NMPA, formerly known as CFDA) and granted priority review status. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumors in the United States, Europe, Japan and the rest of world outside Asia.