On March 1, 2017 Bristol-Myers Squibb Company (NYSE: BMY) reported that new clinical data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 in Washington, D.C., from April 1-5 (Press release, Bristol-Myers Squibb, MAR 1, 2017, View Source [SID1234517923]).

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Research to be presented represents the company’s ongoing commitment to investigating long-term survival and safety data in advanced cancers, and to exploring the interaction between biomarkers and Immuno-Oncology (I-O) therapy across multiple tumor types. Results will be disclosed for Opdivo (nivolumab), as a single-agent and in combination with Yervoy (ipilimumab), as well as an investigational, optimized, once-daily IDO1 inhibitor alone or in combination with Opdivo. IDO is part of Bristol-Myers Squibb’s robust early clinical development pipeline and one of 21 oncology compounds in clinical study. Bristol-Myers Squibb will also share data generated as part of the International Immuno-Oncology Network (II-ON), a global peer-to-peer collaboration with academia established in 2012 and focused on advancing the science of I-O through a series of preclinical, translational and biology-focused research objectives.

"At Bristol-Myers Squibb, we are committed to translational research as we advance the development of next-generation Immuno-Oncology therapies and conduct biomarker research that will help us determine which patients are most likely to benefit from our treatments," said Fouad Namouni, M.D., head of development, Oncology, Bristol-Myers Squibb. "In all of our research efforts, we are driven by our overarching goal of changing the way patients live with cancer."

The full set of data to be presented by Bristol-Myers Squibb includes:

Melanoma / Skin Cancer

Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-naïve patients with advanced melanoma (CheckMate -067)
Author: James Larkin
Abstract # CT075
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials
Monday, April 3, 2017, 3:35 – 3:50 p.m., Ballroom C, Level 3
Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab in patients with virus-associated tumors (CheckMate -358): Efficacy and safety in Merkel cell carcinoma
Author: Suzanne Topalian
Abstract # CT074
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials
Monday, April 3, 2017, 3:05 – 3:20 p.m. Ballroom C, Level 3
Overall survival and safety experience from an expanded access program of nivolumab for patients with advanced melanoma who progressed after prior ipilimumab treatment (CheckMate -168)
Author: Milton Barros e Silva
Abstract # LB-055
Late-Breaking Poster Session: Clinical Research 1
Monday, April 3, 2017, 8:00 a.m. – 12:00 p.m., Poster Section 34; Poster Board #18
Lung

Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage IV or recurrent non-small cell lung cancer: an exploratory analysis of CheckMate -026
Author: Solange Peters
Abstract # CT082
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials
Monday, April 3, 2017, 5:20 – 5:30 p.m., Ballroom C, Level 3
Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer: Clinical characteristics of long-term survivors
Author: Julie Renee Brahmer
Abstract # CT077
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials Monday, April 3, 2017, 4:05 – 4:20 p.m., Ballroom C, Level 3
An Open-label Phase 3b/4 Safety Trial of Flat-Dose Nivolumab in Combination With Ipilimumab in Patients With Advanced Non-Small Cell Lung Cancer
Author: Rathi N. Pillai
Abstract # CT070
Poster Session: Phase II/III Clinical Trials in Progress
Monday, April 3, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster Section 33, Poster Board #20
Head and Neck Cancer

Treatment Beyond Progression With Nivolumab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck in the Phase 3 Checkmate -141 Study
Author: Robert Haddad
Abstract # CT157
Poster Session: Phase II/III Clinical Trials in Progress
Monday, April 3, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster Section 33
Pipeline

BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic activity, alone and in combination with nivolumab in advanced cancers in a phase 1/2a trial
Author: Lillian L. Siu
Abstract # CT116
Plenary Session: Novel Immuno-oncology Agent Clinical Trials
Tuesday, April 4, 2017, 11:13 – 11:28 a.m., Ballroom C, Level 3
Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical stage IDO1 inhibitor
Author: John T. Hunt
Abstract # 4964
Minisymposium: Novel Approaches for Experimental Therapeutics
Tuesday, April 4, 2017, 3:20 – 3:35 p.m. ET, Room 144, Level 1
Biomarkers and Dosing

Evaluation of oral microbiome profiling as a response biomarker in squamous cell carcinoma of the head and neck: Analyses from CheckMate -141
Author: Robert L. Ferris
Abstract # CT022
Clinical Trials Plenary Session: Immuno-oncology Biomarkers in Clinical Trials
Sunday, April 2, 2017, 4:48 – 5:03 p.m., Hall D-E, Level 2
Tumor-associated immune cell PD-L1 expression and peripheral immune profiling: Analyses from CheckMate -141
Author: Robert L. Ferris
Abstract # CT021
Clinical Trials Plenary Session: Immuno-oncology Biomarkers in Clinical Trials
Sunday, April 2, 2017, 4:33 – 4:48 p.m., Hall D-E, Level 2
Immunogenomic analyses of tumor cells and microenvironment in patients with advanced melanoma before and after treatment with nivolumab
Author: Timothy A. Chan
Abstract # 2988
Minisymposium: Clinical Biomarkers
Monday, April 3, 2017, 3:35 – 3:50 p.m. ET, Room 151, Level 1
Immunomodulatory effects of nivolumab and ipilimumab in combination or nivolumab monotherapy in advanced melanoma patients: CheckMate -038
Author: Antoni Ribas
Abstract # CT073
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials
Monday, April 3, 2017, 3:20 – 3:35 p.m., Ballroom C, Level 3
A model-based exposure-response assessment of a nivolumab 4-weekly (Q4W) dosing schedule across multiple tumor types
Author: Xiaochen Zhao
Abstract # CT101
Poster Session: Phase I Clinical Trials
Tuesday, April 4, 2017, 8:00 a.m. – 12:00 p.m. ET, Halls A-C, Poster Section 33
A Comparative Study of PD-L1 IHC 22C3 and 28-8 FDA-Approved Diagnostic Assays in Cancer
Author: Cory Batenchuk
Abstract # 4015
Poster Session: Assay Technology
Tuesday, April 4, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster section 1
Soluble HLA-G and -E (sHLA-G/E) as potential biomarkers of clinical outcomes in patients with advanced, refractory squamous (SQ) NSCLC treated with nivolumab: CheckMate -063
Author: Vera Rebmann
Abstract # CT126
Poster Session: Phase I-III Clinical Trials and Pediatric Clinical Trials
Tuesday, April 4, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster Section 33
Pooled analysis of PD-L1 expression across 6 tumor types in the nivolumab clinical program
Author: Gabriel Krigsfeld
Abstract # CT143
Poster Session: Phase I-III Clinical Trials and Pediatric Clinical Trials
Tuesday, April 4, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster Section 33
II-ON

RNA-sequencing of tumor-educated platelets enables nivolumab immunotherapy response prediction
Author: Mirte Muller
Abstract # LB-248
Poster Session: Lake-Breaking Clinical Research 2 / Endocrinology
Tuesday, April 4, 2017,1:00 – 5:00 p.m. ET, Poster Section 34
Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines that will raise survival expectations in hard-to-treat cancers and will change the way patients live with cancer.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents, including the first combination of two I-O agents in metastatic melanoma, and our differentiated clinical development program, which is studying broad patient populations across more than 35 types of cancers with 13 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and inform which patients will benefit most from I-O therapies.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO . The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]). In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infections, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (≥20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Checkmate Trials and Patient Populations

Checkmate 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 017 – squamous non-small cell lung cancer (NSCLC); Checkmate 057 – non-squamous NSCLC; Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck; Checkmate 275 – urothelial carcinoma.

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

On March 1, 2017 Amgen (NASDAQ:AMGN) reported that new data from the KYPROLIS (carfilzomib) and XGEVA (denosumab) clinical development programs will be presented at the 16th International Myeloma Workshop (IMW), March 1-4, 2017, in New Delhi (Press release, Amgen, MAR 1, 2017, View Source [SID1234517922]).

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Highlighted presentations include detailed results from the planned overall survival (OS) interim analysis of the Phase 3 head-to-head ENDEAVOR trial which showed that patients treated with KYPROLIS and dexamethasone lived longer than those treated with Velcade (bortezomib) and dexamethasone, as well as detailed results from the Phase 3 study in which XGEVA demonstrated non-inferiority to zoledronic acid in delaying bone complications in patients with multiple myeloma.

"Amgen is committed to advancing innovative treatments for patients with multiple myeloma across the disease continuum, including treatments to help patients live longer and supportive therapies that may help to address its impact," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We look forward to sharing new data on KYPROLIS, demonstrating for the first time an overall survival benefit in relapsed or refractory multiple myeloma over a current standard of care regimen, along with XGEVA data, showing its potential as a novel agent in preventing bone complications in multiple myeloma patients."

Detailed results will be presented from the Phase 3 ENDEAVOR study which showed that KYPROLIS improved OS in patients with relapsed or refractory multiple myeloma.

Overall Survival of Patients with Relapsed or Refractory Multiple Myeloma Treated with Carfilzomib and Dexamethasone versus Bortezomib and Dexamethasone: Interim Analysis from the Randomized Phase 3 ENDEAVOR Trial
Late-Breaking Oral Presentation, Saturday, March 4, 7:30 a.m. – 8:30 a.m. IST, at Hotel Pullman New Delhi Aerocity, Peacock Ballroom.
Adverse events observed in this updated analysis were consistent with those previously reported for ENDEAVOR. The most common adverse events (greater than or equal to 20 percent) in the KYPROLIS arm were anemia, diarrhea, pyrexia, dyspnea, fatigue, hypertension, cough, insomnia, upper respiratory tract infection, peripheral edema, nausea, bronchitis, asthenia, back pain, thrombocytopenia and headache.

Detailed results will be presented from the Phase 3 ‘482 trial that demonstrated XGEVA was non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (SRE) in patients with multiple myeloma. These data are being shared with regulatory authorities worldwide to seek approval for this investigational use. XGEVA is a fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) – an essential mediator of osteoclast formation, activation and survival – thereby inhibiting osteoclast-mediated bone destruction.

An International, Randomized, Double Blind Trial Comparing Denosumab With Zoledronic Acid (ZA) for the Treatment of Bone Disease in Patients (Pts) With Newly Diagnosed Multiple Myeloma
Abstract #546, Late-Breaking Oral Presentation, Saturday, March 4, 8:15 a.m. – 8:30 a.m. IST, at Hotel Pullman New Delhi Aerocity, Peacock Ballroom.
Additional KYPROLIS abstracts at IMW include new sub-analyses from the ASPIRE, ENDEAVOR and CHAMPION clinical trial programs, as well as results from the CLARION study. These results provide further insights into the safety and efficacy of KYPROLIS in different combinations and patient groups.

Updated Results from ASPIRE and ENDEAVOR, Randomized, Open-Label, Multicenter Phase 3 Studies of Carfilzomib in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM)
Abstract #335, Poster Discussion, Friday, March 3, 6 p.m. – 7 p.m. IST, at JW Marriott Hotel New Delhi Aerocity, Crystal Ballroom 1-2.
Efficacy and Safety of Once-Weekly Carfilzomib and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma: Secondary Analysis from the CHAMPION-1 Study by Prior Lines of Therapy
Abstract #285, Poster Session, Thursday, March 2, 7 a.m. – 6 p.m. IST, at JW Marriott Hotel New Delhi Aerocity, Crystal Ballroom 1-2.
A Multicenter, Open-Label, Phase 1b Study of Carfilzomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients (CHAMPION-2)
Abstract #210, Oral Presentation, Thursday, March 2, 3:04 p.m. – 3:15 p.m. IST, at Hotel Pullman New Delhi Aerocity, Peacock Ballroom.
Phase 3 Study (CLARION) of Carfilzomib, Melphalan, Prednisone (KMP) versus Bortezomib, Melphalan, Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM)
Abstract #373, Late-Breaking Oral Presentation, Saturday, March 4, 7:45 a.m. – 8 a.m. IST, at Hotel Pullman New Delhi Aerocity, Peacock Ballroom.
KYPROLIS is the only proteasome inhibitor to show superior OS in a head-to-head trial with a standard of care regimen, and superior progression-free survival in two Phase 3 studies in relapsed multiple myeloma patients. KYPROLIS is available for patients whose myeloma has relapsed or become resistant to another treatment.

Abstracts are currently available on the IMW website.

About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone microenvironment.1,2 It is characterized by a recurring pattern of remission and relapse, with patients eventually becoming refractory to treatment.3 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.1

Osteolytic bone lesions accompany multiple myeloma and are part of diagnosis (CRAB criteria). These lesions can increase the risk of bone complications over the course of the disease.4,5 Bone complications, also known as SREs, are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.

About Amgen’s Commitment to Oncology
Amgen Oncology is committed to helping patients take on some of the toughest cancers, such as those that have been resistant to drugs, those that progress rapidly through the body and those where limited treatment options exist. Amgen’s supportive care treatments help patients combat certain side effects of strong chemotherapy, and our targeted medicines and immunotherapies focus on more than a dozen different malignancies, ranging from blood cancers to solid tumors. With decades of experience providing therapies for cancer patients, Amgen continues to grow its portfolio of innovative and biosimilar oncology medicines.

About XGEVA (denosumab)
XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of SREs in patients with bone metastases from solid tumors and for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA is also indicated in the United States (U.S.) for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. XGEVA is not indicated for the prevention of SREs in patients with multiple myeloma.

U.S. Important Safety Information

Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has occurred in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroid, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Embryo-Fetal Toxicity
XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least five months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.

The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Denosumab is also marketed as Prolia in other indications.

Please visit www.amgen.com or www.xgeva.com for Full U.S. Prescribing Information.

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed. KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells. In some cells, KYPROLIS can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.

KYPROLIS is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
KYPROLIS is also approved in Argentina, Australia, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Macao, Mexico, Thailand, Colombia, S. Korea, Canada, Qatar, Switzerland, United Arab Emirates, Turkey, Russia, Brazil, India and the European Union. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

For more U.S. information, please visit www.kyprolis.com.

IMPORTANT SAFETY INFORMATION

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.
Acute Renal Failure

Cases of acute renal failure and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions

Infusion reactions, including life-threatening reactions, have occurred in patients receiving KYPROLIS.
Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.
Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients receiving KYPROLIS. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.
Please see full prescribing information at www.kyprolis.com.

On March 1, 2017 Aduro Biotech, Inc. (NASDAQ:ADRO) reported financial results for the year ended December 31, 2016 (Press release, Aduro Biotech, MAR 1, 2017, View Source [SID1234517919]). Net loss for the fourth quarter and year ended December 31, 2016 was $29.6 million, or $0.44 per share, and $91.1 million, or $1.40 per share, respectively. This compared to net income of $3.1 million, or $0.05 per share, and net loss of $39.2 million, or $0.88 per share, respectively, for the same periods in 2015.

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Cash, cash equivalents and marketable securities totaled $361.9 million at December 31, 2016, compared to $431.0 million at December 31, 2015.

"In 2016, we made a number of advancements to position us as a leader in the discovery and development of immunotherapies, and in 2017, we expect to have multiple agents across all three of our platforms advancing through the clinic," said Stephen T. Isaacs, chairman, president and chief executive officer of Aduro. "With a diversified and robust pipeline, strong cash position and validating pharmaceutical partnerships for each of our technologies, we believe we are poised to bring innovative therapies to patients."

Key 2016 Accomplishments

Development achievements

Unprecedented disease control rate in Phase 1b mesothelioma trial presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting
First patient dosed in a Phase 1 study of ADU-S100, the first STING Pathway Activator compound to enter the clinic, for treatment of cutaneously accessible tumors and receipt of $35 million development milestone from Novartis
Preclinical data demonstrated acute and systemic immune activation with ADU-S100
Anti-CD27 agonist advancing through preclinical development towards the clinic under licensing agreement with Merck
Preclinical data presented supporting clinical development of anti-APRIL antibody in multiple myeloma
Personalized LADD therapy (pLADD) featured in an oral presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (STIC) meeting
Investigational New Drug application cleared for pLADD clinical development
Preclinical data demonstrated synergy of Aduro’s immunotherapies with checkpoint inhibitors
Corporate achievements and notable news

Steve Isaacs named 2016 Visionary Leader by Berkeley Chamber of Commerce
Oncology expert and industry veteran Natalie Sacks, M.D. joined as chief medical officer
Hans van Eenennaam, Ph.D., and John Dulos, Ph.D., honored with award for contributions in discovery of KEYTRUDA
Launched industry-leading Immunotherapeutics and Vaccine Research Initiative with U.C. Berkeley
Expanded patent portfolio with key composition and methods patents
Anticipated 2017 Milestones

Initiate Phase 2 mesothelioma trial with CRS-207 in combination with anti-PD1 in the first half of 2017 and report early results in the second half of 2017
Initiate Phase 2 gastric trial with CRS-207 in combination with anti-PD1 in the first half of 2017
Initiate Phase 1 pLADD trial in advanced gastro-intestinal cancers in the second half of 2017
Janssen to assess data from Phase 1 trial of ADU-741 in prostate cancer
Janssen expected to initiate Phase 1b/2 trial of ADU-214 in lung cancer in the second half of 2017
Report top-line findings from Phase 1 monotherapy trial of ADU-S100 (STING) in the second half of 2017
In collaboration with Novartis, initiate Phase 1b trial of ADU-S100 in combination with anti-PD1 in the second half of 2017
File Investigational New Drug Application for BION-1301, anti-APRIL antibody, in the second half of 2017
Initiate Phase 1 multiple myeloma trial with anti-APRIL antibody in the second half of 2017
Financial Performance

Revenues were $3.9 million for the fourth quarter of 2016 and $50.7 million for the full year 2016, compared to $34.4 million and $73.0 million, respectively, for the same periods in 2015. The decrease in revenue for the fourth quarter of 2016 was primarily due to recognition of milestones and a portion of upfront fees under Aduro’s research and license agreements with Janssen in 2015. The decrease in revenue for the full year 2016 was also due to recognition of milestones and a portion of upfront fees under the Janssen agreements in 2015 partially offset by a $35.0 million payment recognized in 2016 upon achievement of a milestone under Aduro’s collaboration and license agreement with Novartis.

Research and development expenses were $20.9 million for the fourth quarter of 2016 and $87.7 million for the full year 2016, compared to $22.7 million and $58.6 million, respectively, for the same periods in 2015. The decrease in research and development expenses for the fourth quarter of 2016 was primarily due to higher licensing fees paid in 2015. The increase in research and development expenses for the full year 2016 was primarily due to contract manufacturing and research expenses associated with our ongoing studies and increased personnel and facility-related costs.

General and administrative expenses were $8.0 million for the fourth quarter of 2016 and $34.3 million for the full year 2016, compared to $8.8 million and $27.8 million, respectively, for the same periods in 2015. The decrease in general and administrative expenses for the fourth quarter of 2016 was primarily due to lower professional fees in 2016. The increase in general and administrative expenses for the full year 2016 was primarily due to higher personnel and facility related costs. There was no loss from remeasurement of fair value of warrants during the fourth quarter or full year 2016. There was a $26.1 million loss from remeasurement of fair value of warrants in the full year 2015 that occurred in April 2015 when certain outstanding warrants were no longer subject to future remeasurement.

Provision for income taxes was $5.1 million for the fourth quarter of 2016 and $21.5 million for the full year 2016. There was no provision for income taxes for the comparable periods in 2015. The income tax expense recorded for the fourth quarter and full year 2016 was primarily related to current and deferred federal income taxes.

On March 1, 2017 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that nine abstracts highlighting the breath of the Company’s expertise in ADCs will be presented at the upcoming American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting to be held from April 1-5, 2017 in Washington D.C (Press release, ImmunoGen, MAR 1, 2017, View Source [SID1234517918]). The presentations at AACR (Free AACR Whitepaper) cover a wide-array of ADC innovations, including further advancements to linkers and payloads and novel targets for both solid tumors and hematological malignancies.

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"ImmunoGen has an unmatched expertise and understanding of the core components of ADCs and the data being presented at AACR (Free AACR Whitepaper) further validate our full-spectrum of knowledge and leadership in this space," said Richard Gregory, Ph.D., ImmunoGen’s chief scientific officer. "ImmunoGen will be presenting nine abstracts at the conference with preclinical data demonstrating technology advances that will enable us to continue to drive innovation in ADC approaches."

ImmunoGen presentations at AACR (Free AACR Whitepaper) relate to:

Platform linker and payload innovations

Title: Comparison of site-specific and lysine-linked indolino-benzodiazepine antibody-drug conjugates (ADCs) – abstract # 75

While site-specific conjugation can lead to improved efficacy and tolerability, the advantages and disadvantages of site-specific conjugation should be carefully considered for every ADC candidate.
Title: Bystander activity and in vivo efficacy of a folate receptor α (FRα)-targeting antibody-drug conjugate with a novel peptide linker – abstract # 71

Folate receptor (FRα) is an antigen that is overexpressed on the cell surface of solid tumors including ovarian cancer. M9346A-NL-DM is a novel ADC, employing a new linker, with enhanced bystander activity and anti-tumor activity that can target tumors with heterogeneous expression of FRα.
Title: Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo – abstract # 2186

A new promising type of maytansinoid ADC provides a high degree of bystander killing, improved activity in tumor models in vivo, and has a differentiated mechanism of metabolite release.
Title: Antibody-drug conjugates (ADCs) of peptide-linked Indolino-Benzodiazepine (IGN) DNA-alkylator provides improved anti-tumor activity over that of a crosslinker – abstract # 53

Preclinical research shows that DNA-alkylating IGNs provide improved anti-tumor activity over that of a DNA-crosslinking ADC.
Preclinical research focused on novel targets

Title: Novel antibody-drug conjugates targeting ADAM9-expressing solid tumors demonstrate potent preclinical activity – abstract #37

ADAM9 is a promising cell surface target for antibody-drug conjugate development that is overexpressed in multiple solid tumor indications relative to corresponding normal tissues.
Title: Target validation, antibody discovery and preclinical data supporting ADAM9 as an antibody-drug conjugate therapeutic target for solid tumors – abstract #38

These data demonstrate that anti-ADAM9 ADCs exhibit antitumor activity against a broad panel of ADAM9-positive malignancies and cause durable remissions in preclinical models at doses expected to be clinically achievable. Anti-ADAM9 ADCs represent a promising therapeutic strategy to a wide range of ADAM9-expressing tumors.
Title: In vitro and in vivo activity of a novel c-Met-targeting antibody-drug conjugate using a DNA-alkylating, indolinobenzodiazepine payload – abstract #45

cMet dysregulation and/or overexpression are associated with tumor progression, metastasis and poor prognosis in numerous cancers. An anti-cMet antibody conjugated with the payload DGN549 exhibits compelling, c-Met targeted anti-cancer activity in vitro and in vivo, and represents a promising therapeutic strategy to deliver a potent cytotoxic agent to tumor cells bearing a wide range of c-Met expression.
Preclinical research focused on B-cell targets

Title: A novel CD19-targeting antibody-drug conjugate, huB4-DGN462, shows promising in vitro and in vivo activity in CD19-positive lymphoma models – abstract #2651

CD19 is a cell surface membrane protein expressed in most mature and immature B cell neoplasms, which make it a promising target for ADC therapy for B cell malignancies. A novel CD19-targeting ADC presents strong preclinical anti-lymphoma activity.
Title: Increased internalization and processing of the CD37-targeting antibody-drug conjugate, naratuximab emtansine (IMGN529), in the presence of rituximab leads to enhanced potency in diffuse large B-cell lymphoma models – abstract #1073

Data show enhanced activity of rituximab plus IMGN529 combination in DLBCL models, supporting the clinical development of this combination.
Additional information – including presentation schedule and full abstracts – can be found at www.aacr.org.

On March 1, 2017 Amgen (NASDAQ:AMGN) reported the New England Journal of Medicine published results from the Phase 3 TOWER study evaluating the efficacy of BLINCYTO (blinatumomab) versus standard of care (SOC) chemotherapy in high-risk adult patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), one of the most aggressive B-cell malignancies (Press release, Amgen, MAR 1, 2017, View Source [SID1234517917]). Results from the analysis showed that median overall survival (OS) was 7.7 months (95 percent CI: 5.6, 9.6) for BLINCYTO versus four months (95 percent CI: 2.9, 5.3) for SOC (hazard ratio [HR] for death=0.71; p=0.012).

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The TOWER study is the confirmatory study for the Phase 2 trial that supported the U.S. Food and Drug Administration’s (FDA) accelerated approval designation for BLINCYTO in 2014.

BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct. It is the first bispecific antibody construct from Amgen’s BiTE platform, which helps the body’s immune system target cancer cells and represents an entirely new area of oncology research. BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers.

"Historically, patients with relapsed or refractory ALL have a poor prognosis, with an overall survival of just four months on standard of care chemotherapy," said Max S. Topp, M.D., professor and head of Hematology, University Hospital of Wuerzburg, Germany. "Findings from this head-to-head study showed that BLINCYTO almost doubled the median overall survival from four to 7.7 months, offering these high-risk patients a much needed alternative to chemotherapy that is both innovative and effective."

The survival benefit for BLINCYTO was independent of allogeneic stem cell transplant (alloSCT), as the median OS, censored at the time of alloSCT, was 6.9 months for BLINCYTO versus 3.9 months for SOC. Improvement in OS was generally consistent regardless of age, prior salvage therapy or prior alloSCT. The magnitude of this benefit appeared greatest in earlier lines of salvage. Neutropenia and infection greater than or equal to Grade 3 appeared less frequently with BLINCYTO compared to SOC, while neurological events appeared at a similar rate between arms.

"Adults with Ph- relapsed or refractory B-cell precursor ALL are in critical need of new treatment options," said Hagop M. Kantarjian, M.D., professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston. "Results from the TOWER study reinforce the potential of this single agent bispecific T cell engager immunotherapy, which helped a higher percentage of patients achieve minimal residual disease response versus standard of care chemotherapy, highlighting the depth and quality of remissions achieved."

Evaluation of key secondary endpoints showed that remission rates were also higher for BLINCYTO versus SOC. In the BLINCYTO group, 34 percent of patients achieved complete remission versus 16 percent in the SOC group. Patients receiving BLINCYTO also had a higher rate of combined complete remission or complete remission with partial or incomplete hematologic recovery (44 percent versus 25 percent).

Among patients with complete remission or complete remission with partial or incomplete hematologic recovery, 76 percent in the BLINCYTO group versus 48 percent in the SOC group achieved minimal residual disease (MRD) negative status, a measure of eradication of residual disease at the molecular level. Also among these patients, the median duration of remission was 7.3 months in the BLINCYTO group versus 4.6 months in the SOC group. For the key secondary efficacy endpoint of event-free survival, six month estimates in the BLINCYTO and chemotherapy groups were 30.7 percent and 12.5 percent, and the HR was 0.55 (95 percent CI: 0.43, 0.71), favoring BLINCYTO.

"As the first study of an immunotherapy to demonstrate overall survival benefit in adult patients with Ph- relapsed or refractory B-cell precursor ALL, TOWER represents an important advance in the understanding of this aggressive, ultra-orphan disease," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "As demonstrated by the data published today in the New England Journal of Medicine, BLINCYTO has proven to improve overall survival, extend remission rates and reduce minimal residual disease in these high-risk patients who previously have had limited effective options."

Safety results among subjects who received BLINCYTO were comparable to those seen in the Phase 2 studies in adult patients with Ph- relapsed or refractory B-cell precursor ALL. For the most common adverse events (greater than or equal to 10 percent incidence rate) in the BLINCYTO arm, only three events (cough, pyrexia, cytokine release syndrome) occurred at an incidence rate that was at least 5 percent higher for BLINCYTO compared to SOC chemotherapy.

ALL is a rare and rapidly progressing cancer of the blood and bone marrow.1,2 Adult patients diagnosed with Ph- B-cell precursor ALL are often young, with a median age at diagnosis of 34-39.3,4 Currently, there is no broadly accepted standard treatment regimen for adult patients with relapsed or refractory ALL beyond chemotherapy.5 Adults with relapsed or refractory ALL typically have a very poor prognosis, with a median OS of three to five months.6

About the TOWER Study
The TOWER study was a Phase 3, randomized, open-label study investigating the efficacy of BLINCYTO versus SOC chemotherapy in 405 adult patients with Ph- relapsed or refractory B-cell precursor ALL. Patients were randomized in a 2:1 ratio to receive BLINCYTO (n=271) or treatment with investigator choice of one of four protocol-defined SOC chemotherapy regimens (n=134). The primary endpoint was OS. Key secondary endpoints included complete remission within 12 weeks, the combined endpoint of complete remission plus complete remission with partial or incomplete hematologic recovery and event-free survival. Other secondary endpoints included remission duration, MRD remission (<10–4), alloSCT rate and adverse event rates.

The TOWER study is the confirmatory trial for BLINCYTO. Click here to read about the trial on ClinicalTrials.gov.

About Adult ALL
In the United States (U.S.), the incidence of adult ALL is approximately 0.9 per 100,000 persons per year.7 The incidence of adult ALL in European countries is generally between 0.6 to 0.9 per 100,000 persons per year.7 In adult ALL, approximately 75 percent is B-cell precursor ALL, of which 75-80 percent is Ph- and roughly half will be refractory to treatment or experience relapse.7 In the U.S., the incidence of adult Ph- relapsed or refractory B-cell precursor ALL was approximately 650 patients in 2015 and in the European Union (EU), the estimated incidence is approximately 1,200 patients per year.7,8

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BLINCYTO was granted breakthrough therapy and priority review designations by the FDA, and is now approved in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

In November 2015, BLINCYTO was granted conditional marketing authorization in the EU for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

About BiTE Technology
Bispecific T cell engager (BiTE) antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers. For more information, visit www.biteantibodies.com.

BLINCYTO U.S. Product Safety Information

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications
BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI).
Neurological Toxicities: Approximately 64% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to onset of any neurological toxicity was 4 days. The most common (≥ 10%) manifestations of neurological toxicity were headache, tremor, dizziness, and altered state of consciousness. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 17% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The neurological toxicity profile varied by age group. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO experienced serious infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS): TLS, which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Adverse Reactions

The most common adverse reactions (≥ 20%) in the safety population studied in clinical trials were pyrexia (66%), headache (34%), nausea (27%), edema (26%), hypokalemia (26%), anemia (25%), febrile neutropenia (24%), neutropenia (22%), thrombocytopenia (20%), and abdominal pain (20%). The safety population included 225 patients weighing 45 kg or more and 57 patients weighing less than 45 kg. For some adverse reactions, there were differences in the incidence rates by age subgroup.
In patients weighing greater than or equal to 45 kg, serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia (9%), pyrexia (6%), sepsis (5%), pneumonia (5%), device-related infection (4%), neutropenia (3%), tremor (3%), overdose (3%), encephalopathy (3%), infection (2%), confusion (3%) and headache (2%).
In patients weighing less than 45 kg, serious adverse reactions were reported in 51% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia (12%), febrile neutropenia (9%), cytokine release syndrome (4%), convulsion (4%), device-related infection (4%), hypoxia (4%), sepsis (4%), and overdose (4%).
U.S. Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO at www.BLINCYTO.com.

Important EU Product Safety Information

This product is subject to additional monitoring in the EU and EEA. All suspected adverse reactions should be reported in accordance with the national reporting system.

The adverse reactions described in this section were identified in the pivotal clinical study (N=189).The most serious adverse reactions that may occur during blinatumomab treatment include: infections (31.7%), neurologic events (16.4%), neutropenia/febrile neutropenia (15.3%) cytokine release syndrome (0.5%), and tumor lysis syndrome (0.5%). The most common adverse reactions were: infusion-related reactions (67.2%), infections (63.0%), pyrexia (59.8%), headache (34.4%), febrile neutropenia (28%), peripheral edema (25.9%), nausea (24.3%), hypokalaemia (23.8%), constipation (20.6%), anaemia (20.1%), cough (18.5%), diarrhea (18.0%), tremor (17.5%), neutropenia (17.5%), abdominal pain (16.9%), insomnia (15.3%), fatigue (15.3%), and chills (15.3%).

Please refer to the Summary of Product Characteristics for full European prescribing information.