PRINCETON, N.J.--(Bristol-Myers Squibb Company (NYSE:BMY) today announced that new data on its approved and investigational oncology compounds will be featured in ten oral presentations at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago from June 1-5. The data further characterize the Company’s cancer immunotherapies, including YERVOY® (ipilimumab) in metastatic melanoma, anti-PD-1 (BMS-936558) and elotuzumab, and support the potential role of immuno-oncology in the treatment of a range of cancers.)--
New data on YERVOY, a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody for the treatment of metastatic melanoma, will be presented in 27 abstracts at the meeting. Safety and efficacy data for YERVOY in 830 U.S. patients with metastatic melanoma, including 3 year survival results, from the Company’s global expanded access program will be presented in an oral session on Saturday, June 2. Other important data include safety results in patients with a minimum of two-years of survival in the first-line 024 Phase 3 study in combination with DTIC, and data on YERVOY in combination with existing and investigational treatments for melanoma.
Clinical data on the investigational cancer immunotherapies anti-PD-1 and anti-PD-L1 (BMS-936559) in advanced non-small-cell lung cancer, metastatic melanoma and renal cell cancer will be featured in five oral presentations – four on Saturday, June 2 and one on Monday, June 4 – and in the ASCO press briefing on Friday, June 1.
“With the rapidly expanding knowledge of how to harness the immune system to fight cancer, we are at the tipping point of a new era of cancer treatment,” said Elliott Sigal, M.D., Ph.D., executive vice president, chief scientific officer and president, Research and Development, Bristol-Myers Squibb. “Immuno-oncology is a key area of focus for Bristol-Myers Squibb and we are committed to driving advances in this important field of research to help address significant unmet medical needs in a broad range of cancers.”
Additional Key Oncology Compound Data
Bristol-Myers Squibb and its partner, Abbott, will present updated Phase 2 results on the investigational cancer immunotherapy elotuzumab, which is in Phase 3 development for the treatment of multiple myeloma. Elotuzumab is a humanized monoclonal antibody specifically targeted against CS1, a cell-surface glycoprotein that is highly and uniformly expressed on multiple myeloma cells. On Monday, June 4, updated results evaluating the safety and efficacy of elotuzumab plus lenalidomide and low-dose dexamethasone in patients with relapsed multiple myeloma will be presented during an oral session. Phase 3 clinical trials for elotuzumab in previously untreated and relapsed multiple myeloma are actively recruiting patients.
Separately, the company and its partner, Otsuka Pharmaceutical Co., Ltd., will present three-year follow up data from the Phase 3 head-to-head DASISION trial, evaluating SPRYCEL® (dasatinib) vs. Gleevec®* (imatinib mesylate) in the treatment of patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic-phase. Long-term follow up data (6 years) from the Phase 3 study (-034) that evaluated the safety and efficacy of SPRYCEL in the treatment of Ph+ CML patients with resistance or intolerance to Gleevec will also be presented. Data from both studies will be discussed during oral sessions on Monday, June 4.
ERBITUX® (cetuximab) data in abstracts that span a wide range of investigational uses in solid tumors such as colorectal and head and neck will be presented. On Monday, June 4, additional analysis from the CRYSTAL study of ERBITUX in the first-line treatment of metastatic colorectal cancer (mCRC) will be presented. CRYSTAL served as the basis for the first-line mCRC supplement biologics application for ERBITUX. The Company expects the FDA to take action on the filing in the second half of this year. Bristol-Myers Squibb is developing ERBITUX in partnership with Eli Lilly and Company.
Advancing Disease State Understanding
In addition to research on its oncology compounds, the Company is committed to studies that advance understanding of unmet medical needs and help to inform effective disease management. At ASCO this year, the Company will present data from the BRIDGE study, a global study of more than 18,000 patients describing the management and outcomes of hepatocellular carcinoma (HCC), which characterizes treatment patterns and survival results across regions.
In addition to HCC, Bristol-Myers Squibb is exploring observational studies in other tumor types, including the IMAGE study in metastatic melanoma and the SIMPLICITY trial in CML. IMAGE is a multi-national, prospective, observational study of patients diagnosed with unresectable or metastatic melanoma and followed for a minimum of three years. SIMPLICITY (Studying Interventions for Managing Patients with Chronic Myeloid Leukemia In ChronIc Phase: The 5-Year Prospective Cohort Study, CA180-330) is a multi-regional observational research study of approximately 1,400 patients designed to better understand the use of SPRYCEL and other tyrosine kinase inhibitors, including imatinib and nilotinib, in the first-line treatment of CML in the real-world setting.
YERVOY® (ipilimumab) INDICATIONS & IMPORTANT SAFETY INFORMATION
YERVOY is indicated for the treatment of unresectable or metastatic melanoma.
Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. 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) 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.
Recommended Dose Modifications
Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day.
Permanently discontinue YERVOY for any of the following:
- Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day
- Failure to complete full treatment course within 16 weeks from administration of first dose
Severe or life-threatening adverse reactions, including any of the
- Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation
- AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin >3 × the ULN
- Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations
- Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis
- Severe immune-mediated reactions involving any organ system
- Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy
- In the pivotal Phase 3 study in YERVOY-treated patients, 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%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients
- Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis
- Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids
- Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms
- Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients
- Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent)
- In the pivotal Phase 3 study in YERVOY-treated patients, 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%
- 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2)
- Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution
- Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids
- Withhold YERVOY in patients with Grade 2 hepatotoxicity
In the pivotal Phase 3 study in YERVOY-treated patients, severe,
life-threatening or fatal immune-mediated dermatitis (e.g.,
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%)
- 1 (0.2%) patient died as a result of toxic epidermal necrolysis
- 1 additional patient required hospitalization for severe dermatitis
- There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis
- Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated
- Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms
- Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week
- In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported
- Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported
- Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes
- Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities)
In the pivotal Phase 3 study in YERVOY- treated patients, 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
- Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome
- Median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY
Monitor patients for clinical signs and symptoms of hypophysitis,
adrenal insufficiency (including adrenal crisis), and hyper- or
- Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated
- Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland
- Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. Long-term hormone replacement therapy may be necessary
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:
- In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia
- Across the clinical development program for YERVOY, immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis
- Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions
- Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy
Pregnancy & Nursing:
- YERVOY is classified as pregnancy category C. There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus
- Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus
- It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY
Common Adverse Reactions:
- 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%)
Please see full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions available at www.bms.com.
YERVOY is a registered trademark of Bristol-Myers Squibb Company.
SPRYCEL® (dasatinib) INDICATIONS & IMPORTANT SAFETY INFORMATION
SPRYCEL® (dasatinib) is indicated for the treatment of adults with:
- Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome
- Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
- Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy
IMPORTANT SAFETY INFORMATION
Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade
3/4) thrombocytopenia, neutropenia, and anemia, occurring more
frequently in advanced phase CML or Ph+ ALL than in chronic phase CML.
Myelosuppression was reported in patients with normal baseline
laboratory values as well as in patients with pre-existing laboratory
- Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as clinically indicated
- Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction, or discontinuation
- Hematopoietic growth factor has been used in patients with resistant myelosuppression
Bleeding Related Events:
SPRYCEL caused platelet dysfunction in vitro and
thrombocytopenia in humans
- In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients. Severe gastrointestinal (GI) hemorrhage, including fatalities, occurred in 4% of patients receiving SPRYCEL, which generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients
Most bleeding events were associated with severe thrombocytopenia
- Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants
SPRYCEL is associated with fluid retention
- In clinical trials fluid retention was severe in up to 10% of patients. Ascites (<1%), generalized edema (<1%), and severe pulmonary edema (1%) were also reported
- Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray
- Severe pleural effusion may require thoracentesis and oxygen therapy
- Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids
- In vitro data suggest that SPRYCEL (dasatinib) has the potential to prolong cardiac ventricular repolarization (QT interval)
- In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms
- In clinical trials of CML patients treated with SPRYCEL (N=2440), 15 patients (<1%) had QTc prolongation as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms
Administer SPRYCEL with caution to patients who have or may develop
prolongation of QTc, including patients with hypokalemia,
hypomagnesemia, or congenital long QT syndrome and patients taking
anti-arrhythmic drugs, other medicinal products that lead to QT
prolongation, and cumulative high-dose anthracycline therapy
- Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration
Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction:
Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.
Pulmonary Arterial Hypertension (PAH)
SPRYCEL may increase the risk of developing PAH, which may occur anytime after initiation, including after more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed SPRYCEL should be permanently discontinued.
Use in Pregnancy:
SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant when taking SPRYCEL.
It is unknown whether SPRYCEL is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue SPRYCEL.
SPRYCEL is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4
Drugs that may increase SPRYCEL plasma concentrations are:
CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs
that inhibit CYP3A4 should be avoided. If administration of a
potent CYP3A4 inhibitor cannot be avoided, close monitoring for
toxicity and a SPRYCEL dose reduction or temporary discontinuation
should be considered
- Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered
- Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided
- CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered
Drugs that may decrease SPRYCEL plasma concentrations are:
CYP3A4 inducers: If SPRYCEL must be administered with a
CYP3A4 inducer, a dose increase in SPRYCEL should be considered.
- Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital), should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity
- St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided
- Antacids. Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL
- H2 antagonists/proton pump inhibitors, such as famotidine and omeprazole. Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended
- CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered.
Drugs that may have their plasma concentration altered by SPRYCEL are:
- CYP3A4 substrates such as simvastatin. CYP3A4 substrates with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL
The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical study (median duration of therapy was 18 months) and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL in clinical studies (minimum of 2 years follow-up).
The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML study, SPRYCEL was discontinued for adverse reactions in 6% of patients. In patients resistant or intolerant to prior imatinib therapy, SPRYCEL was discontinued for adverse reactions in 15% patients in chronic phase, 16% in accelerated phase, 15% in myeloid blast phase, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL.
In newly diagnosed chronic phase CML patients:
- The most frequently reported serious adverse reactions included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%)
- The most frequently reported adverse reactions (reported in ≥10% of patients) included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash
- Grade 3/4 laboratory abnormalities included neutropenia (22%), thrombocytopenia (19%), anemia (11%), hypophosphatemia (5%), hypocalcemia (3%), and elevated bilirubin (1%)
In patients resistant or intolerant to prior imatinib therapy:
- The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%)
- The most frequently reported adverse reactions (reported in ≥20% of patients) included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage
- Grade 3/4 laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily included neutropenia (36%), thrombocytopenia (23%), anemia (13%), hypophosphatemia (10%), and hypokalemia (2%)
Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4
hypocalcemia, hypokalemia and hypophosphatemia were reported in
patients with all phases of CML, but were reported with an increased
frequency in patients with myeloid or lymphoid blast phase CML
- Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption
- Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation
Please see the full Prescribing Information www.bms.com.
SPRYCEL is a registered trademark of Bristol-Myers Squibb Company.
ERBITUX® (cetuximab) INDICATIONS & IMPORTANT SAFETY INFORMATION Including BOXED WARNING
Head and Neck Cancer
- ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck
- ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck.
- ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed
- ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens
- ERBITUX, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma
- Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations
IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS
Grade 3/4 infusion reactions occurred in approximately 3% of
patients receiving ERBITUX® (cetuximab) in
clinical trials, with fatal outcome reported in less than 1 in 1000
- Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest
- Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions
Most (90%) of the severe infusion reactions were associated with
the first infusion of ERBITUX despite premedication with antihistamines
- Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions
- Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions
Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of
208 patients with squamous cell carcinoma of the head and neck treated
with radiation therapy and ERBITUX, as compared to none of 212
patients treated with radiation therapy alone. In three patients with
prior history of coronary artery disease, death occurred 27, 32, and
43 days after the last dose of ERBITUX. One patient with no prior
history of coronary artery disease died one day after the last dose of
ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7
(3%) of the 219 patients with squamous cell carcinoma of the head and
neck treated with platinum-based therapy with 5-fluorouracil (FU) and
European Union (EU)-approved cetuximab as compared to 4 (2%) of the
215 patients treated with chemotherapy alone. Five of these 7 patients
in the chemotherapy plus cetuximab arm received concomitant cisplatin
and 2 patients received concomitant carboplatin. All 4 patients in the
chemotherapy-alone arm received cisplatin
- Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks
- Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy
- Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 5, as well as other studies, in colorectal cancer and head and neck cancer.. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD
In clinical studies of ERBITUX, dermatologic toxicities, including
acneiform rash, skin drying and fissuring, paronychial inflammation,
infectious sequelae (eg, S. aureus sepsis, abscess formation,
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative
keratitis with decreased visual acuity, cheilitis), and
hypertrichosis, occurred in patients receiving ERBITUX therapy.
Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX
in Studies 1, 3, 4, and 5. Severe acneiform rash occurred in 1-17% of
- Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days
- Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae
- Sun exposure may exacerbate these effects
ERBITUX Plus Radiation Therapy and Cisplatin
The safety of ERBITUX in combination with radiation therapy and
cisplatin has not been established
- Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck
- Two of 21 patients died, one as a result of pneumonia and one of an unknown cause
- Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events
Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in
Study 4 and two other clinical trials in colorectal cancer and head
and neck cancer, respectively and was severe (NCI CTC grades 3 & 4) in
6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin
and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs.
6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin
and 5-FU alone. In contrast, the incidence of hypomagnesemia was
similar for those who received cetuximab, carboplatin, and 5-FU
compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced
Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.
The onset of hypomagnesemia and accompanying electrolyte abnormalities
occurred days to months after initiation of ERBITUX therapy.
- Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy
- Replete electrolytes as necessary
Late Radiation Toxicities
The overall incidence of late radiation toxicities (any grade) was
higher with ERBITUX in combination with radiation therapy compared
with radiation therapy alone. The following sites were affected:
salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue
(49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin
(42%/33%) in the ERBITUX and radiation versus radiation alone arms,
- The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms
Pregnancy and Nursing
- In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus
- It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX
- The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus
- The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection
- The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)
- The most frequent adverse events for EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) vs CT alone (n=215) (incidence ≥ 40%) were acneiform rash (70%/2%), nausea (54%/47%), and infection (44%/27%). The most common grade 3/4 adverse events for cetuximab in combination with CT (≥10%) vs CT alone included: infection (11%/8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX
- The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)
- The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥ 10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)
Please see Important Safety Information and U.S. Complete Product Information including Boxed WARNINGS about allergic reactions and heart attack.
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This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the investigational compounds described in this release will receive regulatory approvals or, if approved, that they will become commercially successful products. There is also no guarantee that the investigational uses of currently-approved products described in this release will lead to additional approved indications for such products. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2011, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
* Gleevec® is a registered trademark of Novartis AG