On June 3, 2016 Celgene Corporation (NASDAQ:CELG) reported data from a meta-analysis of overall survival in multiple myeloma (MM) patients receiving investigational maintenance treatment with REVLIMID (lenalidomide) capsules following high-dose melphalan and autologous stem cell transplant (ASCT) were presented during the 52nd ASCO (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois (Press release, Celgene, JUN 3, 2016, View Source [SID:1234512990]). The analysis, based on data from studies conducted by the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B) with support from the National Cancer Institute, Intergroupe Francophone du Myélome (IFM) and the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA), was presented by Dr. Philip McCarthy of Roswell Park Cancer Institute and lead investigator of the CALGB (Alliance) 100104 study. The findings demonstrated significantly prolonged overall survival (OS) compared to the control arm of placebo or no maintenance.

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A meta-analysis of patient-level data from 1,209 patients in three randomized, controlled phase III studies (CALGB (Alliance) 100104, IFM 2005-02, GIMEMA-RVMM-PI-209) was conducted comparing lenalidomide maintenance (n=605) to either placebo or no maintenance (n=604). Each of these studies had individually shown that investigational lenalidomide maintenance treatment following autologous stem cell transplant reduced the risk of disease progression or death (PFS), the primary endpoint, by approximately 50% (McCarthy NEJM 2012; Attal NEJM 2012; Palumbo NEJM 2014).

Results of this analysis showed that at a median follow-up of 80 months, the median overall survival had not been reached for patients receiving lenalidomide maintenance compared with 86 months for the control arm [95% CI: HR 0.74 (0.62-0.89); p=0.001], representing an estimated 2.5-year benefit in favor of lenalidomide maintenance. Hazard ratios for each of the three studies favored maintenance treatment with lenalidomide. While not individually powered to evaluate this endpoint, each study contributed to the pooled OS benefit observed in the meta-analysis.

The risk of developing a hematologic second primary malignancy (SPM) in the lenalidomide arm in the pooled analysis had a hazard ratio of 2.03 (95% CI: 1.14-3.61). The risk of developing a solid tumor SPM in the lenalidomide arm had a hazard ratio of 1.71 (95% CI: 1.04-2.79). Hematologic SPMs observed in the studies totaled 15 for the lenalidomide arm and eight for the control arm in CALGB (Alliance) 100104, 21 for lenalidomide and nine for control in IFM 2005-02, and none for either arm in the GIMEMA-RVMM-PI-209 study. Solid tumor SPMs observed in the studies totaled 17 for the lenalidomide arm and 10 for the control arm in CALGB (Alliance) 100104, 21 for lenalidomide and 13 for control in IFM 2005-02, and five for lenalidomide and two for the control arm in the GIMEMA-RVMM-PI-209 study.

"The results of this meta-analysis reinforce the long-term benefit that lenalidomide maintenance therapy has demonstrated in myeloma patients who receive an autologous stem cell transplant within the large, phase III studies individually," said Dr. Antonio Palumbo of the University of Torino and the lead investigator of the GIMEMA study.

"Lenalidomide has consistently demonstrated improvement in progression-free survival in this setting," said Prof. Michel Attal of the University of Toulouse and the lead investigator of the IFM study. "The improved overall survival shown by this meta-analysis further supports the positive benefit-risk ratio observed in the individual phase III studies."

REVLIMID is not indicated for maintenance treatment following ASCT.

About the studies

CALGB (Alliance) 100104

The study is a phase III, multicenter, randomized, double-blind, placebo-controlled trial in the first-line setting of MM that was conducted at 47 centers in the U.S. The study was sponsored and conducted by the CALGB, which is now part of the Alliance for Clinical Trials in Oncology, a U.S. national oncology cooperative group. The primary objective was to determine if maintenance treatment with lenalidomide would prolong time to tumor progression. Subjects were registered after completion of induction therapy and before ASCT. The starting dosage of lenalidomide was 10 mg/day (to be increased to 15 mg/day after three months for subjects who tolerated maintenance therapy).

IFM 2005-02

This study is a phase III, multicenter, randomized, double-blind, placebo-controlled trial that was conducted in the first-line setting of MM by the IFM, an independent French myeloma cooperative group, at 78 centers in France, Belgium and Switzerland. The primary objective of the IFM study was to evaluate the efficacy of maintenance treatment with lenalidomide following ASCT in extending post-transplant PFS, the primary endpoint. Subjects underwent induction chemotherapy and ASCT before inclusion in the study.

Patients were randomly assigned in a 1:1 ratio to receive either consolidation treatment with lenalidomide (at a dose of 25 mg/day, on days 1 to 21 of each 28-day cycle, for two cycles), followed by maintenance therapy with lenalidomide at a starting dose of 10 mg/day (to be increased up to 15 mg/day after three months in absence of dose-limiting toxicity), or the same consolidation treatment with lenalidomide, followed by maintenance therapy with placebo.

GIMEMA-RVMM-PI-209

This study is a phase III, multicenter, open-label, 2 x 2 factorial, controlled study conducted by Fondazione Neoplasie Sangue Onlus (FO.NE.SA Onlus), an independent Italian cooperative group, in the first-line setting of transplant-eligible newly diagnosed MM (NDMM). The study was conducted at 62 centers in Italy and Israel. The primary objective was to determine (after induction treatment with a standard Rd regimen) the efficacy and safety of treatment with melphalan, prednisone, REVLIMID versus high-dose melphalan (200 mg/m2) followed by ASCT in NDMM subjects in extending PFS, the primary endpoint. As a secondary objective, the efficacy and safety of lenalidomide as maintenance treatment were evaluated.

About REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program (formerly known as the "RevAssist" program).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism
REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of invasive SPM notably AML and MDS have been observed. Monitor patients for the development of SPMs. Take into account both the potential benefit of REVLIMID and risk of SPMs when considering treatment

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose; risk-benefit of treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation of TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment ( > 4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or RD18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash, (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
After at least one prior therapy the most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin

NURSING MOTHERS

Discontinue drug or nursing taking into consideration the importance of the drug to the mother

PEDIATRIC USE

Safety and effectiveness in patients below the age of 18 have not been established

RENAL IMPAIRMENT

REVLIMID is primarily excreted unchanged by the kidneys; adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis

Please see accompanying full Prescribing Information, including Boxed WARNINGS.

On June 3, 2016 Amgen (NASDAQ:AMGN) reported the launch of KYPROLIS CENTRAL, an online media resource about the impact of living with relapsed or refractory multiple myeloma (Press release, Amgen, JUN 3, 2016, View Source;p=RssLanding&cat=news&id=2175038 [SID:1234512985]). Intended to drive awareness of a rare blood cancer that is increasingly becoming more prevalent in the United States (U.S.), KYPROLIS CENTRAL provides real-life stories from relapsed multiple myeloma patients, as well as educational materials and third party resources.1

"In my opinion, one of the most difficult parts of living with multiple myeloma is the uncertainty. Relapse is always in the back of my mind," said Michele A., a relapsed multiple myeloma patient from Ludlow, Mass. "I’ve found that talking to others helps me cope with this uncertainty, and I hope that sharing my story publicly will generate more awareness and help others navigating relapsed multiple myeloma."

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Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.2 It is a disease that, in 2012, accounted for approximately one percent of all cancers globally.3,4 In the U.S., there were more than 95,000 people living with, or in remission from, multiple myeloma in 2013.1

Each of the patients featured on KYPROLIS CENTRAL has been treated with Kyprolis (carfilzomib) following a relapse. Kyprolis is a second-generation proteasome inhibitor indicated in the U.S. 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.5,6 Kyprolis is also indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.6

Resources available on KYPROLIS CENTRAL are intended to share the experiences of patients living with relapsed multiple myeloma and educate about this complex disease. With each relapse, disease burden worsens, which can have a great impact on patients.7 The journey back to remission requires teamwork and patients need to know they are not alone.

About Kyprolis (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.8 Kyprolis has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.8 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.8,9

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, Israel, Kuwait, Mexico, Thailand, Colombia, Korea, Canada, Switzerland, Russia, and the European Union. Additional regulatory applications for Kyprolis are underway and have been submitted to health authorities worldwide.

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

Patient Support Program
Onyx Pharmaceuticals 360 is a patient support program that provides patients prescribed Kyprolis with an Onyx Oncology Nurse Ambassador (ONA). The ONA is a single point of contact who takes the time to help Kyprolis patients and their caregivers identify supports and resources most important to them based on their particular needs, and helps facilitate those connections allowing patients and their caregivers time to focus on treatment. Whether it’s helping patients with insurance verification for Kyprolis, with connections to local independent third-party organizations that may provide transportation and lodging assistance, helping connect to programs that may be able to help to make treatment more affordable, or helping connect with other patients through a network of independent third-party organizations, program ONAs are available. Connections with independent third-party organizations are made as a courtesy and Amgen has no influence over program requirements or eligibility/acceptance criteria. For more information, please visit www.kyprolis.com/assistance-during-treatment.

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection

INDICATIONS

KYPROLIS (carfilzomib) is indicated 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.
KYPROLIS is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
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.
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 events 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 events 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 June 3, 2016 Bayer and Orion Corporation reported the expansion of the global clinical development program for the investigational androgen receptor (AR) antagonist BAY-1841788 (ODM-201) in the area of prostate cancer (Press release, Bayer, JUN 3, 2016, View Source;sessionID=1464982658 [SID:1234512984]). A new Phase III study ARASENS will evaluate the compound in combination with standard androgen deprivation therapy (ADT) and the chemotherapy docetaxel in men with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), who are starting first line hormone therapy. BAY-1841788 (ODM-201) is an investigational oral AR-antagonist that has a unique chemical structure designed to block the growth of cancer cells through binding to the AR with high affinity and inhibiting the receptor function. The compound is currently in Phase III development ARAMIS study for high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). The new trial ARASENS is expected to start the enrolment of patients towards the end of 2016.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"Although the treatment options for patients with advanced prostate cancer who are castration-resistant have evolved considerably in recent years, there were only few advances in the earlier, hormone-sensitive stage of metastatic disease. Novel treatment approaches are urgently needed for patients to delay the progress of the cancer and improve survival," said Dr. Joerg Moeller, member of the Executive Committee of Bayer AG’s Pharmaceutical Division and Head of Development. "Bayer’s commitment to prostate cancer research runs deep, and the initiation of ARASENS is the latest in a long line of studies designed to evaluate treatment options for patients with advanced disease."

Bayer and Orion have recently expanded the 2014 agreement to include the joint development of BAY-1841788 (ODM-201) for mHSPC. Under that agreement, Bayer will commercialize the product globally; Orion has the option to co-promote BAY-1841788 in Europe, and is responsible for the manufacturing of the product.

"We believe that the profile of ODM-201 makes it an excellent treatment candidate for patients with metastatic hormone-sensitive prostate cancer. This is another example of how Orion’s oncology research is aiming to contribute to the benefit of patients. We are also happy to see Bayer’s continuous commitment to ODM-201", said Dr. Reijo Salonen, Senior Vice President of R&D at Orion.

About ARASENS
ARASENS (A Randomized, double-blind, placebo-controlled Phase III study of ODM 201 versus placebo in addition to standard Androgen deprivation therapy and docetaxel in patients with metastatic castration SENSitive prostate cancer) is planned to be initiated towards the end of 2016. Approximately 1,300 patients will be randomized (1:1 ratio) to receive either BAY-1841788 or placebo in combination with an ADT of investigator’s choice (LHRH agonist/antagonists or orchiectomy), started ≤12 weeks before randomization. Six cycles of docetaxel will be administered after randomization. The primary endpoint of the study is overall survival, and secondary endpoints include time to castration-resistant prostate cancer (time to CRPC), time to initiation of subsequent antineoplastic therapy, symptomatic skeletal event free survival (SSE-FS), time to first symptomatic skeletal event (time to SSE), time to initiation of opioid use, time to pain progression, time to worsening of physical symptoms of disease and safety.

ARASENS adds to the ongoing clinical development program for BAY-1841788, which includes ARAMIS (NCT02200614), a randomized, Phase III, multicenter, double-blind, placebo-controlled trial evaluating patients with non-metastatic CRPC who are at high risk for developing metastatic disease. ARAMIS is currently enrolling patients.
 
About Metastatic Hormone-Sensitive Prostate Cancer
Prostate cancer (PC) is the second most common form of cancer worldwide and the fifth leading cause of cancer-related death in men. More than 1.1 million men worldwide were diagnosed with the disease in 2012.

At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. Upon relapse when the disease will metastasize or spread, androgen deprivation therapy (ADT) is the cornerstone of treatment for this hormone-sensitive disease. Approximately five percent of men will already suffer from prostate cancer with distant metastases when first diagnosed. Men with newly diagnosed metastatic hormone-sensitive prostate cancer (HSPC) will start their treatment with hormone therapy, such as ADT or a combination of the chemotherapy docetaxel and ADT. Despite this first line treatment, most men with metastatic HSPC will eventually progress to castration-resistant prostate cancer (CRPC), which can impact survival and quality of life.

About BAY-1841788 (ODM-201)
BAY-1841788 (ODM-201) is an investigational oral androgen receptor (AR) antagonist that has a unique chemical structure designed to block the growth of cancer cells through binding to the AR with high affinity and inhibiting the receptor function. In preclinical studies, BAY-1841788 and its main circulating metabolite are active also in known AR mutants (ex W742L, F877L), and have been found to have negligible blood-brain barrier penetration.

BAY-1841788 (ODM-201) is not approved by the U.S. Food and Drug Administration, the European Medicines Agency or any other health authority.

On June 3, 2016 CellAct Pharma, a developer of innovative treatments for cancer, reported that population pharmacokinetic (PK) data from a phase 2 study of CAP7.1 supports efficacy findings in biliary tract cancer patients. CAP7.1 is a newly designed prodrug of the well-established anticancer agent etoposide, converted by carboxylesterases into etoposide in selected tissues (Press release, CellAct Pharma, JUN 3, 2016, View Source [SID:1234512981]). Analysis of the population PK indicated higher blood concentrations of etoposide resulted in the majority of patients maintaining an increase in tumor size below 20%. Data were published in conjunction with the 52nd Annual Meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract e15602).

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"Population pharmacokinetics is an important consideration in the drug development process as it helps to explain the variable effects of certain inter patient characteristics, such as age, body weight and co-medication, can have on a drug’s efficacy and safety. The data presented at ASCO (Free ASCO Whitepaper) will help in determining a standard dosing regimen for CAP7.1," explained Nalân Utku, MD, PhD, MDRA, Chief Executive Officer of CellAct Pharma. "These population PK data provide additional support to the results from our Phase 2 with CAP7.1, where encouragingly, planned interim analysis showed that more than half of therapy refractory, advanced stage biliary tract cancer patients met the primary objective of disease control, as presented at the ASCO (Free ASCO Whitepaper) GI Meeting in San Francisco."

Study Details

Data for the population PK model was analyzed from a total of 434 observations taken from 39 patients from Phase 1 and 2 studies. Using PK modeling software, etoposide AUC0-24h, cmax and cmin for each biliary cancer patient were simulated and compared with the individual changes in total target lesion (TTL) size. A higher AUC0-24h was found to be associated with a lower increase in TTL size (R2=0.172). Out of all patients for which PK information was available, 50% maintained a TTL size increase below 20%. This compared to 80% of patients with an 24hAUC > 120 h ug/mL who maintained a TTL size increase below 20%. Similarly, a higher cmax (R2=0.177) or cmin (R2=0.11) were associated with a larger effect on TTL size.

On June 3, 2016 Mylan N.V. (NASDAQ, TASE: MYL) and Biocon Ltd. (BSE code: 532523, NSE: BIOCON) reported the presentation of data from the HERITAGE study at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, June 3-7 (Press release, Mylan, JUN 3, 2016, View Source [SID:1234512980]). The study confirmed the efficacy, safety and immunogenicity of MYL-1401O, the proposed biosimilar trastuzumab co-developed by Biocon and Mylan, in comparison to branded trastuzumab.

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"As one of the first companies in the industry to successfully complete a confirmatory efficacy and safety study comparing a proposed biosimilar to a branded cancer drug, this is a significant milestone for Mylan’s biosimilar program," Mylan President Rajiv Malik said. "There is an urgent, unmet need for more affordable versions of biologic products and through our collaboration with Biocon we are well-positioned to be at the forefront to help deliver these complex products to patients around the world. We’re pleased that ASCO (Free ASCO Whitepaper) has recognized the importance of biosimilars in advancing cancer care and the significant role they will play in providing patients greater access to affordable treatment."

Kiran Mazumdar Shaw, Chairperson and Managing Director, Biocon, added: "The positive outcomes of the global Phase 3 clinical study with our proposed biosimilar trastuzumab for HER2-positive breast cancer patients are a significant milestone in our joint biosimilars development program with Mylan. The trial will enable regulatory filings of our product in the developed markets. Biocon remains committed to develop affordable biologics and these study results will help us in enhancing access for cancer patients, caregivers and healthcare systems across the globe."

Worldwide, nearly 2 million women are diagnosed with breast cancer each year, making it the second most common cancer in the world. HER2-positive metastatic breast cancer is an aggressive form of breast cancer that tests positive for the human epidermal growth factor receptor 2 (HER2), which promotes cancer cell growth. Approximately 20% to 30% of primary breast cancers are HER2-positive.

Trastuzumab is indicated for the treatment of HER2-positive metastatic breast cancer patients. It is also indicated for adjuvant treatment of HER2 overexpressing breast cancer and metastatic gastric cancer. It is a targeted therapy that interferes with the HER2 protein and impedes cancer cell growth.

"The HERITAGE study successfully met the predefined endpoints of response equivalency. We are proud of this international collaboration which puts us one step closer to approval of this proposed biosimilar. The response rates at 24 weeks were 69.6% with MYL-1401O combined with taxane chemotherapy versus 64% with branded trastuzumab combined with the same chemotherapy agent. The ratio of overall response and difference in overall response fell within a narrow, pre-defined equivalence margin suggesting equal efficacy of both products. Safety was comparable between treatment groups. The rates of serious adverse events were 38% with MYL-1401O and 36% with branded trastuzumab, and there was no difference in cardiac safety," commented lead study author Dr. Hope S. Rugo, professor of Medicine at the University of California, San Francisco.

Details of the sessions as on the ASCO (Free ASCO Whitepaper) website are as follows:
"Abstract 583: A pharmacokinetics (PK) bioequivalence trial of proposed trastuzumab biosimilar Myl-1401O (A) vs EU-Herceptin (B) and US-Herceptin ©"
June 5, 8-11 a.m. CDT (Poster Session)
Poster #71
Presenter: Cornelius F. Waller, MD, University of Freiburg Medical Center
Location: Hall A
Link to abstract on the ASCO (Free ASCO Whitepaper) website: View Source

"Abstract LBA503: HERITAGE: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin"
June 6, 2:15-2:27 p.m. CDT (Oral Abstract Session)
Presenter: Hope S. Rugo, MD, University of California, San Francisco
Location: Hall D1
Link to abstract on the ASCO (Free ASCO Whitepaper) website: View Source
The abstract for the HERITAGE study has also been selected for the Best of ASCO (Free ASCO Whitepaper) program this summer which will include several meetings across the globe.
Full session details and abstracts for the 2016 Annual Meeting can be found on the ASCO (Free ASCO Whitepaper) website at am.asco.org.

About the HERITAGE Study
HERITAGE is a double-blind, randomized clinical trial designed to evaluate comparative efficacy and safety of the proposed trastuzumab biosimilar, MYL-1401O, versus branded trastuzumab. Eligible patients had centrally confirmed, measurable HER2-positive metastatic breast cancer without prior chemotherapy or trastuzumab for metastatic disease. Patients were randomized to receive either MYL-1401O or branded trastuzumab with docetaxel or paclitaxel for a minimum of eight cycles. Trastuzumab was continued until progression. The primary endpoint is overall response at week 24 by blinded central evaluation using RECIST 1.1. Secondary endpoints include progression free survival, overall survival, and safety. A sample size of 456 patients was calculated to demonstrate equivalence in overall response at week 24 for MYL-1401O versus branded trastuzumab, defined as a 90% confidence interval for the ratio of best overall response within the equivalence margin (0.81, 1.24).

About Biosimilars
A biosimilar medicine is a biological medicine that is developed to be similar to an existing biological medicine and has demonstrated no clinically meaningful differences in safety, purity, and potency compared to that of the reference biologic. A biosimilar product and its reference biologic product are expected to have the same safety and efficacy profile and are generally used to treat the same conditions. Biosimilars may offer a less-costly alternative to existing biological medicinal products that have lost their exclusivity rights.