Overall Survival Analysis From KYPROLIS® (carfilzomib) Phase 3 Endeavor Trial Published In The Lancet Oncology

THOUSAND OAKS, Calif., Aug. 23, 2017 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced that results from an overall survival (OS) analysis of the Phase 3 head-to-head ENDEAVOR trial were published online first in The Lancet Oncology. Data showed that KYPROLIS(®) (carfilzomib) administered at 56 mg/m(2) twice weekly and dexamethasone (Kd56) reduced the risk of death by 21 percent over Velcade(®) (bortezomib) and dexamethasone (Vd), resulting in a 7.6 month OS benefit (median OS 47.6 months for Kd56 versus 40.0 for Vd, HR=0.79; p=0.01). The OS benefit was consistent regardless of prior Velcade therapy (HR=0.75 for no prior Velcade; HR=0.84 for prior Velcade). This Kd56 regimen is already approved in the U.S., European Union and other countries based on the primary analysis of progression-free survival (PFS) in the ENDEAVOR study.

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"These results showed KYPROLIS and dexamethasone significantly reduced the risk of death compared to Velcade and dexamethasone in patients with relapsed or refractory multiple myeloma," said study co-author and investigator Meletios A. Dimopoulos, M.D., professor of Clinical Therapeutics at the National and Kapodistrian University of Athens, School of Medicine. "These results support the use of KYPROLIS and dexamethasone as a standard of care for multiple myeloma patients at first relapse."

"In recent years, few clinical trials have demonstrated overall survival benefits in patients with relapsed or refractory multiple myeloma," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "In ENDEAVOR, the only head-to-head trial comparing proteasome inhibitors, KYPROLIS showed a statistically significant overall survival benefit of 7.6 months over Velcade. These results published today in The Lancet Oncology support KYPROLIS as a superior proteasome inhibitor in relapsed multiple myeloma patients. We've shared these data with regulatory agencies in the U.S. and Europe to support a potential label update."

Adverse events observed in this updated analysis were consistent with those previously reported for ENDEAVOR. Notably, rates of grade 2 or higher peripheral neuropathy, a frequent dose-limiting toxicity of Velcade, were five-times lower in patients receiving Kd56 versus patients receiving Vd (7 percent versus 35 percent, respectively). 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.

As previously published in The Lancet Oncology, patients treated with Kd56 also achieved PFS of 18.7 months compared to 9.4 months in those receiving Vd, meeting the primary endpoint of the study (HR=0.53; 95 percent CI: 0.44 - 0.65; p<0.0001).

Since its approval in 2012, KYPROLIS has been prescribed to over 50,000 patients worldwide. The KYPROLIS clinical program continues to focus on providing solutions for physicians and patients in treating this frequently relapsing and difficult-to-treat cancer. KYPROLIS is available for patients whose myeloma has relapsed or become resistant to another treatment and continues to be studied in a range of combinations and patient populations.

About ENDEAVOR
The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated Kd56 versus Vd in patients whose multiple myeloma has relapsed after at least one, but not more than three, prior therapeutic regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The primary analysis was published in The Lancet Oncology and is described in the Prescribing Information.

Patients received treatment until progression with KYPROLIS as a 30-minute infusion on days 1, 2, 8, 9, 15 and 16 of 28 day treatment cycles, along with low-dose dexamethasone (20 mg). For Cycle 1 only, KYPROLIS was administered at 20 mg/m(2) on days 1 and 2, and if tolerated was escalated to 56 mg/m(2) from day 8 Cycle 1 onwards. Patients who received bortezomib (1.3 mg/m(2)) with low-dose dexamethasone (20 mg) were treated with bortezomib administered subcutaneously or intravenously at the discretion of the investigator and in accordance with regional regulatory approval of bortezomib. More than 75 percent of the patients in the control arm received bortezomib subcutaneously. This study was conducted at 235 sites worldwide.

For information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT01568866 or the News Release section of Amgen.com.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.(1) It is a rare and very aggressive disease that accounts for approximately one percent of all cancers.(2,3) In the U.S., there are nearly 95,000 people living with, or in remission from, multiple myeloma.(4) Approximately 30,330 Americans are diagnosed with multiple myeloma each year and 12,650 patient deaths are reported on an annual basis.(4)

About KYPROLIS(®) (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.(5) KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.(5) 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.(5,6)

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, Oman and the European Union. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

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.

Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant?ineligible Patients

    --  In a clinical trial of transplant?ineligible patients with newly
        diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone
        (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence
        of serious and fatal adverse events was observed in patients in the KMP
        arm. KYPROLIS in combination with melphalan and prednisone is not
        indicated for transplant?ineligible patients with newly diagnosed
        multiple myeloma.

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.

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 Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.

Forward-Looking Statements
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No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. Even when clinical trials are successful, regulatory authorities may question the sufficiency for approval of the trial endpoints we have selected. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market.

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