On June 4, 2016 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported new data, including updated response rates, progression-free survival (PFS) and overall survival (OS) with KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy in patients with advanced non-small cell lung cancer (NSCLC) whose tumors express PD-L1 from two studies: KEYNOTE-010 and KEYNOTE-001 (Press release, Merck & Co, JUN 4, 2016, View Source [SID:1234513113]). The findings are being presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstracts #9015 and #9026).

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A sub-analysis from the phase 2/3 KEYNOTE-010 trial includes OS data with KEYTRUDA compared to chemotherapy in previously treated patients with advanced NSCLC based on varying levels of PD-L1 expression; other data from KEYNOTE-010 are currently under review by the U.S. Food and Drug Administration (FDA) and are intended to serve as the basis for the full approval of KEYTRUDA in lung cancer in patients whose tumors express PD-L1. Additionally, updated findings from the phase 1b KEYNOTE-001 trial, the study that supported the accelerated approval of KEYTRUDA in NSCLC, include overall response rate (ORR), PFS, safety and two-year survival data.

"We are particularly excited by the results we are seeing with KEYTRUDA in lung cancer from both studies including longer term follow-up data in KEYNOTE-001 that continues to demonstrate durable responses in treatment-naïve and treatment-experienced patients," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "The KEYNOTE-010 data show that there is a correlation between increased levels of PD-L1 expression and improved benefit, which further underscores the importance of understanding a patient’s PD-L1 expression when determining a specific treatment plan."

Merck has a robust clinical development program for KEYTRUDA (pembrolizumab) in lung cancer, with five registration-enabling studies currently underway. The KEYTRUDA clinical development program includes more than 30 tumor types in more than 270 clinical trials, including more than 100 trials that combine KEYTRUDA with other cancer treatments.

Findings from KEYNOTE-010 (Abstract #9015)

KEYNOTE-010 is a global, open-label, randomized, pivotal phase 2/3 study evaluating KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to standard of care chemotherapy (docetaxel, 75 mg/m2 every three weeks) in patients with previously treated advanced NSCLC. The primary endpoints were OS and PFS and were assessed based on patients whose tumors express high levels of PD-L1 (greater than or equal to 50 percent) and in patients with any level of PD-L1 expression (greater than or equal to one percent) – as reflected by tumor proportion scores (TPS). KEYNOTE-010 is the first study of its kind to evaluate the potential of an immunotherapy compared to chemotherapy based on prospective measurement of PD-L1 expression in patients with advanced NSCLC. As previously announced, the study met its primary objective showing that KEYTRUDA significantly improved OS compared to chemotherapy in patients with any level of PD-L1 expression. Findings were similar in patients who received the FDA-approved dose of KEYTRUDA (2 mg/kg every three weeks) and the investigational dose of KEYTRUDA (10 mg/kg every three weeks). These findings also served as the basis for the KEYTRUDA application currently under review by the FDA.

Findings from abstract #9015 were based on a sub-analysis of patient outcomes across four PD-L1 expression categories as determined by TPS (one to 24 percent; 25 to 49 percent; 50 to 74 percent; and greater than or equal to 75 percent) (n=1,033). Results showed that the OS, PFS, and overall response rate (ORR) generally increased with increasing levels of PD-L1 expression in those patients treated with KEYTRUDA, but not chemotherapy (docetaxel) – with the longest OS and PFS and highest ORR observed in patients who were in the highest PD-L1 TPS category.

In patients treated with KEYTRUDA (pembrolizumab), median OS was 16.6 months in patients in the highest PD-L1 TPS category (95% CI, 11.2-NR) and 9.7 months in patients in the lowest PD-L1 TPS category (95% CI, 8.9-11.6); median PFS was 6.2 months in patients in the highest PD-L1 TPS category (95% CI, 4.2-8.2) and 2.6 months in the lowest PD-L1 TPS category (95% CI, 2.1-3.4); ORR was 33.7 percent in patients in the highest PD-L1 TPS category and 8.6 percent in the lowest PD-L1 TPS category.

In patients treated with chemotherapy, median OS was 8.2 months in patients in the highest PD-L1 TPS category (95% CI, 5.8-10.9) and 8.5 months in patients in the lowest PD-L1 TPS category (95% CI, 7.5-9.9); median PFS was 4.0 months in patients in the highest PD-L1 TPS category (95% CI, 2.2-4.5) and 4.0 months in the lowest PD-L1 TPS category (95% CI, 2.3-5.5); ORR was 7.0 percent in patients in the highest PD-L1 TPS category and 10.9 percent in the lowest PD-L1 TPS category.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies of KEYTRUDA.

On June 4, these data will be presented in a poster session from 8:00 – 11:30 a.m. CDT (Location: Hall A) and in a poster discussion from 3:00 – 4:15 p.m. CDT (Location: E354b).

Findings from KEYNOTE-001 (Abstract #9026)

KEYNOTE-001 is a multicenter, open-label, multi-cohort, activity-estimating phase 1b trial evaluating KEYTRUDA (2 mg/kg every three weeks or 10 mg/kg every two or three weeks) in various advanced cancers, including lung cancer. The lung cancer cohort included treatment-naïve and previously treated patients with advanced NSCLC. The primary efficacy outcome measure was confirmed ORR as assessed by blinded independent central review using RECIST v1.1. Tumor response was assessed every nine weeks. The secondary outcome measures included PFS, OS, and duration of response. Findings from this study supported the accelerated approval of KEYTRUDA in previously treated NSCLC based on ORR and safety data.

Primary outcome measures observed in treatment-naïve patients (n=101) showed ORR of 58.3 percent (TPS greater than or equal to 50 percent), 17.4 percent (TPS of one to 49 percent), and 10.0 percent (TPS of less than one percent); and ORR in previously treated patients (n=449) of 38.3 percent (TPS greater than or equal to 50 percent), 12.9 percent (TPS of one to 49 percent), and 9.9 percent (TPS of less than one percent). Data at ASCO (Free ASCO Whitepaper) also assessed secondary outcome measures, including OS. In treatment-naïve patients, results showed a median OS of 22.1 months (95% CI, 16.8-27.2) with an 18-month OS rate of 58.1 percent and a 24-month OS rate of 44.5 percent. In previously treated patients, results showed a median OS of 10.6 months (95% CI, 8.6-13.3) with an 18-month OS rate of 36.6 percent and a 24-month OS rate of 30.4 percent.

Outcomes were further assessed based on three PD-L1 TPS categories (greater than or equal to 50 percent; one to 49 percent; and less than one percent). Results of this analysis showed that while a benefit was observed across all PD-L1 categories, the greatest benefit was observed in treatment-naïve patients with higher levels of PD-L1 expression (greater than or equal to 50 percent of cells expressing PD-L1). In this group, the 18-month OS rate was 72.7 percent and the 24-month OS rate was 60.6 percent; the median OS had not been reached at the time of analysis.

The safety profile of KEYTRUDA (pembrolizumab) was consistent with that observed in previously reported KEYTRUDA studies. Immune-mediated adverse events of Grade 3-5 were hypothyroidism, pneumonitis, hyperthyroidism, severe skin toxicities, colitis, adrenal insufficiency, and hypophysitis. There were two treatment-related deaths (one case each of interstitial lung disease and cardiopulmonary arrest).

These data will be presented in a poster session on June 4, 8:00 – 11:30 a.m. CDT (Location: Hall A).

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA (pembrolizumab) is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-mediated pneumonitis occurred in 19 (3.5%) of 550 patients, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis and occurred more frequently in patients with a history of asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic radiation (6.0%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-mediated colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in patients receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in patients receiving KEYTRUDA (pembrolizumab). Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 14% of 550 patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

It is not known whether KEYTRUDA (pembrolizumab) is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 270 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On June 4, 2016 Genus Oncology reported that it collaborates with leaders in leukemia research at Harvard’s Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center on an investigator-initiated Phase 1b/2a trial of GO-203 in combination with Decitabine for the treatment of patients with relapsed/refractory AML (Press release, Genus Oncology, JUN 4, 2016, View Source [SID:SID1234515226]).

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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 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 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that its U.S. subsidiary Eisai Inc. has entered into an agreement with Novartis Pharmaceuticals Corporation (Novartis), a U.S. affiliate of Novartis AG (Headquarters: Basel, Switzerland, CEO: Joseph Jimenez), to collaborate on commercial and medical affairs activities (including the provision of scientific evidence to healthcare professionals) for Eisai’s in-house developed novel anticancer agent Lenvima (lenvatinib mesylate) and the anticancer agent everolimus in the United States (Press release, Eisai, JUN 3, 2016, View Source [SID:1234512973]).

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On May 13, 2016, Eisai Inc. received approval from the U.S. Food and Drug Administration for an additional indication for Lenvima in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy. This is the only combination regimen approved in the United States to significantly prolong progression-free survival when compared with a standard of care in patients with advanced renal cell carcinoma following prior anti-angiogenic therapy. Under the terms of the collaboration agreement, Eisai and Novartis sales representatives will promote the availability of this combination regimen to healthcare professionals in the United States. The companies will also collaborate on medical affairs activities. Each company will continue to book sales of their respective product.

The number of patients with kidney cancer in the United States is estimated to be approximately 58,0001 and renal cell carcinoma comprises more than 90% of all malignancies of the kidney.2 For advanced or metastatic renal cell carcinoma that is difficult to treat with surgery, the standard treatment is molecular targeted drug therapy, however with low 5-year survival rates, this is a disease with significant unmet medical need.

Lenvima is approved for thyroid cancer in over 40 countries including the United States, Japan, in Europe, South Korea and Canada. Lenvima is also approved in combination with everolimus for patients with advanced renal cell carcinoma in the United States. A new drug application seeking approval for an indication covering advanced or metastatic renal cell carcinoma submitted in Europe in January 2016 is under review, and Eisai intends to discuss further steps regarding submission strategies for this potential indication with the regulatory authorities in Japan.

Through this agreement, Eisai is committed to maximizing the clinical value of Lenvima in order to address the diverse needs of, and further contribute to, patients with cancer, their families and healthcare professionals.

About Lenvima (lenvatinib mesylate)
Discovered and developed in-house, Lenvima is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation.
Currently, Eisai has obtained approval for Lenvima as a treatment for refractory thyroid cancer in over 40 countries including the United States, Japan, in Europe, Korea and Canada, and the agent is undergoing regulatory review throughout the world including in Asia, Russia, Australia, Brazil and Mexico. Specifically, Eisai has obtained approval for the agent indicated in the United States for treatment for locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, in Japan for the treatment of unresectable thyroid cancer, and in Europe for the treatment of adult patients with progressive, locally advanced or metastatic differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine, respectively.
In May 2016, Lenvima was also approved for an additional indication in the United States in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy. A new drug application seeking approval for an indication covering advanced or metastatic renal cell carcinoma submitted in Europe in January 2016 is under review, and Eisai intends to discuss further steps regarding submission strategies for this potential indication with the regulatory authorities in Japan.
Meanwhile, Eisai is conducting clinical studies of Lenvima in several other tumor types such as hepatocellular carcinoma (Phase III), endometrial carcinoma (Phase II), biliary tract cancer (Phase II), and in combination with an immune checkpoint inhibitor (Phase Ib/II).
For further information on Lenvima in the United States, including Important Safety Information (ISI), please visit the Lenvima product website (View Source).

About Afinitor (everolimus) Tablets
Afinitor (everolimus) tablets is approved in 112 countries, including the United States and in the European Union, for locally advanced, metastatic or unresectable progressive neuroendocrine tumors (NET) of pancreatic origin. Afinitor is not indicated for the treatment of patients with functional carcinoid tumors in the United States. Afinitor is now approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with progressive, well-differentiated, nonfunctional NET of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic.
It is also approved in more than 120 countries including the United States and European Union for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy (in the United States, specifically following sunitinib and sorafenib).
Additionally, Afinitor is approved in more than 110 countries including the United States and European Union for advanced HR+/HER2- breast cancer in combination with exemestane, after prior endocrine therapy.
Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor or Votubia, Certican and Zortress and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.
Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets
Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors may be at an increased risk for angioedema. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.
The most common adverse drug reactions (incidence ≥10 percent) are infections (including sore throat and runny nose, upper respiratory tract infection, pneumonia, sinusitis, and urinary tract infection), mouth ulcers, skin rash, feeling tired, diarrhea, fever, vomiting, nausea, cough, decreased appetite, low level of red blood cells, headache, abnormal taste, absence of menstrual periods, acne, inflammation of lung tissue, irregular menstrual periods, swelling of extremities or other parts of the body, high level of blood sugar, feeling weak, itching, weight loss, high levels of cholesterol, and nose bleeds. The most common Grade 3-4 adverse drug reactions (incidence ≥2 percent) are mouth ulcers, infections (including pneumonia), low level of red blood cells, high level of blood sugar, feeling tired, absence of menstrual periods, diarrhea, low white blood cells, inflammation of lung tissue, feeling weak, fever, and spontaneous bleeding or bruising. Cases of hepatitis B reactivation, blood clots in the lung or legs, and pneumocystis jirovecii pneumonia (PJP) have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Afinitor, Votubia, Certican and Zortress are registered trademarks of Novartis AG, or its affiliates.

About Study 2053
The U.S. Food and Drug Administration’s approval of the additional indication for Lenvima in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy in the United States was based on the results of Study 205. Study 205 was a multicenter, randomized, open-label study of the combination of Lenvima (18 mg) plus everolimus (5 mg), Lenvima alone (24 mg), and everolimus alone (10 mg) in patients with unresectable advanced or metastatic renal cell carcinoma following one prior VEGF-targeted therapy, and was conducted in Europe and the United States. 153 patients were randomized in a 1:1:1 ratio to one of three treatment arms to compare the efficacy and safety of these three regimens.
From the results of the study, the combination of Lenvima plus everolimus group demonstrated a significant extension in the study’s primary endpoint of progression free survival (PFS) compared to the everolimus alone group (median PFS for the Lenvima plus everolimus group: 14.6 months vs median PFS for the everolimus alone group: 5.5 months; Hazard Ratio (HR) 0.40 [95% CI: 0.24-0.68], p=0.0005). Additionally, median PFS for the Lenvima alone group was 7.4 months, demonstrating an extension in PFS compared to the everolimus alone group (HR: 0.61 [95% CI: 0.38-0.98]).
The study also assessed objective response rate (ORR) and overall survival (OS) as secondary endpoints. Regarding ORR, both the Lenvima plus everolimus group and the Lenvima alone group showed an improvement in ORR compared to the everolimus alone group (Lenvima plus everolimus: 43%, Lenvima alone: 27%, everolimus alone: 6%). Furthermore, regarding OS, an updated analysis carried out in December 2014 suggested that Lenvima plus everolimus extends OS compared to everolimus alone (HR 0.51 [95% CI=0.30-0.88]).
The most common treatment-emergent adverse events (TEAEs) reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher were diarrhea, hypertension and fatigue.

About Renal Cell Carcinoma
The number of patients with renal cancer was estimated to be approximately 338,000 worldwide, including approximately 58,000 in the United States, 115,000 in Europe and 17,000 in Japan.1 Renal cell carcinoma comprises more than 90% of all malignancies of the kidney,2 and occurs when malignant cells are found in the lining of the tubules of the kidney. The incidence of renal cell carcinoma in people aged in their late 50s is rising, and is more likely to affect men than women. For advanced or metastatic renal cell carcinoma that is difficult to treat with surgery, the standard treatment method is molecular targeted drug therapy, however with low 5-year survival rates, this is a disease with significant unmet medical need.