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New Phase 3 Secondary Analysis Shows Progression-Free Survival Benefit In Early Relapsing Multiple Myeloma Patients Treated With Kyprolis® (Carfilzomib)-Based Regimen

On June 6, 2016 Amgen (NASDAQ:AMGN) reported data from a secondary analysis of the pivotal Phase 3 ASPIRE trial that showed Kyprolis (carfilzomib) for Injection in combination with lenalidomide and dexamethasone (KRd) improved progression-free survival (PFS) and overall response rate (ORR) compared to lenalidomide and dexamethasone (Rd) alone in patients with relapsed multiple myeloma with early disease progression after initial therapy or transplant (Press release, Amgen, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175458 [SID:1234513065]). The results were presented today at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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The analysis showed that patients relapsing within one year of initial therapy treated with KRd (n=87) experienced a median PFS of 24.1 months versus 12.5 months in those treated with Rd (n=72) (HR=0.75; 95 percent CI: 0.50-1.13). In addition, ORR in the KRd arm was 79.3 percent versus 61.1 percent in the Rd arm. Patients relapsing early after first prior transplant treated with KRd (n=48) experienced a median PFS of 17.3 months versus 11.1 months in those treated with Rd (n=49) (HR=0.87; 95 percent CI: 0.54-1.41). In addition, the ORR in the KRd arm was 83.3 percent versus 61.2 percent in the Rd arm. Grade 3 adverse events that occurred at least five percent more frequently in the KRd arm compared to the Rd arm in either subgroup were hypokalemia, neutropenia, febrile neutropenia, hypophosphatemia and respiratory tract infection (ASCO abstract #8045).

"A goal in treating relapsed multiple myeloma is to get patients into remission, and keep them in remission as long as possible. For some patients who relapse early, this may be a sign of a more aggressive disease1," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "This analysis showed that in early relapsing multiple myeloma patients, the addition of Kyprolis to lenalidomide and dexamethasone resulted in patients living longer without their disease progressing, a significant milestone for patients living with this difficult-to-treat disease."

ASCO Abstract #8045: Carfilzomib, Lenalidomide, and Dexamethasone (KRd) vs. Lenalidomide and Dexamethasone (Rd) in Patients with Relapsed Multiple Myeloma (RMM) and Early Progression During Prior Therapy: Secondary Analysis From the Phase 3 Study ASPIRE (NCT01080391)

An exploratory sub-group analysis assessed the efficacy and safety of KRd compared with Rd alone in 159 patients with multiple myeloma who had relapsed less than or equal to one year from their first treatment. A second sub-group analysis examined 97 patients with multiple myeloma who had relapsed less than or equal to one year from prior transplant.

In patients who had relapsed less than or equal to one year from their first treatment, median PFS in the KRd arm was 24.1 months versus 12.5 months for Rd (HR=0.75; 95 percent CI: 0.50-1.13), and ORR was 79.3 percent for KRd versus 61.1 percent for Rd. In addition, 21.8 percent of patients in the KRd arm experienced a complete response versus 4.2 percent treated with Rd.
In patients who had relapsed less than or equal to one year after transplant, median PFS in the KRd arm was 17.3 months versus 11.1 months for Rd (HR=0.87; 95 percent CI: 0.54-1.41), and ORR was 83.3 percent for KRd versus 61.2 percent for Rd. Complete responses in the KRd and Rd arms were 12.5 percent and 4.1 percent, respectively.
Grade 3 or higher adverse events that occurred in greater than or equal to five percent more frequently in KRd than Rd in both groups were hypokalemia, neutropenia, febrile neutropenia, hypophosphatemia and respiratory tract infection.
About ASPIRE
The international, randomized Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial evaluated Kyprolis in combination with lenalidomide and dexamethasone, versus lenalidomide and dexamethasone alone, in patients with relapsed multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate, health-related quality of life (HR-QoL) and safety. Patients were randomized to receive Kyprolis (20 mg/m2 on days 1 and 2 of cycle one only, escalating to 27 mg/m2 on days 8, 9, 15 and 16 of cycle one and continuing on days 1, 2, 8, 9, 15 and 16 of subsequent cycles), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and low-dose dexamethasone (40 mg per week in four-week cycles), versus lenalidomide and low-dose dexamethasone alone. The study randomized 792 patients at sites in North America, Europe and Israel.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.2 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 90,000 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.5

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 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, 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.

Kyprolis is a product of Onyx Pharmaceuticals, Inc. Onyx Pharmaceuticals is a subsidiary of Amgen and holds development and commercialization rights to Kyprolis globally, excluding Japan.

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

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 (carfilzomib) 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 neuroradiological 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.

Final Analysis of First-in-Human Phase 1 Study of MM-151 Shows Positive Clinical Activity in Multiple Solid Tumor Types, Including Colorectal Cancer

On June 6, 2016 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK) reported results from the final analysis of the Phase 1 study of MM-151, a novel investigational oligoclonal epidermal growth factor receptor (EGFR) inhibitor, in patients with refractory solid tumors (Press release, Merrimack, JUN 6, 2016, View Source [SID:1234513061]). These results were presented at a Poster Discussion Session at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

Data from the Phase 1 study show positive clinical activity across multiple solid tumor types in a heavily pretreated patient population. Twenty-one percent of evaluable patients in the metastatic colorectal cancer (CRC) cohort achieved an objective response and 54 percent of patients showed a decrease in tumor size. A median progression-free survival (PFS) of four months was also observed within the CRC cohort. MM-151 also exhibited positive clinical activity in both EGFR-treatment refractory and EGFR-treatment naïve populations. These preliminary data support the potential for broad clinical effect, and demonstrate an acceptable safety profile consistent with existing EGFR therapies.

"We are excited to present the final analysis of the Phase 1 data of MM-151, Merrimack’s novel oligoclonal EGFR-inhibitor," said J. Marc Pipas, M.D., Senior Medical Director at Merrimack. "The promising preliminary Phase 1 data highlights MM-151’s ability to impair EGFR-driven signaling and overcome resistance, particularly in colorectal cancer patients. We are encouraged by these results given the unmet needs in this patient population, and we look forward to further evaluating this investigational therapy’s potential to address this challenging disease."

CRC is the third most common cancer and is the second leading cause of cancer death in the United States. An estimated 144,000 new cases are expected to be diagnosed in 2016. The five-year survival rate for metastatic CRC is estimated at 11 percent.i The two most recent approved drugs for late stage metastatic CRC demonstrated objective response rates of less than two percent and PFS below two months in their clinical studies, while demonstrating an overall survival benefit versus best supportive care (no drug treatment)ii iii.

Methodology and Results

This study evaluated MM-151 as a monotherapy and in combination with irinotecan. An expansion cohort was enrolled to evaluate clinical activity in EGFR-refractory metastatic CRC patients. Subset analyses and additional biomarker evaluations were performed in EGFR-driven indications. A total of 111 patients were treated with escalating dose levels; 87 patients on monotherapy and 24 patients receiving MM-151 in combination with irinotecan. The most common tumor types were CRC (45 [41%]), head and neck cancers (14 [13%]) and non-small cell lung cancer (11 [10%]).

Safety of MM-151

MM-151 demonstrated a comparable safety profile to approved EGFR inhibitors as a monotherapy and in combination with irinotecan.
Apart from infusion reactions, which occurred at decreasing frequency and severity as the dosing schedule was modified over the course of the study, the most common adverse events reported were rash, hypomagnesemia, fatigue and diarrhea in the monotherapy cohorts. These adverse events were expected and consistent with EGFR inhibition class toxicities.
Results

Preliminary indications of clinical activity with MM-151, across both the EGFR-refractory and naïve populations, suggest there is potential for broad effect.
Biomarker profiling suggests MM-151 may overcome mechanisms of resistance.
Preliminary data in the CRC subset show 54 percent of evaluable patients had a reduction in tumors. Forty-five percent (13/29) of patients in the CRC subset achieved stable disease or partial response at three cycles of treatment and 17 percent (5/29) achieved a partial response, with highly durable responses and disease control.
Preliminary biomarker analysis of blood samples ("liquid biopsies") following MM-151 treatment show low occurrence of acquired KRAS/NRAS/BRAF mutations in the CRC cohort and no occurrence of acquired EGFR extracellular domain mutations, which have been reported to mediate resistance to cetuximab and panitumumab.
A median PFS of four months was observed in the CRC cohort.
Observations in exploratory biomarker analyses are consistent with the multiple mechanisms of action that have been previously described for MM-151 in preclinical studies, including EGFR downregulation, expression of high-affinity EGFR ligands across indications (including refractory metastatic CRC) and activity in tumors expressing EGFR and downstream mutations.
Further clinical evaluation is underway.
About MM-151

Merrimack used its systems biology approach to engineer MM-151, an oligoclonal therapeutic that is a mixture of three fully human monoclonal antibodies designed to bind and inhibit signaling of EGFR. EGFR-mediated signaling promotes the growth and survival of cancer cells and is recognized as an important drug target in several types of cancer, including colon, lung, breast, pancreatic and head and neck cancers. The use of three antibodies maximizes receptor inhibition, and provides mechanisms to overcome resistance to EGFR-targeted therapies. MM-151 is also being evaluated in two other Phase 1 studies; one in combination with the ONIVYDE (irinotecan liposome injection) regimen for metastatic CRC, and another in a first-of-its-kind, multi-arm basket study in combination with three other novel agents, two of which are from Merrimack’s oncology pipeline. Merrimack initiated these studies in May.

AbbVie Builds Upon Robust Body of IMBRUVICA® (ibrutinib) Data with Phase 3 Longer-Term Studies in Patients with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting

On June 6, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported longer-term follow-up results from Phase 3 studies of IMBRUVICA (ibrutinib) in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, JUN 6, 2016, View Source [SID:1234513058]). Findings include an analysis of outcomes from the RESONATETM (PCYC-1112) and RESONATETM-2 (PCYC-1115) trials, which showed IMBRUVICA was associated with favorable progression-free survival (PFS) and overall survival (OS) regardless of line of therapy (previously treated or treatment-naïve; abstract 7520). Other data include first-ever presentation of longer-term follow-up data from the HELIOS (CLL3001) trial showing IMBRUVICA in combination with bendamustine and rituximab (BR) continued to demonstrate superiority over time versus placebo plus BR in relapsed/refractory CLL/SLL patients (abstract 7525), along with improvements in quality of response.

These data showcasing additional clinical evidence of IMBRUVICA in CLL/SLL will be presented today in a poster session at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago from 8:00 – 11:30 a.m. CDT. The RESONATE and RESONATE-2 analysis will also be featured as a poster discussion today from 1:15 – 2:45 p.m. CDT. IMBRUVICA is jointly developed and commercialized in the U.S. by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc.

"Our clinical data presented at this year’s ASCO (Free ASCO Whitepaper) from several randomized studies demonstrate solid durability of response with IMBRUVICA in patients with CLL/SLL with additional follow-up of up to three years," said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. "This evidence of deepening responses with continued therapy and long-term survival with IMBRUVICA over time, used either as a single agent or in combination, positions this therapy as a potentially beneficial treatment option for a variety of patients with CLL or SLL, regardless of when it is prescribed in the treatment journey."

An analysis of the RESONATE and RESONATE-2 trials showed IMBRUVICA was associated with favorable PFS and OS outcomes, as well as a high overall response rate (ORR) in previously treated and treatment-naïve patients with CLL/SLL, regardless of line of therapy. The median PFS and OS were not reached in treatment-naïve or previously-treated patients; 89-92% of patients treated with ibrutinib at first or second line of therapy remained progression-free at two years. Additionally, ORR was high in both previously treated and treatment-naïve patients (92% and 91%, respectively). The safety profile was similar for both patient groups1 and was consistent with previously-reported outcomes. Data from the RESONATE and RESONATE-2 studies served as the basis for the 2014 and 2016 FDA approvals of IMBRUVICA for patients with CLL/SLL.

The most commonly occurring adverse reactions (? 20%) in studies that supported the FDA approvals for patients with CLL/SLL were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10% of patients receiving IMBRUVICA discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately 6% of patients.

Additionally, after a median follow-up of 25.4 months, data from the HELIOS trial showed the combination of IMBRUVICA plus BR continued to demonstrate a significant improvement in investigator-assessed PFS (the primary endpoint) (74.8%) versus placebo plus BR (20.9%) in patients with relapsed/refractory CLL/SLL (median not reached versus 14.2 months, respectively; HR [95% CI]: 0.199 [0.15, 0.26], P<0.0001). The updated investigator-assessed ORR for IMBRUVICA plus BR was 87.2%, as compared with 66.1% for placebo plus BR (P<0.0001) and the rate of complete responses (CRs) and CRs with incomplete bone marrow recovery (CRi) improved in the IMBRUVICA plus BR arm (33.9% versus 7.2% in the placebo plus BR arm). OS was not reached in either arm (HR [95% CI]: 0.670 [0.44, 1.02], P=0.587). Safety was consistent with the first analysis.2 Notably, positive results from the initial analysis (median follow-up: 17 months) supported the May 2016 update to the IMBRUVICA U.S. Prescribing Information.

The prevalence of CLL is approximately 115,000 patients in the U.S.3 with approximately 15,000 newly diagnosed patients every year.4 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.5 CLL and SLL are predominately diseases of the elderly, with a median age of 71 at diagnosis.3

About the RESONATE Study
RESONATE is a Pharmacyclics-sponsored randomized, multi-center, open-label, international Phase 3 study that examined ibrutinib versus ofatumumab in relapsed/refractory patients with CLL/SLL who had received at least one prior therapy and were not considered appropriate candidates for treatment with a purine analog (n=391). Patients were administered either 420 mg oral ibrutinib (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). The study met its primary endpoint, demonstrating improved PFS.

Results from RESONATE were featured in the official press program at ASCO (Free ASCO Whitepaper) in Chicago in June 2014 and simultaneously published in The New England Journal of Medicine.

About the RESONATE-2 Study
RESONATE-2 is a Pharmacyclics-sponsored, randomized, multi-center, open-label, Phase 3 study which enrolled 269 treatment-naïve patients with CLL/SLL aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The study met its primary endpoint, demonstrating improved PFS, as assessed by an independent review committee (IRC).

Results from RESONATE-2 were first presented in an oral session at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in Orlando, FL in December 2015 and simultaneously published in The New England Journal of Medicine. The results were also part of the official press program at ASH (Free ASH Whitepaper) 2015.

About the HELIOS Study
HELIOS is a Janssen-sponsored, randomized, multi-center, double-blind, placebo-controlled, Phase 3 study which enrolled 578 CLL/SLL patients who had received at least one prior systemic therapy. Patients were randomized to receive IMBRUVICA or placebo, once daily continuing until disease progression or unacceptable toxicity with six cycles of BR. The study met its primary endpoint, demonstrating improved IRC assessed PFS.

Data from an interim analysis of HELIOS were first presented during the official press program at ASCO (Free ASCO Whitepaper) in Chicago in May 2015. The results were also published in The Lancet Oncology in December 2015.

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK).6 BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.7 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably. 7

IMBRUVICA is approved to treat patients with CLL/SLL, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.7

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers. More than 6,000 patients have been treated with IMBRUVICA in clinical trials. Currently, 14 Phase 3 trials have been initiated with IMBRUVICA and more than 90 trials are registered on www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. 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 a fetus.

ADVERSE REACTIONS

The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia* (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

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Sunesis Announces Study Examining the Value of Complete Remission Prior to HCT in Patients with AML Presented at 2016 ASCO Annual Meeting

On June 06, 2016 Sunesis Pharmaceuticals, Inc. (NASDAQ:SNSS) reported the presentation of results from a study conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) at the Medical College of Wisconsin evaluating the value of achieving complete remission prior to allogeneic hematopoietic cell transplantation (HCT) in patients with acute myeloid leukemia (AML) (Press release, Sunesis, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175348 [SID:1234513056]). The study was funded jointly by Sunesis and CIBMTR. The results are being presented today, Monday, June 6th from 8:00 a.m. to 11:30 a.m. Central Time at the Hematologic Malignancies – Leukemia, Myelodyplastic Syndromes, and Allotransplant General Poster Session of the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago, Illinois.

The poster presentation (Poster #25, Abstract 7033, Hall A), titled "Allogeneic transplantation for advanced acute myelogenous leukemia: The value of complete remission," will be available on the Sunesis website at www.sunesis.com, following the ASCO (Free ASCO Whitepaper) presentation.

For the study, researchers evaluated records from 4,382 patients with AML who had proceeded to allogeneic transplantation to understand comparative survival between those in complete remission following additional salvage therapy and those receiving prompt HCT without achieving complete remission or in first relapse following primary induction. Of the 4,382 patients, 1,440 had transplantation in primary induction failure (PIF), 1,256 were first relapse (Rel1), and 1,986 had achieved a second complete remission (CR2). Baseline characteristics were similar in the three disease status groups.

The results showed that more patients who had achieved CR2 had de novo AML, a longer duration of a first complete remission (CR1), and were more likely to report performance scores of 90 or 100. Adverse cytogenetics were more common in PIF patients and duration of CR1 was shorter in patients with Rel1 than in those with CR2. Mortality was higher for HCT in Rel1 compared to CR2 regardless of CR1 duration (RR 1.65, p < 0.0001). Similarly, mortality was higher for HCT in PIF compared to CR2 with CR1 duration < 6 (RR 1.26, p < 0.0001), 6-12 (RR 1.60, p < 0.0001) and > 12 months (RR 2.24, p < 0.0001). The probabilities of overall survival by disease status at 6 months are: CR2 73 (71-75)%; Rel1 53 (50-55)%; PIF 58 (56-61)%; and at 2 years, CR2 50 (48-52)%; REL1 27 (24-29)%; PIF 29 (27-32)%.

The data suggest that patients in remission fare better following HCT than those who receive transplant without having achieved CR, and that the ability to achieve remission is a powerful prognostic marker.

"These data point to the importance of achieving remission as an indicator of prognosis after HCT for patients with relapsed/refractory AML, and underscore the need for an effective salvage therapy," said Parvinder S. Hyare, Vice President, Global Oncology Operations and an author of the study. "We thank CIBMTR and their collaborators for this important research, and continue to work toward delivering new treatment options to high unmet need patients with AML around the world."

Seattle Genetics and Astellas Present ASG-15ME and Enfortumab Vedotin Phase I Clinical Data in Metastatic Urothelial Cancer at ASCO Annual Meeting

On June 6, 2016 Seattle Genetics, Inc. (NASDAQ:SGEN) and Astellas Pharma Inc. (TOKYO:4503) reported first clinical data for ASG-15ME and enfortumab vedotin (ASG-22ME) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 51st Annual Meeting being held June 3-7, 2016, in Chicago, IL (Press release, Seattle Genetics, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175252 [SID:1234513055]).

ASG-15ME and enfortumab vedotin are investigational antibody-drug conjugates (ADCs) that consist of monoclonal antibodies designed to deliver microtubule-disrupting agents selectively to tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity. ASG-15ME and enfortumab vedotin target SLITRK6 and Nectin-4, respectively, proteins that are highly expressed in urothelial cancers, particularly bladder cancer. Under the collaboration, the companies are co-developing and plan to globally co-commercialize ASG-15ME and ASG-22ME.

"Bladder cancer is the fifth most common cancer in the U.S., and there have been few treatment advances over the past three decades. For metastatic disease, the five-year survival rate is only 15 percent, representing a significant unmet need to identify additional treatment options," said Len Reyno, M.D., senior vice president and chief medical officer, Agensys, an affiliate of Astellas. "We are pleased to present these first data for ASG-15ME and ASG-22ME in urothelial cancers, which have a particularly high unmet medical need."

"The clinical data from the phase I presented at ASCO (Free ASCO Whitepaper) from the ASG-15ME and enfortumab vedotin programs in heavily pretreated metastatic bladder cancer patients show a manageable safety profile along with objective response rates that are higher than historical rates seen with taxanes," said Jonathan Drachman, M.D., chief medical officer and executive vice president, Research and Development at Seattle Genetics. "We will continue enrolling patients in the ongoing phase I clinical trials to determine the recommended dose for further development."

The following data were presented during poster sessions on Monday, June 6, 2016:

Anti-Tumor Activity, Safety and Pharmacokinetics (PK) of AGS15E (ASG-15ME) in a Phase I Dose Escalation Trial in Patients (Pts) with Metastatic Urothelial Cancer (mUC) (Abstract #4532, poster presentation on Monday, June 6, 2016)
Data were reported from 49 patients with metastatic urothelial cancer. The median age of patients was 64 years. Of the 49 patients, 48 patients (98 percent) had undergone treatment with a platinum-based chemotherapy regimen, including 33 patients (67 percent) with a cisplatin-based regimen, and 14 patients (29 percent) who had progressed on or after treatment with checkpoint inhibitors. Twenty-nine patients (59 percent) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate escalating doses, pharmacokinetics and safety of ASG-15ME as a monotherapy. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. In this dose-escalation study, patients received ASG-15ME at 0.1 to 1.25 milligrams per kilogram (mg/kg) weekly for three of every four week cycles. Key findings include:
Of the 43 patients evaluable for response, 14 patients (33 percent) had an objective response, including one patient (two percent) who achieved a complete response and 13 patients (30 percent) who achieved a partial response. While the study is ongoing, preliminary estimates show median duration of response at 16.1 weeks. Disease control was achieved for 27 patients (63 percent), defined as achieving complete remission, partial remission or stable disease.
In 16 patients treated at the 1.0 mg/kg dose level, seven patients (44 percent) had an objective response. In five patients treated at the 1.25 mg/kg dose level, two patients (40 percent) had an objective response.
In the 13 patients whose cancer had metastasized to the liver, four patients (31 percent) achieved a partial remission. Bladder cancer that metastasizes to the liver typically has a poor prognosis.
In the 14 patients who had previously been treated with checkpoint inhibitors, five patients (36 percent) achieved a partial remission.
The most common treatment-related adverse events of any grade occurring in 15 percent or more of patients were fatigue (43 percent) and nausea (20 percent). Peripheral neuropathy was observed in 10 patients (19 percent) at Grade 1 and six patients (11 percent) at Grade 2. No Grade 3 or 4 peripheral neuropathy was reported.
In the study, eight patients developed ocular symptoms with corneal abnormalities. The majority of patients were managed with dose reductions and recovered.
Enrollment is ongoing at 1.0 and 1.25 mg/kg to identify a recommended dose for future studies.
Anti-Tumor Activity, Safety and Pharmacokinetics (PK) of ASG-22CE (ASG-22ME; enfortumab vedotin) in a Phase I Dose Escalation Trial in Patients (Pts) with Metastatic Urothelial Cancer (mUC) (Abstract #4533, poster presentation on Monday, June 6, 2016)
Data were reported from 44 patients with metastatic urothelial cancer. The median age of patients was 66.5 years. Of the 44 patients, 43 patients (98 percent) had undergone treatment with a platinum-based chemotherapy regimen, including 30 patients (68 percent) with a cisplatin-based regimen, and 12 patients (27 percent) who had progressed on or after treatment with checkpoint inhibitors. Twenty-eight patients (64 percent) had received two or more prior systemic therapies.
The primary endpoints of the ongoing clinical trial are to evaluate escalating doses, pharmacokinetics and safety of enfortumab vedotin as a monotherapy. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. In this dose-escalation study, patients received enfortumab vedotin at 0.5 to 1.25 mg/kg weekly for three of every four week cycles. Key findings include:
Of the 36 patients evaluable for response, 10 patients (28 percent) achieved a partial response. While the study is ongoing, preliminary estimates show median duration of response at 16.1 weeks. Disease control was achieved for 25 patients (69 percent), defined as achieving complete remission, partial remission or stable disease.
In eight patients treated at the 1.25 mg/kg dose level, four patients (50 percent) had an objective response.
In the 10 patients whose cancer had metastasized to the liver, four patients (40 percent) achieved a partial remission. Bladder cancer that metastasizes to the liver typically has a poor prognosis.
In the 12 patients who had previously been treated with checkpoint inhibitors, three patients (25 percent) achieved a partial remission.
The most common treatment-related adverse events of any grade occurring in 15 percent or more of patients were pruritis and nausea (30 percent each), fatigue (25 percent), diarrhea (21 percent) and rash (18 percent). Peripheral neuropathy was observed in 11 patients (19 percent) at Grade 1 and three patients (five percent) at Grade 2. No Grade 3 or 4 peripheral neuropathy was reported.
In the study, two patients developed ocular symptoms with corneal abnormalities. The patients were managed with dose reductions and/or steroid eye drops.
Enrollment is ongoing at 1.0 and 1.25 mg/kg to identify a recommended dose for future studies.
The ASG-15ME and enfortumab vedotin phase I clinical trials are ongoing to identify a recommended dose for future clinical evaluation. More information about the clinical trials, including enrolling centers, is available by visiting www.clinicaltrials.gov.

About Bladder Cancer

Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. Most bladder cancers start in the innermost lining of the bladder, which is called the urothelium or transitional epithelium. Urothelial carcinoma, also known as transitional cell carcinoma (TCC), is the most common type of bladder cancer. Urothelial carcinoma starts in the urothelial cells that line the inside of the bladder.

While patients with early stage bladder cancer are treated with curative intent, outcomes are poor for patients diagnosed with locally advanced or metastatic disease. For the approximately 10 percent of patients with urothelial bladder cancer whose initial diagnoses occur when they have metastatic disease, the average five-year survival is approximately 15 percent. According to the American Cancer Society, in 2016 approximately 77,000 people will be diagnosed and more than 16,000 will die from urothelial bladder cancer.

About ASG-15ME and Enfortumab Vedotin

ASG-15ME is an investigational antibody-drug conjugate (ADC) composed of an anti-SLITRK6 monoclonal antibody attached to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), using Seattle Genetics proprietary, industry-leading linker technology. ASG-15ME is the first and only agent to target SLITRK6, a transmembrane protein identified as an ADC target by Agensys, which is expressed on many solid tumors. Preclinical data demonstrate that ASG-15ME effectively binds to target cells, internalizes and induces cell-killing activity.

Enfortumab vedotin is an investigational ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE, using Seattle Genetics’ proprietary, industry-leading linker technology. Enfortumab vedotin is the first and only agent to target Nectin-4, a cell adhesion molecule identified as an ADC target by Agensys, which is expressed on many solid tumors. Preclinical data demonstrate that enfortumab vedotin effectively binds to target cells, internalizes and induces cell-killing activity.