On December 7, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) reportede several data presentations at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015, evaluating vadastuximab talirine (SGN-CD33A; 33A) in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in frontline acute myeloid leukemia (AML) and as monotherapy in primarily relapsed AML (Press release, Seattle Genetics, DEC 7, 2015, View Source;p=RssLanding&cat=news&id=2120491 [SID:1234508452]). 33A is an antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer. CD33 is expressed on leukemic blasts in nearly all AML patients and expression is generally not influenced by subtype, cytogenetic abnormality or underlying mutations.

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Based on interim data from the ongoing phase 1 clinical trial, a phase 3 clinical trial is planned to begin in 2016. The phase 3 study will evaluate 33A in combination with HMAs in previously untreated older AML patients. Seattle Genetics is also evaluating 33A broadly across multiple lines of therapy in patients with myeloid malignancies, including in ongoing and planned phase 1 and 2 clinical trials for newly diagnosed or relapsed AML and for newly diagnosed myelodysplastic syndrome (MDS). 33A was recently granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States. More information about 33A and ongoing clinical trials can be found at www.ADC-CD33.com.

"For decades, little progress has been made in improving treatment outcomes for AML patients. Older AML patients have particularly poor outcomes and most do not tolerate intensive therapies," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "Hypomethylating agents are a standard of care for these patients, but deliver low response rates and median overall survival of 10 months or less. We are committed to improving the therapeutic options for AML patients through innovative, targeted approaches. Based on the phase 1 data at ASH (Free ASH Whitepaper), we plan to advance 33A into a randomized phase 3 clinical trial in combination with HMAs for newly diagnosed older AML patients in 2016."

"There is a dire need to improve outcomes for older patients with AML," said Amir Fathi, M.D., Massachusetts General Hospital Cancer Center. "I am pleased with the anti-leukemic activity we have observed in phase 1 clinical trials evaluating 33A both as monotherapy and combination therapy in AML patients. This is an incredibly difficult disease to treat and the results to-date, especially in combination therapy, show a balance of activity and tolerability together with low early mortality rates. The response rates and durable remissions with 33A treatment compare favorably to the current standard of care."

SGN-CD33A Plus Hypomethylating Agents: A Novel, Well-Tolerated Regimen with High Remission Rate in Frontline Unfit AML (Abstract #454, oral presentation on Monday, December 7, 2015 at 7:45 a.m. ET)

Outcomes for AML patients who are not candidates for intensive chemotherapy or allogeneic stem cell transplant are dismal. Low intensity treatment options, including HMAs (azacitidine and decitabine), are limited with complete remission and complete remission with incomplete platelet or neutrophil recovery (CR/CRi) rates of 17.8 to 27.8 percent and median overall survival of 7.7 to 10.4 months. Interim results from an ongoing phase 1 study evaluating 33A in combination with HMAs were presented for the first time.

Data were reported from 25 frontline unfit AML patients with a median age of 77 years and predominantly intermediate or adverse cytogenetic risk who had declined intensive therapy. Forty-eight percent of patients had evidence of underlying myelodysplasia. Key findings presented by Dr. Fathi include:

Of 23 efficacy-evaluable patients treated with azacitidine or decitabine combination therapy with 33A, the best clinical response by investigator included 15 patients (65 percent) with a CR or CRi. Responses were observed in higher-risk patients, with remission achieved in eight of 10 patients (80 percent) with underlying myelodysplasia and eight of nine patients (89 percent) with adverse cytogenetics.

At a median follow-up of 7.7 months, median survival had not yet been reached and 72 percent of patients remained alive and on study. The 30- and 60-day mortality rates were zero and four percent, with no treatment-related deaths occurring during that time.

Ninety-six percent of patients (22 of 23) had reduction in bone marrow blasts, with 87 percent (20 of 23) experiencing a reduction of 50 percent or greater.

The most common treatment-related adverse events of any grade occurring in 20 percent or more of patients were fatigue (40 percent), nausea (32 percent), febrile neutropenia (28 percent), thrombocytopenia (24 percent) and neutropenia and anemia (20 percent each). The most common Grade 3 or 4 treatment-emergent adverse events occurring in 20 percent or more of patients were febrile neutropenia (56 percent), thrombocytopenia (32 percent), neutropenia (28 percent), anemia (24 percent) and fatigue (20 percent).

A Phase 1 Trial of SGN-CD33A As Monotherapy in Patients with CD33-Positive Acute Myeloid Leukemia (Abstract #324, oral presentation on Sunday, December 6, 2015 at 5:45 p.m. ET)

Data were reported from 93 AML patients treated with 33A monotherapy with a median age of 74 years and predominantly intermediate or adverse cytogenetic risk. The disease status of the 93 patients was a mixed AML population, consisting of mostly relapsed patients, but also a small percentage of older newly diagnosed patients. Of the 93 patients, 37 percent had previously received intensive therapy, 44 percent had received prior non-intensive therapy and 19 percent had declined intensive therapy. More than 58 percent of patients had evidence of underlying myelodysplasia.

Key findings presented by Anthony Stein, M.D., City of Hope, include:

Of the 85 evaluable patients treated across all dose levels, 48 percent experienced blast clearance, including 23 patients (27 percent) with a CR or CRi. Of the 27 response-evaluable patients treated at the recommended monotherapy dose of 40 micrograms per kilogram (mcg/kg), 11 patients (41 percent) achieved a CR/CRi. Of 12 treatment naïve patients who were treated at 40 mcg/kg, seven patients (58 percent) achieved CR/CRi.

Among all patients treated at the 40 mcg/kg dose level or higher, 91 percent had a reduction in bone marrow blasts, with a majority experiencing a reduction of 50 percent or greater. The median overall survival for these predominantly relapsed AML patients was 8.9 months (95% C.I. 3.9, 13.7).

For patients achieving CR/CRi, 73 percent were negative for minimal residual disease.
The 30- and 60-day mortality rates were five and 27 percent.

The most common treatment-related adverse events of any grade occurring in 15 percent or more of patients were febrile neutropenia (39 percent), fatigue (27 percent), thrombocytopenia (26 percent), anemia (24 percent) and neutropenia (16 percent); the most common Grade 3 or higher adverse events occurring in 20 percent or more of patients were febrile neutropenia (66 percent), thrombocytopenia (28 percent) and anemia (24 percent).

SGN-CD33A in Combination with Hypomethylating Agents is Highly Efficacious in Preclinical Models of AML (Abstract #3785, poster presentation on Monday, December 7, 2015)

A preclinical analysis evaluated the activity of 33A in combination with HMAs, azacitidine and decitabine, in AML models. Data presented in a poster presentation demonstrated enhanced cytotoxicity observed with the combination of 33A and HMAs as well as synergistic mechanisms of action and antitumor activity. In particular, HMA priming appears to increase CD33 expression and enhance DNA incorporation of PBDs released from 33A.

SGN-CD123A, a Pyrrolobenzodiazepine Dimer Linked Anti-CD123 Antibody Drug Conjugate, Demonstrates Effective Anti-Leukemic Activity in Multiple Preclinical Models of AML (Abstract #330, oral presentation on Sunday, December 6, 2015 at 5:45 p.m. ET)

Preclinical data from a novel ADC called SGN-CD123A, consisting of an anti-CD123 antibody attached to a PBD dimer, were also featured in an oral presentation at ASH (Free ASH Whitepaper). CD123 is expressed across AML subtypes, and is particularly prominent on leukemic stem cells, which are difficult to kill and may be responsible for high relapse rates even following intensive therapy. Data presented in an oral session by Eric Feldman, M.D., Senior Medical Director at Seattle Genetics, demonstrated enhanced anti-leukemic activity observed across multiple AML cell lines, including four out of five multi-drug resistant cell lines, and in 20 of 23 AML patient samples. In addition, antitumor activity was observed in all of the in vivo models tested. These preclinical data support a phase 1 clinical trial of SGN-CD123A in AML planned to begin in the second-half of 2016.

About Acute Myeloid Leukemia

Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. AML is a cancer that starts in the cells that are supposed to mature into different types of blood cells. AML starts in the bone marrow (the soft inner part of the bones, where new blood cells are made) and quickly moves into the blood. According to the American Cancer Society, in 2015 more than 20,500 new cases of AML (mostly in adults) will be diagnosed and nearly 10,500 deaths will occur from AML (almost all will be in adults).

About Vadastuximab Talirine (SGN-CD33A)

Vadastuximab talirine (SGN-CD33A; 33A) is a novel ADC targeted to CD33 utilizing Seattle Genetics’ newest ADC technology. CD33 is expressed on most AML cells. The CD33 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer, via a proprietary site-specific conjugation technology to a monoclonal antibody with engineered cysteines (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. The ADC is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells. 33A is being evaluated in ongoing phase 1 and phase 1/2 clinical trials and a planned pivotal phase 3 clinical trial for patients with AML.

On December 7, 2015 NanoString Technologies, Inc. (NASDAQ:NSTG), a provider of life science tools for translational research and molecular diagnostic products, reported that eleven posters for the Prosigna Breast Cancer Gene Signature Assay and the PAM50 gene signature, the basis for Prosigna, will be presented at the 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) (Press release, NanoString Technologies, DEC 7, 2015, View Source [SID:1234508451]). The presentations include:

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Multiple decision impact studies demonstrating Prosigna’s influence on adjuvant therapy selection by physicians
A study by the Danish Breast Cancer Group validating previous observations that the Prosigna risk of recurrence score can predict the probability of loco-regional recurrence

Studies evaluating the ability of Prosigna/PAM50 to predict response to various therapies in the neoadjuvant and metastatic setting
A study describing the differences in intrinsic subtype distribution between patients of African descent and Caucasian descent
A description of the ongoing OPTIMA clinical trial, describing the prospective evaluation of Prosigna as a test to identify node-positive breast cancer patients who may be spared adjuvant chemotherapy

Following are details for the Prosigna/PAM50 posters to be presented (all times shown are Central Standard Time):

Thursday, December 10

Session #: Poster Session 2, P2-08-10
Abstract Title: Validation of prediction of local recurrence (LR) by Prosigna (PAM50) in a Danish breast cancer cooperative group (DBCG) cohort of hormone receptor positive (HR+), postmenopausal early breast cancer (EBC) patients allocated to 5yr of endocrine therapy (ET)
Location: Halls A-B
Time: 7:30AM – 9:00AM

Session #: Poster Session 2, P2-08-16
Abstract Title: Prognostic and predictive abilities of intrinsic subtype in hormone receptor-positive metastatic breast cancer from the EGF30008 phase III clinical trial
Location: Halls A-B
Time: 7:30AM – 9:00AM

Session #: Poster Session 3, P3-07-14
Abstract Title: Prosigna intrinsic subtyping predicts response to neoadjuvant combination therapy in study that includes herceptin within HER2+ (IHC) patients
Location: Halls A-B
Time: 5:00PM – 7:00PM

Session #: Poster Session 3, P3-07-15
Abstract Title: Prosigna subtype correlation is a strong predictor of response to neoadjuvant chemotherapy (NAC) in early breast cancer (EBC) study
Location: Halls A-B
Time: 5:00PM – 7:00PM

Session #: Poster Session 3, P3-07-42
Abstract Title: Predicting outcome and benefit to first-line bevacizumab in advanced/metastatic hormone receptor (HR)+/HER2-negative breast cancer (BC) treated with endocrine therapy: A correlative science study from the LEA phase III clinical trial (GEICAM/2006-11_GBG 051)
Location: Halls A-B
Time: 5:00PM – 7:00PM

Session #: Poster Session 3, P3-07-66
Abstract Title: Efficacy and gene expression results from eribulin SOLTI1007 neoadjuvant study
Location: Halls A-B
Time: 5:00PM – 7:00PM

Session #: Poster Session OT2, OT2-03-02
Abstract Title: DI study: Decision impact of the NanoString Technologies Prosigna in early breast cancers
Location: Halls A-B
Time: 5:00PM – 7:00PM

Friday, December 11

Session #: Poster Session 5, P5-07-03
Abstract Title: Prosigna results impact on adjuvant decision making in early breast cancer (EBC): Final analysis of the prospective WSG study
Location: Halls A-B
Time: 5:00PM – 7:00PM

Session #: Poster Session OT3, OT3-02-12
Abstract Title: OPTIMA (optimal personalised treatment of early breast cancer using multi-parameter analysis), a prospective trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions
Location: Halls A-B
Time: 5:00PM – 7:00PM

Saturday, December 12

Session #: Poster Session 6, P6-04-05
Abstract Title: Genotype-phenotype classification of triple negative breast cancers (TNBC) in women of African descent using the PAM50 NanoString platform and genomic data
Location: Hall C
Time: 7:30AM – 9:00AM

Session #: Poster Session 6, P6-05-02
Abstract Title: Intrinsic subtype and gene expression changes between primary and metastatic breast cancer
Location: Hall C
Time: 7:30AM – 9:00AM
About the Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Dx Analysis System

The Prosigna Assay provides a risk category and numerical score for assessment of the risk of distant recurrence of disease at 10 years in postmenopausal women with node-negative (Stage I or II) or node-positive (Stage II), hormone receptor-positive (HR+) breast cancer. Based on the PAM50 gene signature initially discovered by Charles Perou, Ph.D. and colleagues, the Prosigna Assay is an in vitro diagnostic tool that utilizes gene expression data weighted together with clinical variables to generate a risk category and numerical score to assess a patient’s risk of distant recurrence of disease. The Prosigna Assay measures gene expression levels of RNA extracted from formalin-fixed paraffin embedded (FFPE) breast tumor tissue previously diagnosed as invasive breast carcinoma. The Prosigna Assay requires minimal hands-on time and runs on NanoString’s proprietary nCounter Dx Analysis System, which offers a reproducible and cost-effective way to profile many genes simultaneously with high sensitivity and precision.

The nCounter Dx Analysis System is a highly automated and easy-to-use platform that utilizes a novel digital barcoding chemistry to deliver high precision multiplexed assays. The system is available in the multi-mode FLEX configuration, which is designed to meet the needs of high-complexity clinical laboratories seeking a single platform with the flexibility to run the Prosigna Breast Cancer Assay and, when operated in the "Life Sciences" mode, process translational research experiments and multiplexed assays developed by the laboratory.

In the United States, the Prosigna Assay is available for diagnostic use when ordered by a physician. The Prosigna Assay has been CE-marked and is available for use by healthcare professionals in the European Union and other countries that recognize the CE Mark, as well as Canada, Israel, Australia, New Zealand and Hong Kong.

In the U.S., the Prosigna Assay is indicated in female breast cancer patients who have undergone surgery in conjunction with locoregional treatment consistent with standard of care, either as: (1) a prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with Hormone Receptor-Positive (HR+), lymph node-negative, Stage I or II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors or (2) a prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with Hormone Receptor-Positive (HR+), lymph node-positive (1-3 nodes), Stage II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors. The device is not intended for patients with four or more positive nodes.

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

On December 7, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported new study findings investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in combination with lenalidomide and low-dose dexamethasone (two commonly used treatments for multiple myeloma) in patients whose disease has progressed after at least two lines of prior therapy, including a proteasome inhibitor and an IMiD (immune modulatory drug) (Press release, Merck & Co, DEC 7, 2015, View Source [SID:1234508450]). The initial findings from the ongoing Phase 1 KEYNOTE-023 study showed an overall response rate (ORR) of 76 percent (n=13/17), as assessed by the International Myeloma Working Group (IMWG) 2006 Criteria. These results will be presented today at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting by Jesus San Miguel, M.D., Ph.D., Clínica Universidad de Navarra, Pamplona, Spain (Abstract #505). Based in part on these data, Merck has initiated two Phase 3 studies evaluating KEYTRUDA in the treatment of multiple myeloma.

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"Many patients with multiple myeloma relapse after their initial treatment, reinforcing the need for additional treatment options," said Dr. Jesus San Miguel. "These findings highlight the potential of combining KEYTRUDA with an IMiD and dexamethasone in patients who have multiple myeloma."

"Our clinical program explores the potential for KEYTRUDA across broad patient populations, including in combination with other medicines," said Roger Dansey, M.D., senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "We are encouraged by these results, showing responses in patients who have relapsed following treatment for multiple myeloma when treated with KEYTRUDA in combination with lenalidomide and dexamethasone, and look forward to building on these data."

Results from KEYNOTE-023 Presented at ASH (Free ASH Whitepaper)

In the study with 50 heavily pre-treated patients, initial findings from 17 patients who were treated with KEYTRUDA (pembrolizumab) in combination with lenalidomide and low-dose dexamethasone demonstrated an ORR of 76 percent (n=13/17) (per IMWG 2006), including four very good partial responses (24%) and nine partial responses (53%).

Adverse events in all 50 patients were consistent with previously reported safety data for KEYTRUDA as well as lenalidomide and low-dose dexamethasone. Grade 3 or 4 treatment-related adverse events included: neutropenia (n=11), thrombocytopenia (n=4), diarrhea (n=1), fatigue (n=1), anemia (n=4), hyperglycemia (n=3) and muscle spasms (n=1). Immune-mediated adverse events included: adrenal insufficiency (n=1), hyperthyroidism (n=2), hypothyroidism (n=2), and thyroiditis (n=1). No treatment-related deaths were reported.

About the KEYTRUDA Development Program and KEYNOTE-023

Merck is conducting a broad hematological malignancy program with approximately 20 clinical trials, including four registration-enabling studies and more than 15 combinations across a variety of lymphomas, myeloma, leukemia, and other hematologic malignancies. Registration-enabling trials of KEYTRUDA are currently enrolling patients in melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, esophageal cancer, breast cancer, Hodgkin lymphoma, multiple myeloma and other tumors, with further trials in planning for other cancers.

KEYNOTE-023 is a global, open-label, Phase 1 study designed to evaluate KEYTRUDA treatment in combination with dexamethasone and two different doses of lenalidomide in approximately 75 patients with relapsed/refractory multiple myeloma (RRMM). Patients will receive KEYTRUDA (2 mg/kg every two weeks) in combination with lenalidomide (10 mg or 25 mg) or KEYTRUDA (200 mg fixed dose every two weeks) with lenalidomide (10 mg or 25 mg); all patients will receive 40 mg low-dose dexamethasone weekly. Primary endpoints include safety and tolerability; secondary endpoints include ORR, duration of response, progression-free survival (PFS), and overall survival (OS).

About Multiple Myeloma

Multiple myeloma is a cancer of blood plasma cells in which abnormal plasma cells multiply uncontrollably in the bone marrow and occasionally in other parts of the body. Manifestations of the disease often include bone pain and fractures, and may include kidney problems, a weakened immune system weakness, and confusion. Multiple myeloma is the second most common blood cancer. In 2015, an estimated 26,850 people are expected to be diagnosed and an estimated 11,240 people are expected to die of the disease in the U.S. alone.

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 in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks 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. KEYTRUDA is also indicated at the same dosing for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. These indications are 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 these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Pneumonitis occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis in patients, receiving KEYTRUDA. 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.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients with melanoma, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA. Colitis occurred in 4 (0.7 %) of 550 patients with NSCLC, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving KEYTRUDA. 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.

Hepatitis occurred in patients receiving KEYTRUDA. Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients with melanoma, including a Grade 4 case in 1 (0.2%) patient, 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 2 (0.5%) of 411 patients with melanoma, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Hypophysitis occurred in 1 (0.2 %) of 550 patients with NSCLC, 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 indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients with melanoma, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients with melanoma, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%). 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 Grade 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. 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.

Nephritis occurred in patients receiving KEYTRUDA. Nephritis occurred in 3 (0.7%) patients with melanoma, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. 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 of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following steroid taper. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Across clinical studies with KEYTRUDA, the following clinically significant, immune-mediated adverse reactions have occurred: bullous pemphigoid and Guillain-Barré syndrome. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients with melanoma treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients with NSCLC treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening 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.

Among the 411 patients with metastatic melanoma, KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

Among the 550 patients with metastatic NSCLC, KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in 2% or more 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%), decreased appetite (25%), dyspnea (23%), and cough (29%).

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

It is not known whether KEYTRUDA 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. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On December 7, 2015 Foundation Medicine, Inc. (NASDAQ:FMI) reported that the company and its collaborators will present 10 poster presentations at the 2015 San Antonio Breast Cancer Symposium (SABCS) Annual Meeting taking place December 8-12, 2015 in San Antonio, Texas (Press release, Foundation Medicine, DEC 7, 2015, View Source [SID:1234508449]).

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The company’s molecular information products, FoundationOne for solid tumors and FoundationOne Heme for hematologic malignancies and sarcomas, provide a comprehensive genomic profile to identify the molecular alterations in a patient’s cancer. The data to be presented at SABCS provide further supporting evidence of the clinical utility of Foundation Medicine’s assays to identify emerging treatment options and inform efforts in treating breast cancer.

The schedule for poster presentations by Foundation Medicine and/or its collaborators is as follows:

Date and Time: Thursday, December 10, 2015, from 5:00-7:00 p.m. CT
Title: Non-Amplification ERBB2 Genomic Alterations in 5,605 Cases of Refractory and Metastatic Breast Cancer: an Emerging Opportunity for anti-HER2 Targeted Therapies
Poster Display Location: P3-07-05
Session: Prognostic and Predictive Factors: Response Predictions — Biomarkers and Other Factors
Presenter: Jeffrey S. Ross MD, Chairman, Dept. of Pathology and Laboratory Medicine, Albany Medical College and Medical Director, Foundation Medicine, Inc.
Collaborators: Albany Medical College, Mayo Clinic Cancer Center, Washington University

Date and Time: Thursday, December 10, 2015, from 5:00-7:00 p.m. CT
Title: Evolution of Genomic Alterations on Endocrine Therapy and mTOR Inhibition in Estrogen Receptor (ER)-Positive Breast Cancer
Poster Display Location: P3-05-06
Session: 3 – Tumor Cell and Molecular Biology: Endocrine Therapy and Resistance
Presenter: Suleiman Alfred Massarweh, MD Associate Professor of Medicine(Oncology) at the Stanford University Medical Center
Collaborators: Stanford University Medical School, Stanford Cancer Institute, University of Kentucky, Markey Cancer Center

Date and Time: Friday, December 11, 2015, from 5:00-7:00 p.m. CT
Title: Lapatinib Reverses Endocrine Resistance in Select Patients with HER 2 negative, Hormone Positive Metastatic Breast Cancer
Poster Display Location: P5-14-06
Session: 5 – Advanced Endocrine Therapy
Presenter: Priyanka Sharma, MD, Associate Professor of Medicine at University of Kansas
Collaborators: University of Kansas Medical Center, Hays Medical Center, Truman Medical Center

Date and Time: Friday, December 11, 2015, from 5:00 -7:00 p.m. CT
Title: Individualized molecular analyses guide efforts in breast cancer with comprehensive genomic profiling of tissue and plasma tumor DNA
Poster Display Location: PD6-08
Session: Translational Genomics
Presenter: Heather Parsons, MD, MPH Instructor in Medicine, Harvard Medical School at Dana Farber Cancer Institute
Collaborators: Dana-Farber Cancer Institute, Johns Hopkins Medical Institutions (JHMI)

Date and Time: Saturday, December 12, 2015, from 7:30-9:00 a.m. CT
Title: Comprehensive Genomic Profiling of Clinically Advanced Mucinous Carcinoma of the Breast
Poster Display Location: P6-03-12
Session: Tumor Cell and Molecular Biology: Genomics
Presenter: Jeffrey S. Ross MD, Chairman, Dept. of Pathology and Laboratory Medicine, Albany Medical College and Medical Director, Foundation Medicine, Inc.
Collaborators: Albany Medical College

Date and Time: Saturday, December 12, 2015, from 7:30-9:00 a.m. CT
Title: Clinicopathologic Characterization and Comprehensive Genomic Profiling (CGP) of Advanced Breast Cancer Patients with Fibroblast Growth Factor Receptor (FGFR) Alterations
Poster Display Location: P6-07-06
Session: 6 – Tumor Cell and Molecular Biology: Genetics — Somatic Changes
Presenter: Ricardo Alvarez, MD, MSc , Director of Cancer Research & Breast Medical Oncologist, Southeastern Regional Medical Center, CTCA
Collaborators: Cancer Treatment Centers of America

Date and Time: Saturday, December 12, 2015, from 7:30-9:00 a.m. CT
Title: EGFR Genomic Alterations in 5,605 Cases of Refractory and Metastatic Breast Cancer
Poster Display Location: P6-03-02
Session: 6 – Tumor Cell and Molecular Biology: Genetics — Somatic Changes
Presenter: Siraj M. Ali MD, PhD, Director Clinical Development, Foundation Medicine
Collaborators: Houston Methodist Hospital

On December 7, 2015 ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) reported the initiation of a randomized Phase 3 trial of Iclusig (ponatinib) in second-line patients with chronic myeloid leukemia (CML) in the chronic phase (CP) (Press release, Ariad, DEC 7, 2015, View Source;p=RssLanding&cat=news&id=2120512 [SID:1234508447]). The OPTIC-2L (Optimizing Ponatinib Treatment In CML, Second Line) trial is designed to investigate the efficacy and safety of ponatinib, administered at two starting doses, compared with nilotinib, in patients who are resistant to front-line treatment with imatinib. The primary endpoint of the OPTIC-2L study, now open for patient enrollment, is major molecular response (MMR) by 12 months. Approximately 600 patients are expected to be enrolled at clinical sites in Europe, Asia, Latin America and Canada.

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"Physicians treating CML patients will be extremely interested in the outcome of this clinical trial in which ponatinib — at two different doses — will be compared to nilotinib in patients resistant to imatinib," stated Dr. D. Selleslag, Department of Hematology, St-Jan Bruges-Ostend Hospital in Belgium. "By comparing ponatinib to nilotinib in the second-line setting, we will garner valuable, randomized clinical data to better understand the potential utilization of ponatinib in this broad patient population."

Major Design Features of the Trial

This study is designed to demonstrate superiority of ponatinib over nilotinib and will enroll patients with CP-CML who have become resistant to imatinib and have received no other tyrosine kinase inhibitor. These patients will be randomized to receive once-daily administration of ponatinib at a starting dose of either 30 mg (cohort A) or 15 mg (cohort B), or 400 mg of nilotinib administered twice daily (cohort C). Patients will be randomized in a ratio of 1:2:1 respectively. Upon reaching MMR, patients in cohort A will have their daily dose of ponatinib reduced to 15 mg and patients in cohort B will have their dose reduced to 10 mg.

The primary endpoint of the trial is MMR by 12 months for each cohort. Secondary endpoints include rate of vascular occlusive events in each cohort, rates of adverse events and rates of serious adverse events.

"The OPTIC-2L trial is the first direct randomized comparison of ponatinib to an approved BCR-ABL tyrosine kinase inhibitor following imatinib therapy. We expect this trial to provide important head-to-head data regarding the efficacy and safety of treating patients with ponatinib versus nilotinib in the second-line," said Frank G. Haluska, M.D., Ph.D., senior vice president of clinical research and development and chief medical officer at ARIAD. "The trial will examine lower ponatinib starting and maintenance doses than presently approved, along with a direct comparison to nilotinib, from which we may be able to obtain regulatory authorizations that would provide patients with more treatment options in an earlier line of therapy."

Patients will be enrolled at up to 90 cancer centers in Europe, Asia, Latin America and Canada. For more information about the trial, patients and physicians should call the U.S. toll-free number 855-552-7423, the EU toll-free number 800 00027423, or the international number +1 617-503-7423 or email ARIAD at [email protected].

About Iclusig (ponatinib) tablets

Iclusig is approved in the U.S., EU, Australia, Switzerland, Israel and Canada.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning

Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.

Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (22/449). Eight percent of patients (35/449) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4). Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate.

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the full U.S. Prescribing Information for Iclusig, including the Boxed Warning, for additional important safety information.