On September 28, 2015 Novartis treported updated data from the Phase III COMBI-v study showing a significant overall survival benefit for patients with BRAF V600E/K mutation-positive metastatic melanoma when treated with the combination of Tafinlar (dabrafenib) + Mekinist (trametinib) compared to vemurafenib monotherapy (Press release, Novartis, SEP 27, 2015, View Source;year=2015 [SID:1234507578]). The combination also demonstrated significant health-related quality of life improvements in the trial, including overall health, physical and social functioning. Results are being presented at the European Cancer Congress 2015 in Vienna.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"It is remarkable to see so many patients with BRAF V600E/K mutation-positive metastatic melanoma having long term responses and obtaining a significant decrease of the risk of death as compared with vemurafenib monotherapy," said Caroline Robert, MD, PhD, Head of Dermatology, Institute Gustave-Roussy. "This is the second Phase III trial of Tafinlar + Mekinist combination therapy to demonstrate a significant overall survival benefit over BRAF inhibitor monotherapy, further establishing Tafinlar + Mekinist as a standard of care for patients fighting BRAF V600 mutation-positive metastatic melanoma."

The significant overall survival benefit of Tafinlar + Mekinist from COMBI-v is consistent with the results demonstrated by the combination in COMBI-d, another Phase III trial previously reported at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting earlier this year.

In the COMBI-v study, the combination of Tafinlar + Mekinist achieved a statistically significant overall survival (OS) benefit compared to vemurafenib monotherapy (median for the combination 25.6 months vs 18.0 months; HR 0.66 [95% CI, 0.53-0.81], p<0.001). The rate of OS at two years was 51% for those receiving the Tafinlar + Mekinist combination and 38% for those receiving vemurafenib monotherapy[3]. In addition, the median overall response rate (ORR) was 65.6% in patients receiving the Tafinlar + Mekinist combination compared to 52.8% for those receiving vemurafenib monotherapy. The safety results from this study were consistent with the profile observed to date for the combination; no new safety concerns were observed[3].

"Helping patients live longer with our targeted combination therapy, Tafinlar and Mekinist, is very gratifying," said Bruno Strigini, President, Novartis Oncology. "This exemplifies our mission to transform cancer care with the ultimate goal of identifying the right treatment for the right patient at the right time."

Metastatic melanoma is the most serious and life-threatening type of skin cancer[1] and only about one in five patients survives for five years following diagnosis with late-stage disease[2]. There are about 200,000 new cases of melanoma diagnosed worldwide each year[4], approximately half of which have BRAF mutations[2]. Gene tests can determine whether a tumor has a BRAF mutation, and results can play a key role in prognosis and determining appropriate treatment[2].

In August 2015, the European Commission approved the combination of Tafinlar + Mekinist for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. The European Commission approval applies to all 28 EU member states, plus Iceland, Norway and Liechtenstein. In July 2015, the US Food and Drug Administration (FDA) granted priority review for an application to obtain regular approval of the Tafinlar + Mekinist combination in BRAF V600E/K mutation-positive metastatic melanoma. Since January 2014, the combination of Tafinlar + Mekinist has been approved for use in the US in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. The combination was approved through the FDA’s Accelerated Approval program and reviewed under a priority review designation. The approval was contingent on the results of the COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation.

About the COMBI-v Study
COMBI-v was a two-arm, open-label, Phase III study comparing the combination of Tafinlar + Mekinist with vemurafenib monotherapy in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma. The primary endpoint of this study was OS[3].

Results from the COMBI-v study showed that the combination of Tafinlar + Mekinist achieved a statistically significant OS benefit compared to vemurafenib monotherapy (median for the combination 25.6 months vs 18.0 months; HR 0.66 [95% CI, 0.53-0.81], p<0.001). A statistically significant reduction of 34% in the risk of death among patients receiving combination therapy was observed in the study. The analysis reported median progression free survival (PFS) of 12.6 months, ORR of 65.6%, and median duration of response (DoR) of 13.8 months for the Tafinlar + Mekinist combination arm compared to PFS of 7.3 months, ORR of 52.8%, and median DoR of 8.5 months for the vemurafenib monotherapy arm. The most frequent adverse events in the Tafinlar + Mekinist combination arm (>=30%) were pyrexia, nausea, diarrhea, and chills. More patients had AEs leading to dose modifications in the combination arm compared to the vemurafenib monotherapy arm. For the combination group compared to the vemurafenib group, there was a lower incidence of rash, 22% (n=76) vs 43% (n=149); photosensitivity reaction, 4% (n=13) vs 22% (n=78); hand-foot syndrome, 4% (n=14) vs 25% (n=87); skin papillomas, 2% (n=6) vs 23% (n=80); squamous-cell carcinomas and keratoacanthomas, 1% (n=5) vs 18% (n=63); and hyperkeratosis, 4% (n=15) vs 25% (n=86). Adverse events occurring more frequently in the combination arm compared with the vemurafenib monotherapy arm included pyrexia, 53% (n=184) vs 21% (n=73), respectively, and bleeding events, 18% (n=62) vs 7% (n=25), respectively. Discontinuation of treatment due to adverse events was similar between the treatment groups: 13% (n=44) for the combination group compared to 12% (n=41) for the monotherapy group[3].

Results from an analysis of the COMBI-v study of the patients’ health-related quality of life showed statistically significant and clinically meaningful improvements among those receiving the combination of Tafinlar + Mekinist, compared to those receiving vemurafenib monotherapy. Overall health, physical and social functioning, and specific symptoms such as pain, insomnia, and loss of appetite were all improved in the group receiving combination therapy[5].

About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Australia, Canada and additional countries.

Tafinlar and Mekinist target different kinases within the serine/threonine kinase family – BRAF and MEK1/2, respectively – in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

In 2015, as part of its purchase of oncology products from GlaxoSmithKline, Novartis obtained the worldwide exclusive rights granted by Japan Tobacco Inc. (JT) to develop, manufacture, and commercialize trametinib. JT retains co-promotion rights in Japan.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indication.

Tafinlar and Mekinist are also indicated in more than 35 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Tafinlar + Mekinist Combination Important Safety Information for Metastatic Melanoma
Tafinlar + Mekinist combination may cause serious side effects, such as:

When Tafinlar is used in combination with Mekinist, or when Tafinlar is administered as monotherapy, it can cause new cancers (both skin cancer and non-skin cancer). Patients should be advised to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies.

Before taking Tafinlar in combination with Mekinist, doctors should test their patients for BRAF wild-type melanoma, as patients without BRAF mutation and with RAS mutation can be at risk of increased cell proliferation in the presence of a BRAF inhibitor.

When Tafinlar is used in combination with Mekinist, it can increase the incidence and severity of bleeding, and in some cases can lead to death. Patients should be advised to call their healthcare provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," have red or black stools that look like tar, or any unusual signs of bleeding.

Tafinlar, in combination with Mekinist, can cause blood clots in the arms or legs, which can travel to the lungs and can lead to death. Patients should be advised to get medical help right away if they have the following symptoms: chest pain, sudden shortness of breath or trouble breathing, pain in their legs with or without swelling, swelling in their arms or legs, or a cool or pale arm or leg.

Tafinlar in combination with Mekinist can cause heart problems, including heart failure. A patient’s heart function should be checked before and during treatment. Patients should be advised to call their healthcare provider right away if they have any of the following signs and symptoms of a heart problem: feeling like their heart is pounding or racing, shortness of breath, swelling of their ankles and feet, or feeling lightheaded.

Tafinlar alone, or in combination with Mekinist, can cause severe eye problems that can lead to blindness. Patients should be advised to call their healthcare provider right away if they get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes, seeing color dots, halo (seeing blurred outline around objects), eye pain, swelling, or redness.

Patients should notify their doctor if they experience any new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.

Tafinlar alone or in combination with Mekinist can cause fever, which may be serious. When taking Tafinlar in combination with Mekinist, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Patients should be advised to call their healthcare provider right away if they get a fever above 38.5oC (101.3oF) while taking Tafinlar.

Rash is a common side effect of Tafinlar alone, or when used in combination with Mekinist. Tafinlar alone, or in combination with Mekinist, can also cause other skin reactions. In some cases these rashes and other skin reactions can be severe, and may need to be treated in a hospital. Patients should be advised to call their healthcare provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, skin redness.

Some people may develop high blood sugar or worsening diabetes during treatment with Tafinlar, alone or in combination with Mekinist. For patients who are diabetic, their healthcare provider should check their blood sugar levels closely during treatment. Their diabetes medicine may need to be changed. Patients should be advised to tell their healthcare provider if they have any of the following symptoms of severe high blood sugar: increased thirst or urinating more often than normal, or urinating an increased amount of urine.

Tafinlar may cause healthy red blood cells to break down too early in people with G6PD deficiency. This may lead to a type of anemia called hemolytic anemia where the body does not have enough healthy red blood cells. Patients should be advised to tell their healthcare provider if they have any of the following signs or symptoms of anemia or breakdown of red blood cells: yellow skin (jaundice), weakness or dizziness, or shortness of breath.

Tafinlar and Mekinist both can cause harm to an unborn baby when taken by a pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.

The most common side effects of Tafinlar + Mekinist combination include fever, nausea, tiredness, rash, chills, diarrhea, headache, vomiting, hypertension, joint pain, peripheral edema and cough. The incidence and severity of fever is increased when Mekinist is used in combination with Tafinlar.

Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Tafinlar + Mekinist combination. For more information, patients should ask their doctor or pharmacist.

Patients should take Tafinlar + Mekinist combination exactly as their health care provider tells them. Patients should not change their dose or stop taking Tafinlar + Mekinist combination unless their health care provider advises them to. Mekinist should be taken only once daily (either in the morning or evening, at the same time as Tafinlar). The first and second dose of Tafinlar should be taken approximately 12 hours apart. Patients should take Tafinlar + Mekinist at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or break Tafinlar capsules. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist.

Please see full Prescribing Information for Tafinlar and Mekinist.

On September 27, 2015 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company at the forefront of discovering, developing and commercializing novel immuno-oncology product candidates to improve the lives of patients with cancer, reported promising early-stage clinical data from a phase 1a study of GDC-0919, an IDO checkpoint inhibitor being developed in collaboration with Genentech, a member of the Roche Group, was presented today at the European Cancer Congress 2015 (ECC) in Vienna, Austria (Press release, NewLink Genetics, SEP 27, 2015, View Source [SID:1234507576]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

The data reported today are from a Phase 1a study of the safety, pharmacokinetics and pharmacodynamics of GDC-0919 in 19 patients with recurrent or advanced solid tumors. The primary objectives of this study are to evaluate the safety and tolerability of GDC-0919 in patients with advanced solid tumors as well as to define the maximum tolerated dose (MTD) or maximum biologically effective dose and recommended Phase 2 dose. GDC-0919, a small molecule investigational immunotherapy designed to inhibit IDO1 for the treatment of immune tolerance associated with cancer, is intended as a combination therapy with other immunotherapies and oncology therapeutics.

The data showed an acceptable safety profile, disease stabilization and preliminary evidence of peripheral pharmacodynamic modulation.

GDC-0919 was well tolerated up to 800 mg BID (twice daily) on a 21/28 day cycle. Thirty seven percent of patients available for tumor assessments (7/17) achieved stable disease. The MTD was not reached.

Single and multiple dose exposure from 50 to 800 mg of GDC-0919 increased in approximately dose-proportional manner, and higher doses of GDC-0919 modulated plasma Kynurenine in a manner consistent with the half-life of GDC-0919.

The most common adverse events related to GDC-0919 were lower grade and included pruritus or itching (37%), fatigue, (26%) and decreased appetite (21%).

The study continues to evaluate safety, PK, activity and pharmacodynamics of GDC-0919 at a continuous dosing schedule (BID 28/28) to enable greater flexibility in future dosing regimens. GDC-0919 also is being evaluated in a Phase 1b study in combination with atezolizumab (PD-L1 inhibitor) in patients with recurrent or advanced solid tumors.

About NewLink Genetics’ IDO Collaboration with Genentech

NewLink Genetics entered into an exclusive worldwide license agreement with Genentech in October 2014 for the development of GDC-0919, NewLink Genetics’ IDO checkpoint inhibitor, previously known as NLG919. The parties also entered into a research collaboration for the discovery of next generation IDO/TDO compounds.

Under the terms of the agreement, NewLink Genetics received an upfront payment of $150 million and will be eligible to receive in excess of $1 billion in milestone payments based on achievement of certain predetermined milestones as well as escalating double-digit royalties on potential commercial sales of multiple products by Genentech.

Genentech continues to fund future research, development, manufacturing and commercialization costs and also provides research funding to NewLink Genetics for support of the research collaboration. NewLink Genetics retains the option for co-promotion rights for GDC-0919 and potential next generation IDO/TDO compounds in the U.S.

On September 27, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported new findings from the KEYNOTE-028 Phase 1b study, the clinical trial investigating the use of the company’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in multiple, difficult-to-treat cancers (Press release, Merck & Co, SEP 27, 2015, View Source [SID:1234507574]). Data from this trial, to be presented at the European Cancer Congress (ECC) in Vienna, Austria, Sept. 25-29, include the first-time findings for KEYTRUDA in two gastrointestinal cancers, advanced anal cancer and advanced biliary tract cancer, and add to Merck’s growing body of clinical data for KEYTRUDA.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial – a trial design that allows for the study of multiple sub-populations of different tumor or histological types within one study. The study is evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients across 20 different types of cancer. The study was designed to evaluate patients with advanced solid tumors that express PD-L1 and which have not responded to current therapy or for which current therapy is not appropriate.

"Through innovative trials like KEYNOTE-028, we are advancing our understanding of the potential benefit of KEYTRUDA in a wide range of difficult-to-treat cancers," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "Merck is committed to evaluating KEYTRUDA across as many tumor types as possible and the expansion of our clinical development program over the years reflects this. We are encouraged by these early stage data, and will continue to advance KEYTRUDA in order to deliver on our goal of helping as many people with cancer as possible."

The KEYTRUDA clinical development program has rapidly expanded to encompass more than 30 tumor types in more than 130 clinical trials, of which more than 70 trials combine KEYTRUDA with other cancer treatments. Registration-enabling trials of KEYTRUDA monotherapy are currently enrolling patients in melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, and Hodgkin Lymphoma, with further trials in planning for other cancers.

Early Findings from Advanced Squamous Cell Carcinoma (SCC) of the Anal Canal (Abstract #500)

Early findings from 25 heavily pre-treated patients with advanced anal cancer – to be presented in an oral session on Sunday, Sept. 27 by Dr. Patrick Ott, Dana-Farber Cancer Institute – demonstrated an overall response rate (ORR) of 20 percent (confirmed and unconfirmed) (95% CI, 6.8-40.7) and a disease control rate (DCR) of 64 percent (95% CI, 42.5-82.0). Five partial responses (95% CI, 6.8-40.7) were observed, and 44 percent of patients (n=11/25) had stable disease (95% CI, 24.4-65.1). Additionally, the 6-month progression-free survival (PFS) rate was 31.6 percent and the 12-month PFS rate was 19.7 percent. At the time of the analysis, response duration ranged from 0.1+ to 9.2+ months, with the median not yet reached. The median stable disease duration was 3.6 months (range, 1.8+ to 11.0+).

Adverse events were generally consistent with previously reported safety data for KEYTRUDA. Grade 3-4 investigator-assessed, treatment-related adverse events were thyroid-stimulating hormone increased (n=1), colitis (n=1), diarrhea (n=1), and general physical health deterioration (n=1). Immune-mediated adverse events were hypothyroidism (n=3) and colitis (n=1). There were no treatment-related deaths.

Early Findings from Advanced Biliary Tract Cancer (Abstract #525)

Early findings from 24 heavily pre-treated patients with advanced biliary tract cancer – presented in a poster session on Saturday, Sept. 26 by Dr. Yung-Jue Bang, Seoul National University Hospital, Seoul, Korea – demonstrated an ORR of 17.4 percent (confirmed and unconfirmed) (95% CI, 5.0-38.8) (n=4/23); 17.4 percent of patients had stable disease (95% CI, 5.0-38.8) (n=4/23). As the time of the analysis, three of four responses were ongoing, and the median response duration had not yet been reached (range, 5.4+ to 9.3+ weeks).

Adverse events were generally consistent with previously reported safety data for KEYTRUDA. Grade 3-4 investigator-assessed, treatment-related adverse events were anemia (n=1), autoimmune hemolytic anemia (n=1), colitis (n=1) and dermatitis (n=1). Immune-mediated adverse events were autoimmune hemolytic anemia (n=1), colitis (n=1), hypothyroidism (n=1), and hypothyroidism (n=1). There were no treatment-related deaths.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, 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 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, 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 (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, 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, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, 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, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. 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 corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA in cases of severe hyperglycemia until metabolic control is achieved.

Nephritis occurred in 3 (0.7%) patients, 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. The following clinically significant immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, severe dermatitis including bullous pemphigoid, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

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. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

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

KEYTRUDA was discontinued 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%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. 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. 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 September 27, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that updated interim results of its Phase 1 clinical trials of entrectinib, the company’s proprietary oral tyrosine kinase inhibitor targeting solid tumors that harbor activating alterations to NTRK1, NTRK2, NTRK3, ROS1 or ALK, were presented in an oral presentation session at the 2015 European Cancer Congress (ECC 2015) in Vienna, Austria (Press release, Ignyta, SEP 27, 2015, View Source [SID:1234507570]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"We continue to be excited by the data from our two Phase 1 clinical trials of entrectinib, particularly in patients who would meet the anticipated eligibility criteria for our planned Phase 2 clinical trials," said Pratik Multani, M.D., Chief Medical Officer of Ignyta. "Out of the 18 patients in the two studies who met these criteria, we observed 13 responses, for an overall response rate of 72% across multiple tumor histologies. In addition, based upon an increased dataset of 92 patients, we have been able to confirm entrectinib’s acceptable safety profile for further development at the recommended phase 2 dose (RP2D). We intend to use this clinical experience as the basis for STARTRK-2, our planned, potentially registration-enabling Phase 2 clinical trial of entrectinib."

The clinical trials included the ALKA-372-001 study and the STARTRK-1 study, which is the first of the "Studies of Tumor Alterations Responsive to Targeting Receptor Kinases". Both trials were designed to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose, as well as preliminary anti-cancer activity, of single agent entrectinib in patients with solid tumors with the relevant molecular alterations: NTRK1 (encoding TrkA), ROS1 or ALK for ALKA-372-001 and NTRK1/2/3 (encoding TrkA/TrkB/TrkC), ROS1 or ALK for STARTRK-1.

As of the August 15, 2015, data cut-off for the presentation, the findings showed:

A total of 92 patients with a range of solid tumors had been dosed across both clinical trials, with nine patients treated at or above the RP2D beyond six months and one patient beyond one year.

Entrectinib was well tolerated to date:
Across both studies, the most frequent (>10% incidence) treatment-related adverse events were fatigue, dysgeusia, paresthesia, nausea, and myalgia. Seven of these were Grade 3 in severity, consisting of fatigue (4 patients), cognitive impairment (2 patients), and diarrhea (1 patient). No Grade 4 treatment-related adverse events were observed;

Across both studies, there were only three treatment-related serious adverse events: Grade 3 cognitive impairment and Grade 3 myocarditis, both of which occurred above the RP2D, and Grade 2 fatigue. All events were reversible and resolved upon dose modification;

The fixed daily dose RP2D was determined to be 600 mg, taken orally once per day (QD);
18 patients across both clinical trials met the company’s expected Phase 2 eligibility criteria, which include:
Presence of NTRK1/2/3, ROS1 or ALK gene rearrangements, as opposed to other types of molecular alterations (e.g., SNPs, amplifications, deletions);

ALK-inhibitor and/or ROS1-inhibitor naïve; and

Treatment at or above the RP2D;

The response rate in the 18 patients who met these criteria across both studies was 72% (13 responses out of 18 treated patients, as assessed by the clinical sites). Nine of these responders remain on study treatment with durable responses of up to 21 treatment cycles. An additional 3 patients remain on study with stable disease. The responses included:

3 responses out of 4 patients with NTRK1/2/3 gene rearrangements, including patients with non-small cell lung cancer (NSCLC), colorectal cancer and salivary gland cancer, with one of the responding patients remaining on treatment at 6 months; a fourth patient with an astrocytoma remains on treatment after two months with stable disease;

6 responses, including one complete response, out of 8 patients with ROS1 gene rearrangements, all of which were in NSCLC. All of the patients who responded remain on treatment, the longest at 21 months; and

4 responses out of 6 patients with ALK gene rearrangements, including two NSCLC patients and two patients with other solid tumors; two of the 4 responders subsequently progressed.

Entrectinib has demonstrated objective tumor response in the central nervous system (CNS), a frequent site of metastases and progression of advanced solid tumors.

On Wednesday, September 30, 2015, Ignyta will file a Form-8-K with the U.S. Securities and Exchange Commission (SEC) containing the materials presented at the ECC 2015. The company’s SEC filings can be found on the company’s website at www.ignyta.com and on the SEC’s website at www.sec.gov.

On September 27, 2015 Hospira Japan Co., Ltd. reported that the company has received an approval for the additional dosage/administration of gastric cancer for "Paclitaxel I.V. infusion [Hospira]" by a new drug application (NDA) based on evidence in the public domain with the Ministry of Health, Labour and Welfare (MHLW) in Japan (Press release, Hospira, SEP 27, 2015, View Source;p=RssLanding&cat=news&id=2090640 [SID:1234507569]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

[Product name]
1. Paclitaxel I.V. lnfusion 30mg/5mL [Hospira]
2. Paclitaxel I.V. lnfusion 100mg/16.7mL [Hospira]

[Therapeutic Category]
Anticancer drug

[Dosage /administration for gastric cancer]
The underlined text represents the additional dosage/administration.

Method A or E are used for gastric cancer.
Method A: Normally for adults 210 mg/m2 (body surface area) in terms of Paclitaxel is administered over 3 hours in a single infusion, with intervals of at least three weeks between doses. This forms one course, which is repeated.
Method E: Normally for adults 80 mg/m2 (body surface area) in terms of paclitaxel is administered over 1 hour in a single infusion, once per week for three successive weeks, followed by an interval of at least two weeks. This forms one course, which is repeated.
Doses may be suitably reduced having regard to the condition of the patient.

On the basis of the requirement of the additional dosage/administration for gastric cancer for originator, which includes Paclitaxel, the report was prepared by the "Review Committee on Unapproved Drugs and Indications with High Medical Needs." The decision was made based on the report at the meeting of the Second Committee on New Drugs, Pharmaceutical Affairs and Food Sedation Council, held on March 5, 2015, which confirmed that filing through the "NDA based on evidence in the public domain" was reasonable for this additional dosage/administration.

The MHLW notification related to "NDA based on evidence in the public domain" for generics recommends pharmaceutical companies work on filing for additional dosage/administration for generic at the same time as originators. Hospira Japan filed this additional dosage/administration for "Paclitaxel I.V. infusion 30mg/5mL [Hospira] " and "Paclitaxel I.V. infusion 100mg/16.7mL [Hospira] " by "NDA based on evidence in the public domain."

Hospira Japan is committed to contributing to healthcare in Japan by providing value-added products with its broad portfolio and meeting the expectations of patients and healthcare professionals.