On November 21, 2015 Exelixis, Inc. (NASDAQ:EXEL) reported the presentation of positive overall survival (OS) results from coBRIM, the phase 3 pivotal trial evaluating COTELLIC (cobimetinib) in patients with previously untreated resectable, locally advanced or metastatic melanoma carrying a BRAF V600E or V600K mutation, in combination with vemurafenib (Press release, Exelixis, NOV 21, 2015, View Source;p=RssLanding&cat=news&id=2114503 [SID:1234508308]). Dr. Victoria Atkinson, Medical Oncologist at Princess Alexandra Hospital, Queensland, Australia, presented the data during a late-breaking abstract oral presentation this afternoon at the Society for Melanoma Research (SMR) 2015 International Congress, which is being held November 18-21 in San Francisco. COTELLIC is a selective inhibitor of MEK that was discovered by Exelixis and is now the subject of a worldwide collaboration agreement between Exelixis and Genentech, a member of the Roche Group.

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In October 2015, Exelixis announced the coBRIM trial met its OS secondary endpoint, demonstrating a statistically significant increase in OS for the combination of COTELLIC and vemurafenib compared to vemurafenib monotherapy. Today’s presentation was the first to include detailed data on the endpoint. The median OS was 22.3 months for the combination of COTELLIC and vemurafenib versus 17.4 months for vemurafenib alone, corresponding to a 30% reduction in the rate of death for the combination as compared to vemurafenib alone (hazard ratio [HR]=0.70, 95% confidence interval [CI] 0.55-0.90, p= 0.005). Ongoing study monitoring did not identify any new safety signals.

"The overall survival benefit for COTELLIC and vemurafenib observed in the coBRIM trial further underscores the positive impact that the combination of these two therapies can have on the treatment of advanced BRAF V600 mutation-positive melanoma," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis.

On November 10, 2015, the U.S. Food and Drug Administration (FDA) approved COTELLIC as a treatment for patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib. COTELLIC was first approved in Switzerland in late August 2015. The COTELLIC approvals are based on data from coBRIM, the phase 3 pivotal trial conducted by Genentech in 495 patients with previously untreated unresectable, locally advanced or metastatic melanoma carrying a BRAF V600 mutation (detected by the cobas 4800 BRAF Mutation Test). Genentech sponsored the U.S. New Drug Application and Roche sponsored the Swiss regulatory application. Roche also filed a Marketing Authorization Application (MAA) with the European Medicines Agency in late 2014, and the Committee for Medicinal Products for Human Use issued a positive recommendation on the MAA in September 2015. Roche anticipates a decision from the European Commission by year-end.

About the COTELLIC Development Collaboration

Exelixis discovered COTELLIC internally and advanced the compound to investigational new drug (IND) status. In late 2006, Exelixis entered into a worldwide collaboration agreement with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop COTELLIC.

Under the terms of collaboration, Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and will share in U.S. marketing and commercialization costs. In November 2013, Exelixis exercised its option to co-promote COTELLIC in the United States and, under the terms of the agreement, the company is fielding 25 percent of the U.S. sales force, closely coordinating its efforts with Genentech. Outside of the United States, Exelixis is eligible to receive royalties on any sales.

About COTELLIC in Combination with Vemurafenib

COTELLIC and vemurafenib are prescription medicines used in combination to treat melanoma that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene. Found in approximately half of melanomas, mutated BRAF causes abnormal signaling inside cancer cells leading to tumor growth. Vemurafenib is designed to inhibit some mutated forms of BRAF and COTELLIC is designed to inhibit some forms of MEK. Both BRAF and MEK are proteins in a cell signaling pathway that help control cell growth and survival. When used in combination, COTELLIC and vemurafenib are thought to reduce cancer cell growth longer than with vemurafenib alone. A patient’s healthcare provider will perform a test to make sure COTELLIC and vemurafenib are right for the patient. It is not known if COTELLIC and vemurafenib are safe and effective in children under 18 years of age.

About the coBRIM Trial

CoBRIM is an international, randomized, double-blind, placebo-controlled phase 3 study evaluating the safety and efficacy of 60 mg once daily of cobimetinib plus 960 mg twice daily of vemurafenib compared to 960 mg twice daily of vemurafenib plus placebo. In the study, 495 patients with BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma (detected by the cobas 4800 BRAF Mutation Test) and previously untreated for advanced disease were randomized to receive vemurafenib every day on a 28-day cycle plus either cobimetinib or placebo on days 1-21. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. Investigator-assessed PFS is the primary endpoint. Secondary endpoints include PFS by independent review committee, objective response rate, overall survival, duration of response and other safety, pharmacokinetic and quality of life measures.

About Melanoma and its BRAF V600 Mutation-Positive Form

Melanoma is the less common, but more serious category of skin cancer that starts in the skin’s pigment producing cells known as melanocytes. According to the American Cancer Society, approximately five percent of skin cancer diagnoses are melanoma, but melanoma accounts for a large majority of skin cancer deaths. In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years. It is projected that approximately half of all melanomas, and eight percent of solid tumors, contain a mutation of the BRAF protein. BRAF is a key component of the RAS-RAF-MEK-ERK pathway involved in normal cell growth and survival. However, mutations that keep the BRAF protein in an active state may cause excessive signaling in the pathway, leading to uncontrolled cell growth and survival.

COTELLIC Important Safety Information

Before taking COTELLIC, patients should tell their doctor if they:

have any previous or current skin problems other than melanoma
have any medical conditions and/or are on any medications that increase your risk of bleeding
have any heart problems
have any eye problems
have any liver problems
have any muscle problems
have any other medical conditions
are pregnant or plan to become pregnant. COTELLIC can harm an unborn baby.

Patients who take COTELLIC should use effective methods of birth control during treatment, for at least two weeks after stopping COTELLIC, and for at least two months after stopping vemurafenib.

Patients should talk to their healthcare provider about birth control methods that may be right for them.
Patients should tell their healthcare provider right away if they become pregnant or think they are pregnant during treatment with COTELLIC.

are breastfeeding or plan to breastfeed. It is not known if COTELLIC passes into breast milk, so patients should not breastfeed during treatment with COTELLIC and for two weeks after the final dose. Patients should talk to their healthcare provider about the best way to feed their baby during this time.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements because some types of medicines will make COTELLIC more harmful or less effective. Patients should know the medicines they take and keep a list of them to show their healthcare provider and pharmacist when they get a new medicine.

Patients should avoid sunlight while taking COTELLIC. COTELLIC can make patients’ skin sensitive to sunlight and cause them to burn more easily and get severe sunburns. To help protect against sunburn:

When patients go outside they should wear clothes that protect their skin, including their head, face, hands, arms and legs.
Patients should use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.
COTELLIC may cause serious side effects, including:

Risk of skin cancers. COTELLIC may cause skin cancers (cutaneous squamous cell carcinoma, keratoacanthoma or basal cell carcinoma).

Patients must check their skin and tell their doctor right away about any skin changes, including:

new wart
skin sore or reddish bump that bleeds or does not heal
change in size or color of a mole
A patient’s healthcare provider should check their skin before they start taking COTELLIC and every two months while taking COTELLIC. A patient’s healthcare provider may continue to check their skin for six months after they stop taking COTELLIC.

Increased risk of bleeding. COTELLIC may cause bleeding, including blood in the urine, rectal bleeding, unusual or excessive vaginal bleeding, bleeding of the gums and bleeding within the brain (cerebral hemorrhage).

A patient should tell their healthcare provider right away if they experience any of these symptoms:
red or black stools that look like tar
blood in the urine
headache, dizziness or feeling weak
abdominal pain
unusual vaginal bleeding

Heart problems that can lead to inadequate pumping of the blood by the heart. A patient’s healthcare provider should perform tests before the patient starts taking COTELLIC and during a patient’s treatment with COTELLIC to check the ability of the heart to pump blood. Signs and symptoms of a decrease in the amount of blood pumped include:

persistent coughing or wheezing
shortness of breath
swelling of their ankles and feet
tiredness
increased heart rate
Rash. Patients should tell their healthcare provider right away if they experience any of these symptoms:
a rash that covers a large area of their body, blisters or peeling skin

Eye problems. Patients should tell their healthcare provider right away if they experience any of these symptoms during treatment with COTELLIC:

blurred vision
distorted vision
partly missing vision
halos
any other vision changes
Some of these eye problems may be a result of something called "serous retinopathy" (a build-up of fluid under the retina of the eye). A patient’s healthcare provider should check their eyes if they notice any of the symptoms above.

Abnormal liver test or liver injury. A patient’s healthcare provider should perform blood tests before the start taking COTELLIC, and during treatment. A patient should tell their healthcare provider right away if you experience any of these symptoms:

yellowing of their skin or the white of their eyes
dark or brown (tea color) urine
nausea or vomiting
feeling tired or weak
loss of appetite

Increased levels of an enzyme in the blood. Creatine phosphokinase (CPK) is an enzyme that is primarily found in the muscle, heart and brain. Treatment with COTELLIC may increase the level of this enzyme in your blood and be a sign of muscle damage. A patient’s healthcare provider should perform a blood test before and during treatment. Increased blood levels of CPK can also be an indication of a serious condition caused by injury to the muscles (rhabdomyolysis). A patient should tell their healthcare provider right away if they experience any of these symptoms:

muscle aches
muscle spasms and weakness
dark, reddish urine

Photosensitivity. A patient’s skin may become more sensitive to sunlight while taking COTELLIC. A patient should tell their healthcare provider if they notice any of the following symptoms:
red, painful, itchy skin that is hot to touch
sun rash
skin irritation
bumps or tiny papules
thicken, dry, wrinkled skin

The most common side effects of COTELLIC include:

diarrhea
sunburn or sun sensitivity
nausea
vomiting
fever

A patient’s healthcare provider will take blood tests while they are taking COTELLIC. The most common changes to blood tests include:

increased blood levels of liver enzymes (gamma glutamyltransferase [GGT], alanine aminotransferase [ALT] or aspartate aminotransferase [AST])
increased blood level of enzyme from muscle (creatine phosphokinase)
decreased blood level of phosphate, sodium or potassium
increased blood level of liver or bone enzyme (alkaline phosphatase)
decreased blood level of a type of white blood cell (lymphocyte)
Patients should tell their healthcare provider if they have any side effect that bothers them or that does not go away.

These are not all the possible side effects of COTELLIC. For more information about side effects, patients should ask their healthcare provider or pharmacist. Patients should call their doctor for medical advice about side effects.

On November 21, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported findings from three studies investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in combination with three other immunotherapies – epacadostat, IMLYGICTM (talimogene laherparepvec), and ipilimumab – in patients with advanced melanoma (Press release, Merck & Co, NOV 21, 2015, View Source [SID:1234508309]). The findings, which were featured in separate oral presentations today at the Society for Melanoma Research 2015 International Congress (SMR) in San Francisco, showed robust anti-tumor activity with KEYTRUDA in all three combinations studied.

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"We have demonstrated the benefit of KEYTRUDA as a single agent in advanced/metastatic melanoma and we are now also looking to identify potential combinations for patients with this devastating disease," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "The combination data presented at SMR, including KEYTRUDA combined with epacadostat or IMLYGIC, may further our goal of improving outcomes without substantial increased toxicity."

Additionally, updated data presented at SMR from a Phase 3 study of KEYTRUDA as a single agent showed superior overall response rates (ORR) and progression free survival (PFS) compared to ipilimumab in ipilimumab-naïve patients, with twice as many patients achieving PFS on KEYTRUDA compared to ipilimumab. As previously reported, the study met its endpoint of overall survival. Patient-reported outcomes from the same study were also presented. The KEYTRUDA clinical development program to date includes patients with more than 30 tumor types in more than 160 clinical trials, including more than 80 trials that combine KEYTRUDA with other cancer treatments.

Early Findings from the KEYNOTE-037 Study (KEYTRUDA with Epacadostat)

KEYNOTE-037 is an ongoing Phase 1/2 study of KEYTRUDA (pembrolizumab) in combination with epacadostat (INCB024360) – an investigational selective IDO1 inhibitor – in patients with advanced cancers. The trial is a collaboration between Merck and Incyte Corporation. Data from the melanoma cohort of this study were presented on Nov. 21 at 2:50 p.m. PST by Dr. Omid Hamid, director, Melanoma Center, The Angeles Clinic and Research Institute. These data were previously presented earlier this month at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting as part of a presentation that included several tumor types. The SMR data includes additional safety data.

Early data from this trial showed that in 19 patients with advanced melanoma, the combination of KEYTRUDA (two doses studied – 2 mg/kg or 200 mg every three weeks) with epacadostat (four doses studied – 25, 50, 100 or 300 mg twice daily) demonstrated an ORR of 53 percent (n=10/19), including three complete responses (CRs) and seven partial responses (PRs). The disease control rate (DCR) was 74 percent (n=14/19).

Treatment-related adverse events were consistent with previously reported safety data for KEYTRUDA as a single agent. Fifteen percent (n=9/60) of patients assessed for safety across tumor types experienced Grade 3 investigator-assessed, treatment-related adverse events, including rash (8%), arthralgia (2%), AST increased (2%), mucosal inflammation (2%) and nervous system disorder (2%). Three patients discontinued treatment – one for Grade 3 arthralgia, one for Grade 3 AST increased, and one for Grade 2 nervous system disorder. No Grade 4 treatment-related adverse events or deaths were observed.

As previously announced, based on these findings, a Phase 3 trial of this combination is planned.

Early Findings from the MASTERKEY-265 Study (KEYTRUDA with IMLYGIC)

MASTERKEY-265 is an ongoing Phase 1b study evaluating the safety, efficacy, and tolerability of KEYTRUDA in combination with IMLYGIC – a herpes simplex virus-1 (HSV-1)-based oncolytic immunotherapy – in patients with previously untreated, unresected advanced melanoma. The trial is a collaboration between Merck and Amgen. Data from this study were presented on Nov. 21 at 3:20 p.m. PST by Dr. Georgina Long, associate professor, Melanoma Institute Australia, University of Sydney.

Data presented were of 16 evaluable patients and the first analysis of this study; results showed that the combination of KEYTRUDA (200 mg every two weeks) with IMLYGIC (up to 4 mL of 106 PFU/mL, then 108 PFU/mL every two weeks) resulted in an unconfirmed ORR of 56.3 percent (n=9/16) (95% CI, 19.8, 70.1), including two CRs and seven PRs. The DCR was 68.8 percent (n=11/16) (95% CI, 11, 58.7).

Treatment-related adverse events were consistent with previously reported safety data for KEYTRUDA (pembrolizumab). All 21 patients enrolled had at least one adverse event, and most were Grades 1 and 2. The most common adverse events (occurring in at least 30% of patients) of any grade were fatigue (52%), pyrexia (48%), chills (43%), rash (38%), headache (33%), and nausea (33%). Grade 3 adverse events included headache (5%) and diarrhea (5%). Treatment-related Grade 3 adverse events occurring in 5 patients included anemia, hyperglycemia, hypoglycemia, hypophosphatemia, headache, macular rash and generalized rash. No dose-limiting toxicities were reported.

Based on these findings, a Phase 3 part of this trial is planned.

Early Findings from the KEYNOTE-029 Study (KEYTRUDA with Ipilimumab)

KEYNOTE-029 is an ongoing Phase 1/2 study evaluating the safety, efficacy, and tolerability of KEYTRUDA in combination with low-dose ipilimumab in patients with advanced melanoma to investigate whether lower doses of ipilimumab improve the tolerability of the combination regimen. Early findings from this study were presented on Nov. 21 at 2 p.m. PST by Dr. Georgina Long, associate professor, Melanoma Institute Australia, University of Sydney.

Early findings in 72 evaluable patients with advanced melanoma showed that KEYTRUDA (2 mg/kg every three weeks) in combination with low-dose ipilimumab (1 mg/kg every three weeks for four doses) demonstrated an ORR of 56 percent (95% CI, 43-67), including three CRs and 37 PRs. The DCR was 79 percent (95% CI, 68-88).

Treatment-related adverse events were observed in 93 percent (n=67/72) of patients. Grade 3-4 treatment-related adverse events were observed in 36 percent of patients (n=26/72), including lipase increased (8%), amylase increased (6%), ALT increased (6%), AST increased (4%), rash (3%), and diarrhea (1%). Grade 3-4 immune-mediated adverse events included thyroiditis, hypophysitis, type 1 diabetes mellitus, pneumonitis, colitis, hepatitis, pancreatitis, severe skin reactions and renal events. There were no treatment-related deaths.

Additional Findings from the KEYNOTE-006 Study

KEYNOTE-006 is a global, open-label, randomized, pivotal, Phase 3 study of patients with unresectable stage 3 or 4 advanced melanoma who were naïve to ipilimumab and had no more than one prior systemic therapy. Patients received KEYTRUDA 10 mg/kg every two weeks (n=279), KEYTRUDA 10 mg/kg every three weeks (n=277), or four cycles of ipilimumab 3 mg/kg every three weeks (n=278). Today’s findings provide data on additional endpoints of ORR and PFS based on six months of additional follow-up (median follow-up of 13.8 months), as well as the first-time presentation of patient-reported outcomes. Results were featured in two poster sessions by Dr. Jacob Schachter, Ella Lemelbaum Institute for Melanoma, Sheba Medical Center, and Dr. Teresa Petrella, Sunnybrook Health Sciences Centre, University of Toronto.

Findings showed PFS rates for KEYTRUDA at 12 months were twice as high as ipilimumab – 37.7 percent in the KEYTRUDA every two week cohort and 36.3 percent in the every three week group, compared to 17.2 percent with ipilimumab (hazard ratio: 0.60 [95% CI, 0.49-0.74] and hazard ratio: 0.59 [95% CI, 0.48-0.73], respectively). Additionally, the ORR was 36.2 and 36.1 percent in patients receiving KEYTRUDA every two weeks or every three weeks, respectively [(95% CI, 30.6-42.1) and (95% CI, 30.4-42.1), respectively], compared to 12.9 percent for ipilimumab (95% CI, 9.2-17.5).

There continued to be no treatment-related deaths in the KEYTRUDA arm and there were no treatment-related deaths in the ipilimumab arm beyond one that was previously reported. Grade 3-5 treatment-related adverse events were lower for KEYTRUDA than for ipilimumab – 15.1 and 12.6 percent of patients receiving KEYTRUDA every two weeks and every three weeks had Grade 3-4 adverse events, respectively, compared to 19.9 percent of those receiving ipilimumab. Immune-mediated treatment-related adverse events were consistent with previously reported safety data for KEYTRUDA and included hypothyroidism, hyperthyroidism, colitis, hepatitis, hypophysitis, pneumonitis, type 1 diabetes mellitus, uveitis, myositis and nephritis.

Also reported at SMR from this study was a prespecified analysis of new patient-reported health-related quality of life (HRQoL) outcomes, based on measures such as physical, emotional, cognitive, and social functioning (based on European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire). The study showed that HRQoL was maintained to a greater degree with KEYTRUDA than with ipilimumab – the change from baseline at week 12 (difference in least squares) for KEYTRUDA was -2.3 (95% CI, -5.21 to 0.62) for the two-week group and -2.6 (95% CI, -5.44 to 0.23) for the three-week group, respectively, compared to -9.9 (95% CI, -13.01 to -6.72) for the ipilimumab arm.

In addition, KEYTRUDA was associated with a better symptom profile. Patients in the KEYTRUDA arms had smaller increases from baseline in fatigue, pain, dyspnea, appetite loss, and diarrhea, indicating that although these symptoms worsened with KEYTRUDA, they did so to a lesser degree than with ipilimumab. KEYTRUDA also resulted in improvements over baseline in nausea and vomiting and insomnia, whereas these symptoms worsened with ipilimumab.

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 (pembrolizumab) 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 (pembrolizumab): 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.

On November 20, 2015 Kancera reported an operational update on the PFKFB3 and HDAC6 projects as well as the EU-funded epigenetically targeted parasitic project A-PARADDISE (Press release, Kancera, NOV 20, 2015, View Source;releaseID=1076542 [SID:1234508302]).

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The PFKFB3 project
Recent studies conducted within the framework of the collaboration with Prof. Thomas Helleday show that treatment with Kancera’s PFKFB3 inhibitor KAN0438757 alone inhibits an aggressive breast cancer tumor formed by the cell line MB231 (triple negative breast cancer). The human cancer cells were transplanted into zebra fish and four days treatment with KAN0438757 reduced the size of the tumor by more than 50% in comparison with the control treatment. The results support that Kancera’s PFKFB3 inhibitor is effective when reaching the tumor in sufficient concentration. Previously reported results show that Kancera’s PFKFB3 inhibitor KAN0438757 is able to counteract cancer cell repair of the DNA. Hence there are grounds to examine whether a more potent effect of PFKFB3 inhibitors can be achieved against triple negative breast cancer by combining the treatment with e.g. DNA damaging radiation. However, such a combination effect remains to be demonstrated in vivo.

The HDAC6 project
Since May 2015, when Kancera’s first patent application in the HDAC6 project entered the international stage, new series of potent and selective inhibitors of the enzyme has been developed. An additional patent application that covers these new HDAC6 inhibitors will be registered before the end of January, 2016. In order facilitate the filing of the new patent application, Kancera has decided to postpone the publication of the first patent application for one year.

In June 2015, Vinnova announced that Kancera’s HDAC6 project had been awarded a grant of SEK 2,000,000 for the further development of HDAC6 inhibitors against cancer. The first installment of SEK 436,000 was paid in July. Vinnova has now decided to bring forward the second installment of SEK 750,000 to December 2015.

EU projektet mot parasitsjukdomar – A-PARADDISE
In February 2014 Kancera received an initial payment from the EU amounting to € 523,655 for the execution of the A-PARADDISE project. This project is a collaboration between 15 research groups on three continents to develop drugs against severe parasitic diseases: malaria, schistosomiasis, leishmaniasis and Chagas disease. The project issued an interim report which now has been approved by the EU. This means that a further installment of the grant will be paid to Kancera at year-end according to plan. This installment amounts to € 285,000.

For further information, please contact,

Thomas Olin, CEO: +46 (0) 735 20 40 01
Address:
Kancera AB (publ)
Karolinska Institutet Science Park, Banvaktsvägen 22
SE 171 48 Solna

Please visit the company website; View Source

About the PFKFB3 project
By blocking mechanisms which enable the cancer cells to adapt to periods of oxygen deprivation, possibilities open for new treatment strategies. Kancera’s project is based on a specific inhibition of the enzyme PFKFB3 resulting in a decreased metabolism in cancer cells, and decreased cell growth. In addition, research shows that PFKFB3 is involved in the regulation of both angiogenesis and division of cells, two critical processes that contribute to tumor growth. PFKFB3 is more common in oxygen-deficient tumor tissue compared to healthy tissue, which makes a targeted effect therapy with fewer side effects than traditional chemotherapy possible. Inhibition of PFKFB3 is expected to starve and weaken the tumor cells by reducing their glycolysis and cell division. This is a way to overcome the current problems of tumor resistance to radiation and chemotherapy.

About the HDAC6 project
Histone deacetylases (HDACs) are primarily involved in removing acetyl groups from the so-called histones and thereby affect how our genes are stored and activated in the cell nucleus. Some HDACs also affect the cell function outside the cell nucleus. HDAC6 belongs to this group of HDACs with a major biological role in the regulation of the cancer cell´s ability to migrate and to form metastases. The use of HDAC inhibitors in the treatment of cancer patients has so far yielded promising results, but has been limited due to severe side effects. For this reason, the pharmaceutical industry is now looking for more selective inhibitors of individual HDAC enzymes. Kancera´s discovery of selective HDAC6 inhibitors may provide a solution on how health care could take advantage of the anti-cancer effects of HDAC inhibitors without causing the patient severe side effects.

About the EU-project against parasitic diseases – A-PARADDISE
A-PARADDISE (Anti-Parasitic Drug Discovery in Epigenetics) is an EU-funded project (contract n° 602080), which aims to identify new drug targets for anti-parasitic drug discovery as well as to develop already available lead compounds to candidate drugs against schistosomiasis. The project will also develop lead compounds and possibly drug candidates against targets in the following parasites (diseases): Leishmania (Leishmaniasis), Trypanosoma cruzi (Chagas disease) and Plasmodium falciparum (malaria). The A-PARADDISE project builds on the completed and highly successful SEtTReND project which was focused against schistosomiasis.

On November 20, 2015 the U.S. Food and Drug Administration reported that it has granted approval for Ninlaro (ixazomib) in combination with two other therapies to treat people with multiple myeloma who have received at least one prior therapy (Press release, , NOV 20, 2015, View Source [SID:1234508303]).
Multiple myeloma is a form of blood cancer that occurs in infection-fighting plasma cells (a type of white blood cell) found in the bone marrow. These cancerous cells multiply, produce an abnormal protein and push out other healthy blood cells from the bone marrow. The disease may result in a weakened immune system and cause other bone or kidney problems. The National Cancer Institute estimates there will be 26,850 new cases of multiple myeloma and 11,240 related deaths in the United States this year.

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"As we learn more about the underlying biology of multiple myeloma, we are encouraged to see the development of new ways to treat this disease," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. "Today’s approval is the third drug for multiple myeloma approved this year and provides patients with a new oral treatment that slows disease progression when other therapy has failed." The FDA approved Farydak (panobinostat)in February and Darzalex (daratumumab) earlier this month.

Ninlaro is a type of cancer drug called a proteasome inhibitor and works by blocking enzymes from multiple myeloma cells, hindering their ability to grow and survive. Ninlaro is the first oral proteasome inhibitor and is approved in combination with another FDA-approved treatment for multiple myeloma called Revlimid (lenalidomide) and dexamethasone (a type of corticosteroid).

The safety and efficacy of Ninlaro were demonstrated in an international, randomized, double-blind clinical trial of 722 patients whose multiple myeloma came back after, or did not respond to, previous treatment. Study participants received either Ninlaro in combination with lenalidomide and dexamethasone or placebo plus lenalidomide and dexamethasone. Those taking Ninlaro lived longer without their disease worsening (average 20.6 months) compared to participants taking the other regimen (14.7 months).

The most common side effects of Ninlaro are diarrhea, constipation, low blood platelet count (thrombocytopenia), peripheral neuropathy (numbness and pain from nerve damage, usually in the hands and feet), nausea, peripheral edema (fluid under the skin causing swelling), vomiting and back pain.

The FDA granted priority review and orphan drug designations for Ninlaro. Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as tax credits, user fee waivers, and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

Ninlaro is marketed by Takeda Pharmaceuticals based in Osaka, Japan. Farydak is marketed by East Hanover, New Jersey-based Novartis Pharmaceuticals. Darzalex is marketed by Janssen Biotech of Horsham, Pennsylvania. Revlimid is marketed by Celgene Corporation, based in Summit, New Jersey.

On November 20, 2015 Celldex Therapeutics, Inc. (NASDAQ:CLDX)reported mature survival data from the Company’s randomized, double-blind Phase 2 study of RINTEGA (rindopepimut) in patients with EGFRvIII-positive, recurrent glioblastoma (GBM) at the 20th Annual Scientific Meeting of the Society for Neuro-Oncology (SNO) (Press release, Celldex Therapeutics, NOV 20, 2015, View Source [SID:1234508307]). The data were presented in a podium presentation by David A. Reardon, M.D., Clinical Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School; and President of the Society for Neuro-Oncology, as well as the lead investigator of the ReACT study. RINTEGA is an investigational EGFRvIII specific therapeutic vaccine and was granted Breakthrough Therapy Designation in February 2014. Patients with recurrent glioblastoma that express the EGFRvIII mutation typically have a worse prognosis than the overall glioblastoma population, including poor long-term survival (median time from recurrence to death for EGFRvIII-positive patients is 8.7 months1). As previously reported, the primary endpoint of the study, progression-free survival at six months (PFS6) has been met.

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Mature overall survival (OS) data continue to show a marked benefit [hazard ratio = 0.53 (0.32, 0.88); p=0.0137] with a long-term survival benefit clearly seen in the RINTEGA arm. In May, the Company reported a hazard ratio of 0.57 (0.33, 0.98) (p=0.0386) for OS in the study.

Nine of 10 patients (one patient lost to follow up) on the RINTEGA arm remain alive since the Company last presented data in May compared to only two out of five patients on the control arm.

At two years, the survival rate for RINTEGA patients is 25% versus 0% for control patients in the intent to treat (ITT) population, with five patients extending beyond two years.

Five patients in the RINTEGA arm continue survival follow-up without progression per central review, compared to only one patient on the control arm.

A clear advantage continues to be demonstrated across multiple, clinically important endpoints including overall survival (OS), long-term progression-free survival (PFS), objective response rate (ORR) and need for steroids.
33% of patients on the RINTEGA arm who were receiving steroids at baseline were able to stop steroids for six months or longer compared to none on the control arm.

"The results of the ReACT study change the way we think about glioblastoma—offering patients and their families new hope in the face of one of the most difficult to treat cancers and upending the notion that the brain, masked behind the blood brain barrier, is beyond the reach of the promise of immunotherapy," said David A. Reardon, M.D. "The long-term survival benefit observed in this study is unprecedented as it is exceedingly rare for patients with highly aggressive, EGFRvIII-positive glioblastoma—even in the newly diagnosed setting—to live beyond two years. Most striking perhaps is that not only are patients living considerably longer, they are also living better, with minimal side effects and a reduced need for steroids. The ReACT data also build considerable anticipation for the ACT IV study in newly-diagnosed glioblastoma as these patients typically present with much stronger immune systems and stand to derive an even greater benefit."

"Patients with glioblastoma—especially those who are EGFRvIII-positive—face a staggering diagnosis, and in the face of this news, making the decision to participate in a clinical trial—especially a randomized study—is never an easy decision," said Thomas Davis, M.D., Executive Vice President and Chief Medical Officer of Celldex. "To this end, we are extremely gratified on behalf of our ReACT patients, their families and physicians that RINTEGA continues to tell a very consistent, impressive story across multiple, clinically relevant endpoints including, most importantly, long-term survival. These results replicate what we have seen in earlier RINTEGA studies conducted in newly-diagnosed patients, supporting our belief that RINTEGA will be an important treatment option for all patients with EGFRvIII-positive glioblastoma."

Presentation Details

ReACT is a randomized, controlled Phase 2 exploratory study designed to determine if adding RINTEGA to standard of care bevacizumab (BV; Avastin) improves outcomes for patients with EGFRvIII-positive, recurrent glioblastoma across multiple measures. Patients [n=73, intent to treat (ITT)] were bevacizumab-naïve at study entry. Tumor responses were evaluated in accordance with RANO criteria by an independent expert review committee blinded to treatment group assignment. Data for this long-term update included study results through September 1, 2015.

PFS6: As previously reported, the primary endpoint of PFS6 was met. 10 out of 36 (28%) patients were alive at six months without progression on the RINTEGA arm compared to 6 out of 37 (16%) on the control arm (p=0.1163). Given the exploratory nature and size of the trial, the ReACT study required a PFS6 1-sided p-value of 0.2 (powered at 80%) for positivity.

SURVIVAL: RINTEGA+BV demonstrated a statistically significant, clinically meaningful overall survival benefit compared to BV alone. Consistent with previous studies of RINTEGA and the published data observed for immune-mediated therapeutics, this survival benefit includes a "tail" on the RINTEGA survival curve with multiple patients exceeding what is customary survival for EGFRvIII-positive glioblastoma. Nine patients on the RINTEGA arm continue to be followed for survival, including five without disease progression per central review. Two patients on the control arm continue to be followed for survival, including one without disease progression per central review. At two years, the survival rate for RINTEGA patients in the ITT population is 25% versus 0% for control patients.

OBJECTIVE RESPONSE RATE (ORR): Nine out of 30 evaluable ITT patients (30%) on the RINTEGA arm experienced a confirmed objective response versus six out of 34 evaluable patients (18%) on the control arm. Five patients on the RINTEGA arm experienced durable responses greater than six months, and three of these patients experienced durable responses greater than 18 months (range of 18.6+ to 22.2 months). In contrast, only two patients on the control arm experienced a durable response greater than six months, and none experienced a response greater than 7.4 months.

STEROID USE: Further emphasizing the level of disease control, 50% of the 18 patients on the RINTEGA arm who were on steroids at the start of treatment were able to stop steroids for at least two months during treatment versus only 26% of the 19 patients on the control arm who were on steroids at the start of treatment. 33% of patients on the RINTEGA arm were able to stop steroids for more than six months, and, of these, three were able to stop for more than one year versus none on the control arm for either time point.

IMMUNE RESPONSE: Prolonged survival was associated with high anti-EGFRvIII humoral responses that were predominantly of the cell killing IgG1 isotype, and recent in vivo experiments have shown those immune responses had tumor killing function through antibody dependent cellular cytotoxicity (ADCC) of EGFRvIII-expressing tumor cells. This biologic effector function is rarely proven for immune therapies. Importantly, rapid generation of anti-EGFRvIII humoral response correlated with longer survival; however, even those with slower development of immune responses benefitted. No patient in the control arm had detectable EGFRvIII specific antibody response. This effect is consistent with RINTEGA’s proposed mechanism of action as a targeted immunotherapeutic vaccine.

OTHER: Multiple subgroup and adjusted analyses have concluded that the consistent survival benefit observed in the study was not influenced by potential imbalances in patient demographics.
SAFETY: RINTEGA was very well tolerated without unexpected additive toxicity to bevacizumab.
RINTEGA is a registered trademark of Celldex Therapeutics. Avastin is a registered trademark of Genentech, Inc.
1Data provided the Radiation Therapy Oncology Group (RTOG).

About RINTEGA

RINTEGA is an investigational therapeutic vaccine that targets the tumor specific oncogene EGFRvIII, a functional and permanently activated variant of the epidermal growth factor receptor (EGFR), a protein that has been well validated as a target for cancer therapy. Expression of EGFRvIII correlates with increased tumorigenicity in mouse models and poor long-term survival in clinical studies of patients with glioblastoma (GBM). In addition, EGFRvIII-positive cells are believed to stimulate proliferation of non-EGFRvIII cells through IL-6 cell-to-cell signaling and to release microvesicles containing EGFRvIII, which can merge with neighboring cells, transferring tumor-promoting activity. EGFRvIII expression may also be associated with tumor stem cells that have been identified in GBM. These stem cells contribute to resistance to cytotoxic therapy and tumor recurrence. EGFRvIII is expressed in tumors in about 30% of patients with GBM. It has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to impact healthy tissues.

Three Phase 2 trials of RINTEGA—ACTIVATE, ACT II, and ACT III—have been conducted in newly diagnosed EGFRvIII-positive GBM and have shown consistent improvements in both overall survival and progression-free survival compared to matched historical controls. The most common adverse events for RINTEGA include injection site reactions, fatigue, rash, nausea and pruritus. RINTEGA is currently being studied in two clinical trials in EGFRvIII-positive GBM—an international Phase 3 study called ACT IV in newly diagnosed GBM and a Phase 2 study called ReACT in recurrent GBM. In February 2014, the U.S. Food and Drug Administration (FDA) granted RINTEGA Breakthrough Therapy Designation for the treatment of adult patients with EGFRvIII-positive glioblastoma. The first interim analysis for ACT IV occurred in June 2015, and the study’s Data Safety and Monitoring Board recommended continuation of the study as planned. The Company anticipates that ACT IV will reach the required 75% of events (deaths) to perform the second interim analysis in late 2015 and that the analysis will occur in early 2016.