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Novartis presents data showing Jakavi® is superior to best available therapy in patients with less advanced polycythemia vera (PV)

On June 10, 2016 Novartis reported Phase III data from RESPONSE-2 showing that Jakavi (ruxolitinib) helped patients with polycythemia vera (PV), who did not have an enlarged spleen and were resistant to or intolerant of hydroxyurea, achieve superior hematocrit control compared to best available therapy (BAT) at 28 weeks (62.2% vs 18.7%, respectively; p<0.0001)[1] (Press release, Novartis, JUN 10, 2016, View Source [SID:1234513182]). The findings were presented for the first time at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark.

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Polycythemia vera is a rare and incurable blood cancer associated with an overproduction of blood cells that can cause serious cardiovascular complications, such as blood clots, stroke and heart attack[4]. As the disease progresses, the spleen can become enlarged as it works to clear a greater number of blood cells than normal[5]. In this study, patients did not have an enlarged spleen as assessed by physical examination at baseline (spleen palpation) and a majority (approximately 70%) were previously treated with hydroxyurea only, therefore considered less advanced. The remaining patients were treated with multiple lines of therapy (approximately 30%)[1].

"RESPONSE-2 is the first study of this scale to focus on patients with inadequately controlled polycythemia vera in a less advanced phase of the disease," said lead study investigator, Francesco Passamonti, MD, the University of Insubria, Varese, Italy. "The study supports the use of Jakavi as a second-line treatment option to help this patient population gain better control of their disease."

Patients with PV in the study were classified as inadequately controlled based on the modified European LeukemiaNet (ELN) criteria, which defines resistance to or intolerance of hydroxyurea as hematocrit levels greater than 45%, elevated white blood cell count and/or platelet count, and the presence of hydroxyurea-related non-hematologic toxicities[6].

"Given the limited research and treatment options for polycythemia vera, this trial was initiated to gain a better understanding of Jakavi in patients whose disease is not adequately controlled with hydroxyurea," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "The results demonstrate the potential benefit of Jakavi to help manage the disease in patients who have few other options."

In addition to meeting its primary endpoint of proportion of patients achieving hematocrit control, the RESPONSE-2 study showed that nearly five times more patients with PV achieved complete hematologic remission with Jakavi compared to BAT at 28 weeks (23.0% vs 5.3%, respectively; p=0.0019). Patients taking Jakavi also experienced complete resolution of their symptoms related to PV compared to BAT (50.0% vs 7.7%, respectively). Overall, Jakavi was well tolerated. Findings from this study are consistent with data from the RESPONSE pivotal trial evaluating patients with inadequately controlled PV with an enlarged spleen[1,2].

Additionally, Phase III data from the COMFORT-I study were also presented at EHA (Free EHA Whitepaper). These data suggest an overall survival advantage in patients with intermediate-2 or high-risk myelofibrosis (MF) randomized to Jakavi compared to patients randomized to placebo. The five-year survival showed a 31% reduced risk of death (HR=0.69; 95% CI: 0.50, 0.96; p=0.025) in the Jakavi arm despite more than 70% of patients randomized to the placebo arm crossing over to receive treatment with Jakavi (median time to crossover was 41.1 weeks). Patients treated with Jakavi maintained spleen response (>=35% reduction in size) for an average of three years. These findings further support the durable efficacy and long-term safety profile of Jakavi in MF[3].

About the RESPONSE-2 Study
The Phase IIIb RESPONSE-2 (Randomized Study of Efficacy and Safety in POlycythemia Vera with JAK INhibitor Ruxolitinib VerSus BEst Available Care) study evaluated the efficacy and safety of Jakavi versus BAT. The trial randomized 149 patients with PV who were resistant to or intolerant of hydroxyurea, dependent on phlebotomy for hematocrit control and did not have an enlarged spleen. Patients were randomized 1:1, to receive either Jakavi (10 mg twice daily) or BAT, which was defined as investigator-selected monotherapy or observation only[1].

The primary endpoint of the trial was the proportion of patients who achieved hematocrit control at week 28 (without phlebotomy from week 8 to 28 with no more than one phlebotomy eligibility between randomization and week 8). The key secondary endpoint was the proportion of patients who achieved complete hematologic remission (CHR) at week 28. CHR was defined as achieving hematocrit control without the use of phlebotomy, platelet count <=400 x 109/L and white blood cell count <=10 × 109/L, which are all important markers of disease control in PV[1].

In the study, anemia occurred in 16.2% of patients in the Jakavi-treatment arm compared to 2.7% in the BAT arm. The most common non-hematologic adverse events (>=10% of patients) in either the Jakavi or BAT arm were headache (12.2% vs 10.7%, respectively), constipation (10.8% vs 5.3%, respectively), hypertension (10.8% vs 4.0%, respectively), pruritus (10.8% vs 20.0%, respectively), and weight increase (10.8% vs 1.3%, respectively), which were mainly Grade 1 or 2. Patients treated with Jakavi had fewer thromboembolic events compared to patients taking BAT (1 vs 3, respectively)[1].

About the COMFORT-I Study
The Phase III COMFORT-I (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) study included 309 patients with primary MF, post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF) in 89 study locations in Canada, Australia and the United States. Half of the patients (155) received Jakavi (starting dose 15 or 20 mg twice daily) and half (154) received placebo. Patients receiving placebo could crossover to the Jakavi arm after the primary analysis or at any time if they had pre-specified worsening of their enlarged spleen. A final analysis of the study at five years was performed to evaluate the safety and efficacy of Jakavi in patients with MF[3].

Notable adverse events (AE) at the five-year analysis included herpes zoster (10.3% and 13.5% in Jakavi patients and patients who crossed over from placebo, respectively), basal cell carcinoma (7.7% and 9.0%, respectively) and acute myeloid leukemia (5 patients in each arm)[3].

About Polycythemia Vera
Polycythemia vera affects up to three per 100,000 people globally each year[7]. The disease is driven by the dysregulation of the JAK-STAT pathway[8]. It is typically characterized by elevated hematocrit, the volume percentage of red blood cells in whole blood, which can lead to a thickening of the blood and an increased risk of blood clots, as well as an elevated white blood cell and platelet count[4]. This can cause serious cardiovascular complications, such as stroke and heart attack, resulting in increased morbidity and mortality[9]. PV can also persist for many years and in some cases evolve to myelofibrosis (post-PV MF) or acute myeloid leukemia (AML)[10].

A common PV treatment includes phlebotomy, a procedure to remove blood from the body to reduce the concentration of red blood cells, which is used to help maintain a hematocrit level below 45%[4,9]. However, for a subset of patients, phlebotomy may be unsuitable as a permanent treatment option due to its inability to control symptoms or effectively manage the overproduction of red blood cells, therefore cytoreductive agents, such as hydroxyurea, may be added[9]. For patients requiring phlebotomy in combination with hydroxyurea, hematocrit may fluctuate and remain at unsafe levels for significant periods of time[11]. Unfortunately, approximately 25% of patients with PV become resistant to or intolerant of hydroxyurea treatment according to ELN criteria, resulting in inadequate disease control and an increased risk of progression[12].

About Myelofibrosis
Myelofibrosis is a rare and life-threatening blood cancer that affects approximately one in every 100,000 people and has similar survival rates as other malignancies, such as breast cancer and colon cancer[7,13,14,15,16]. In patients with MF, their bone marrow can no longer produce enough normal blood cells, causing the spleen to enlarge[13]. As a result, patients may suffer from debilitating symptoms and have a poor quality of life[17]. Approximately 90% of patients with MF have mutations that directly or indirectly activate the JAK/STAT signaling pathway, which may explain the development of the disease[18].

Although allogeneic stem cell transplantation may cure MF, the procedure is associated with significant morbidity and transplant-related mortality, and is available to less than 5% of patients who are young and fit enough to undergo the procedure[19].

About Jakavi
Jakavi (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases. Jakavi is approved by the European Commission for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea and for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (MF) (also known as chronic idiopathic MF), post-polycythemia vera MF or post-essential thrombocythemia MF. Jakavi is approved in more than 95 countries for patients with MF, including countries in the European Union, Canada, Japan and countries in Asia, Latin and South America, and in 60 countries for patients with PV, including countries in the European Union, Japan and Canada. The exact indication for Jakavi varies by country. Additional worldwide regulatory filings are underway in MF and PV.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialization outside the United States. Jakavi is marketed in the United States by Incyte Corporation as Jakafi for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea and for the treatment of patients with intermediate or high-risk MF.

The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. The recommended starting dose of Jakavi in MF is 15 mg given orally twice daily for patients with a platelet count between 100,000 cubic millimeters (mm3) and 200,000 mm3, and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses may be titrated based on safety and efficacy. There is limited information to recommend a starting dose for MF and PV patients with platelet counts between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these patients is 5 mg twice daily, and patients should be titrated cautiously[20].

Jakavi is a registered trademark of Novartis AG in countries outside the United States. Jakafi is a registered trademark of Incyte Corporation. The safety and efficacy profile of Jakavi has not yet been established outside the approved indications.

Jakavi Important Safety Information for Treatment of Myelofibrosis (MF) and Polycythemia Vera (PV)
Jakavi can cause serious side effects, including a decrease in blood cell count and infections. Complete blood count monitoring is recommended. Dose reduction or interruption may be required in patients with any hepatic impairment or severe renal impairment or in patients developing hematologic adverse reactions such as thrombocytopenia, anemia and neutropenia. Dose reductions are also recommended when Jakavi is co-administered with strong CYP3A4 inhibitors or fluconazole. Use of Jakavi during pregnancy is not recommended, and women should avoid becoming pregnant during Jakavi therapy. Women taking Jakavi should not breast feed. Progressive multifocal leukoencephalopathy (PML) has been reported. Physicians should be alert for neuropsychiatric symptoms suggestive of PML. Hepatitis B viral load (HBV-DNA titer) increases have been reported in patients with chronic HBV infections. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. Non-melanoma skin cancer (NMSC) has been reported in Jakavi treated patients. Periodic skin examination is recommended. Very common adverse reactions in MF (>10%) include urinary tract infections, anemia, thrombocytopenia, neutropenia, hypercholesterolemia, dizziness, headache, alanine aminotransferase increased, aspartate aminotransferase increased, bruising and weight gain. Common adverse reactions in MF (1 to 10%) include herpes zoster and flatulence. Uncommon adverse reactions in MF include tuberculosis. Very common adverse reactions in PV (>10%) include anemia, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia, dizziness, alanine aminotransferase increased and aspartate aminotransferase increased. Common adverse reactions in PV (1 to 10%) include urinary tract infections, herpes zoster, weight gain, constipation and hypertension.

Please see full Prescribing Information available at www.jakavi.com (link is external).

OXiGENE Receives U.S. Orphan Drug Designation for CA4P to Treat Glioma

On June 10, 2016 OXiGENE, Inc. (Nasdaq:OXGN), a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, reported that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to CA4P for the treatment of glioma (Press release, OXiGENE, JUN 10, 2016, View Source [SID:1234513183]). The designation provides for seven years of marketing exclusivity following product approval. CA4P has previously received orphan drug designation from the FDA for the treatment of ovarian cancer, neuroendocrine tumors and certain thyroid cancers.

Glioma is a broad category of brain tumors that grow from glial cells, and includes glioblastoma multiforme (GBM), which is particularly aggressive and often spreads quickly. OXiGENE has preclinical data that demonstrate a positive treatment effect of CA4P in GBM models.

"I am pleased that the FDA has provided orphan designation to CA4P for the treatment of glioma," stated William D. Schwieterman, M.D., President and Chief Executive Officer of OXiGENE. "While the principal focus of our clinical development program remains on ovarian cancer, we continue to expand the potential indications and improve our proprietary position for CA4P as part of our novel platform of vascular targeted therapies in oncology."

Orphan designation can be granted by the FDA to product candidates that are intended to treat rare diseases that generally affect fewer than 200,000 people in the United States.

Novartis highlights long-term safety data of Revolade® in adults with chronic immune thrombocytopenia, a rare blood disorder

On June 10, 2016 Novartis reported data from the largest study of its kind confirming the long-term safety profile of Revolade (eltrombopag) in adults with chronic immune (idiopathic) thrombocytopenia (ITP), with data for up to 6 years in some patients (median exposure was 2.4 years) (Press release, Novartis, JUN 10, 2016, View Source [SID:1234513181]).[1,2] Additional data from the study will also be presented that showed long-term oral administration of Revolade was effective in increasing and maintaining platelet counts in adult patients who had their spleens removed (splenectomized) as well as those who did not (non-splenectomized)[4]. The final results of the study and sub-analysis will be presented at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark.

ITP is a rare and potentially serious blood disorder where the blood doesn’t clot as it should due to a low number of platelets. As a result, patients experience bruising, bleeding and, in some cases, serious hemorrhage that can be fatal. ITP may also affect a patient’s quality of life, as it is often associated with fatigue and depression as well as a fear of bleeding that may limit everyday activities[3].

"Patients living with chronic diseases will likely remain on therapy for many years, so data about the long-term use of treatments, particularly around safety, are critical," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "EXTEND is the largest study of its kind and reinforces Revolade as a trusted option that adults with chronic ITP can use for the long-term."

The safety profile of Revolade seen in the EXTEND trial is consistent with that observed in the pivotal 24-week Phase III RAISE study[1,2]. Long-term use of Revolade was not associated with a clinically relevant increase in bone marrow reticulin or collagen fibers[5]. The most common adverse events were headache (28%), nasopharyngitis (25%), upper respiratory tract infection (23%), and fatigue (17%)[1,2].

The efficacy results of EXTEND demonstrated that median platelet counts were elevated to >=50 × 109/L within two weeks of Revolade treatment, with median platelet counts >50 × 109/L maintained for more than four years. Post-baseline, overall bleeding rates declined and the majority of bleeding that occurred during more than six years of the study was Grade 1 according to the World Health Organization bleeding scale[1,2]. In addition, 91.4% (276/302) of patients achieved platelet counts >=30 × 109/L without rescue treatment, and 85.8% (259/302) achieved platelet counts >=50 × 109/L without rescue treatment[1,2].

About the EXTEND Clinical Trial
EXTEND, an open-label extension study of four trials (including the pivotal trial) of Revolade, enrolled 302 adults with chronic ITP who had received prior therapy for their ITP, and is the largest study of its kind. The objectives were to assess the safety and efficacy of long-term treatment with Revolade, including the proportion of patients achieving stable platelet counts during treatment with Revolade; maximum duration of platelet count elevation >=50×109/L or >=30×109/L during treatment with Revolade, and the effect of Revolade on reducing and/or sparing concomitant ITP therapies, while maintaining a platelet count >=50×109/L[1,2].

Revolade was started at a dose of 50 mg/day and titrated to 25-75 mg/day or less often based on platelet counts. Maintenance dosing continued after minimization of concomitant ITP medication and optimization of Revolade dosing. The overall median duration of exposure was 2.4 years (range, 2 days to 8.8 years) and mean average daily dose was 50.2 (range, 1-75) mg/day[1,2]. One hundred thirty-five adult patients (45%) completed the study and 75 adult patients (25%) were treated for four or more years. Most patients were aged <65 years, female, and had platelet counts >15 ×109/L at baseline. About one third were using concomitant medications at baseline, and 53% had received three or more prior ITP therapies[1,2].

Grade 3 and 4 adverse events (AEs) occurred in 26% and 6% of patients, respectively. Grade 3 cataract occurred in four (1%) patients and Grade 3 pain in extremity in six (2%) patients. Grade 3 AEs occurring in three (<1%) patients each included diarrhea, headache, migraine, dyspnea, platelet count decreased, and menorrhagia; those occurring in five (2%) patients each included pneumonia, fatigue, back pain, alanine aminotransferase increased, aspartate aminotransferase increased, anemia, and hypertension. Grade 4 anemia and thrombocytopenia occurred in three (<1%) and four (1%) patients, respectively. All other Grade 4 events occurred in one patient each[1,2].

Sub-analysis in patients with or without splenectomy
In addition, a planned sub-analysis compared the safety and efficacy of long-term Revolade treatment in patients with or without splenectomy in the EXTEND trial[4].

Of the 302 adult patients in the trial, 115 with splenectomy (38%) and 187 without splenectomy (62%) had similar characteristics at baseline, except that more splenectomized patients were receiving ITP medications (47% vs 25%) and had a history of clinically significant bleeding (23% vs 13%). More than half of the patients in both groups received Revolade for >=24 months. After Revolade treatment, response rates (patients achieving platelets >=50 ×109/L without rescue therapy) were somewhat higher in the non-splenectomized patients. Overall, rates of some bleeding AEs were higher in splenectomized patients, but most occurred at comparable rates. Events occurring in >=4% of patients in the splenectomized and non-splenectomized groups, respectively, included mouth hemorrhage (4% and 1%), epistaxis (14% and 6%), petechiae (8% and 2%), ecchymosis (2% and 4%), contusion (3% and 4%), and hematuria (2% and 4%). The proportion of patients in each splenectomy group who were able to discontinue or reduce concomitant medications from baseline were similar, with 13% in each group attempting to reduce/discontinue medication and 11-12% stopping at least one medication[4].

About Chronic ITP
People who have ITP often have purple bruises or tiny red or purple dots on the skin. They also may have nosebleeds, bleeding from the gums during dental work, or other bleeding that is hard to stop. In most cases, an autoimmune response in which a person’s immune system attacks and destroys its own platelets is thought to cause ITP[3].

ITP is classified by duration into newly diagnosed, persistent (3-12 months’ duration) and chronic (>12 months’ duration). Chronic ITP is more likely to occur in adults, and women are affected two to three times more often than men[6,7,8].

The goal of treatment in chronic ITP is to maintain a safe platelet count that reduces the risk of bleeding. Treatment is determined by the severity of the symptoms. In most cases, drugs that alter the immune system’s attack on the platelets are prescribed to help manage bleeding and bruising in adults[7,8,9].

About Revolade (eltrombopag)
Revolade is approved in more than 100 countries for the treatment of thrombocytopenia in adult patients with chronic ITP who have had an inadequate response or are intolerant to other treatments. Eltrombopag (marketed as Promacta in the US) is approved in the EU and the US for patients one year and older with chronic ITP who have had an insufficient response to other treatments. Revolade is also approved in 45 countries for the treatment of patients with severe aplastic anemia (SAA) who are refractory to other treatments, and in more than 50 countries for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy.

Revolade Important Safety Information
Revolade may cause serious side effects, such as liver problems, high platelet counts and a higher chance for blood clots, bleeding after stopping treatment, and bone marrow problems.

Revolade may damage the liver and cause serious, even life threatening, illness. Blood tests to check the liver are needed before taking Revolade and during treatment. When certain antiviral treatments are given together with Revolade for the treatment of thrombocytopenia due to hepatitis C virus (HCV) infections, some liver problems can get worse.

A doctor will order the blood tests and any other tests required. In some cases Revolade treatment may need to be stopped. Patients should tell a doctor right away if they have any of these signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), unusual darkening of the urine, unusual tiredness, right upper stomach area pain.

Patients have a higher chance of getting a blood clot if their platelet count is too high during treatment with Revolade, but blood clots can occur with normal or even low platelet counts. Patients who have cirrhosis of the liver are at risk of a blood clot in a blood vessel that feeds the liver. Patients may have severe complications from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. A doctor will check the patient’s blood platelet counts, and change the dose or stop Revolade if platelet counts get too high. Patients should tell their doctor right away if they have signs and symptoms of a blood clot in the leg, such as swelling or pain/tenderness of one leg.

When patients with chronic ITP stop taking Revolade, their blood platelet count will drop back down to what it was before they started taking Revolade. These effects are most likely to happen within 4 weeks after patients stop taking Revolade. The lower platelet counts may increase risk of bleeding. A doctor will check platelet counts for at least 4 weeks after patients stop taking Revolade. Patients should tell their doctor or pharmacist if they have any bruising or bleeding after they stop taking Revolade.

Patients being treated for the disease may have problems with their bone marrow. Medicines like Revolade could make this problem worse. Signs of bone marrow changes may show up as abnormal results in blood tests. A doctor may also carry out tests to directly check the bone marrow during treatment with Revolade.

The most common side effects of Revolade when used to treat adult patients with chronic ITP include headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and peripheral edema.

The most common side effects of Revolade when used to treat pediatric patients with chronic ITP include upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, rash, increased AST and rhinorrhea.

The most common side effects of Revolade when used to treat patients with chronic HCV and antiviral agents include headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and peripheral edema.

The most common side effects of Revolade when used to treat patients with severe aplastic anemia (SAA) include headache, dizziness, insomnia, cough, dyspnea, oropharyngeal pain, rhinorrhea, nausea, diarrhea, abdominal pain, transaminases increased, ecchymosis, arthralgia, muscle spasms, pain in extremity, fatigue, febrile neutropenia, and pyrexia. Common side effects that may show up in blood tests include increase in some liver enzymes and laboratory tests that may show abnormal changes to the cells in the bone marrow.

Please see full EU Summary of Product Characteristics for Revolade (eltrombopag).

New Phase 3 Data Show Jakafi® (ruxolitinib) is Superior to Best Available Therapy in Patients with Polycythemia Vera (PV)

On June 10, 2016 Incyte Corporation (Nasdaq: INCY) reported new 28-week data from the Phase 3 RESPONSE-2 study of Jakafi (ruxolitinib) (Press release, Incyte, JUN 10, 2016, View Source [SID:1234513180]). The data show that Jakafi was superior to best available therapy (BAT) in maintaining hematocrit control (62.2% vs. 18.7%, respectively; P<0.0001)1 without the need for phlebotomy in patients with inadequately controlled polycythemia vera (PV) resistant to or intolerant of hydroxyurea (HU) who did not have an enlarged spleen. The safety profile of Jakafi was consistent with previous studies. These findings were presented at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark.

In RESPONSE-2, patients did not have an enlarged spleen, as assessed by physical examination at each study visit (spleen palpation), and a majority (70%) were previously treated with HU only, therefore considered to have less advanced disease. The remaining patients were treated with multiple lines of therapy (30%).1

"We are pleased with the RESPONSE-2 study results presented at EHA (Free EHA Whitepaper), which reinforce the superiority of Jakafi over best available therapy in achieving hematocrit control, without phlebotomy, in patients with inadequately controlled PV without enlarged spleens," said Steven Stein, M.D., Incyte’s Chief Medical Officer. "These results are meaningful to patients with uncontrolled PV who have few other treatment options to help manage their disease."

Additionally, the RESPONSE-2 study demonstrated that nearly five times more patients with PV achieved complete hematologic remission with Jakafi compared to BAT at 28 weeks (23.0% vs 5.3% respectively, p=0.0019). Patients taking Jakafi also experienced improvement in their PV symptoms compared to BAT (50% vs 7.7%, respectively). Overall, Jakafi was well tolerated. Findings from this study are consistent with data from the RESPONSE pivotal trial, which evaluated patients with inadequately controlled PV with an enlarged spleen.1,2

"A key treatment goal for patients with PV is to achieve and maintain hematocrit control, and compared to best available therapy, these results from the RESPONSE-2 study demonstrate the clinical benefits of Jakafi in PV patients with less advanced disease," said lead study investigator Francesco Passamonti, M.D., the University of Insubria, Varese, Italy. "The results from RESPONSE-2, coupled with the previously reported results, support Jakafi as a second-line treatment option for patients with PV."

About RESPONSE-2
RESPONSE-2 is a multi-center, open label, randomized, Phase 3 study evaluating the efficacy and safety of Jakafi versus BAT. The trial randomized 149 patients with PV who are resistant to or intolerant of HU, dependent on phlebotomy for hematocrit control and do not have an enlarged spleen. Patients were randomized 1:1 (74 and 75 patients were randomized to Jakafi and BAT respectively), by stratification (based on HU-resistance or intolerance) to receive either Jakafi (10 mg twice-daily) or BAT, which was defined as investigator selected monotherapy or observation only. The dose was adjusted as needed throughout the study.

About Polycythemia Vera
Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) and is typically characterized by elevated hematocrit, the volume percentage of red blood cells in whole blood, which can lead to a thickening of the blood and an increased risk of blood clots, as well as an elevated white blood cell and platelet count.3 Patients with PV who fail to consistently maintain appropriate blood count levels, including appropriate hematocrit levels, have an approximately four times higher risk of major thrombosis (blood clots) or cardiovascular death.4 Patients with PV can also suffer from an enlarged spleen and a significant symptom burden which may be attributed to thickening of the blood and lack of oxygen to parts of the body.5 These symptoms commonly include fatigue, itching, night sweats, bone pain, fever, and weight loss.6

Approximately 100,000 patients in the U.S. are living with PV.7 Current standard treatment for PV is phlebotomy (the removal of blood from the body) plus aspirin. When phlebotomy can no longer control PV, chemotherapy such as hydroxyurea, or interferon, is utilized.8,9 Approximately one in four patients with PV are considered uncontrolled10,11 because they have an inadequate response to or are intolerant of hydroxyurea, the most commonly used chemotherapeutic agent for the treatment of PV.

About Jakafi (ruxolitinib)
Jakafi is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. Food and Drug Administration, for treatment of people with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea.
Jakafi is also indicated for treatment of people with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF.
Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi (ruxolitinib) outside the United States.

Important Safety Information
Jakafi can cause serious side effects, including:
Low blood counts: Jakafi (ruxolitinib) may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.
Skin cancers: Some people who take Jakafi have developed certain types of non-melanoma skin cancers. Tell your healthcare provider if you develop any new or changing skin lesions.

Increases in Cholesterol: You may have changes in your blood cholesterol levels. Your healthcare provider will do blood tests to check your cholesterol levels during your treatment with Jakafi.

The most common side effects of Jakafi include: low platelet count, low red blood cell counts, bruising, dizziness, headache.
These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had tuberculosis (TB), or have been in close contact with someone who has TB, have or had hepatitis B, have or had liver or kidney problems, are on dialysis, had skin cancer or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change or stop taking Jakafi without first talking to your healthcare provider. Do not drink grapefruit juice while on Jakafi.

Women should not take Jakafi while pregnant or planning to become pregnant, or if breast-feeding.
Full Prescribing Information, which includes a more complete discussion of the risks associated with Jakafi, is available at www.jakafi.com.

New Data on Bristol-Myers Squibb’s Opdivo (nivolumab) Indicate Benefit in Heavily Pre-Treated Classical Hodgkin Lymphoma Patients in Phase 2, Single-Arm Pivotal Trial

On June 10, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported results from CheckMate -205, a multi-cohort, non-comparative, single-arm, Phase 2 registrational trial evaluating Opdivo (nivolumab) in patients with classical Hodgkin lymphoma (cHL) (Press release, Bristol-Myers Squibb, JUN 10, 2016, View Source [SID:1234513178]).

These results, from cohort B of the trial, included patients who had relapsed or progressed after autologous hematopoietic stem cell transplantation (auto-HSCT) and post-transplantation brentuximab vedotin (n=80). The primary endpoint of objective response rate (ORR) per an independent radiologic review committee (IRRC) was 66.3% (95% CI: 54.8-76.4). Median time to response was 2.1 months, and estimated median duration of remission was 7.8 months (95% CI: 6.6-NE). The majority of responses (62.3%) were ongoing at the time of analysis. In an exploratory analysis, the authors observed more than two-thirds (72.1%) of patients who did not respond to most recent prior brentuximab vedotin treatment did respond to Opdivo. The safety profile of Opdivo in CheckMate -205 was consistent with previously reported data in this tumor type.

These data will be presented at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark on Sunday, June 12 from 8:00 – 8:15 a.m. CEST (Abstract #S793) and is in press with The Lancet Oncology.

"There is currently no standard treatment option for classical Hodgkin lymphoma patients who have relapsed or whose disease has progressed after auto-HSCT and post-transplantation brentuximab vedotin," said Andreas Engert, M.D., lead investigator and professor of Internal Medicine, Hematology and Oncology, University Hospital of Cologne, Cologne, Germany. "We are encouraged by the objective response rates and that the majority of responses were ongoing at the time of analysis in the CheckMate -205 trial evaluating Opdivo in these heavily pre-treated patients."

"Classical Hodgkin lymphoma is a disease that disproportionately impacts young people, and there is a significant unmet need for patients who are not cured by the current standard-of-care treatments and who have a poor prognosis and very limited options," said Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb. "The data presented at EHA (Free EHA Whitepaper) demonstrate that Opdivo is an important treatment option for patients whose disease has progressed after auto-HSCT and post-transplantation brentuximab vedotin."

Opdivo recently received its first U.S. Food and Drug Administration approval in hematology on May 17, 2016, which also marks the first approval of a PD-1 inhibitor in a hematological malignancy. It was granted accelerated approval based on overall response rate for the treatment of patients with cHL who have relapsed or progressed after auto-HSCT and post-transplantation brentuximab vedotin based on a combined analysis of data from the Phase 2 CheckMate -205 trial, which were more limited than the data being presented at EHA (Free EHA Whitepaper), and the Phase 1 CheckMate -039 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Opdivo also is currently under regulatory review for cHL in the European Union and Japan.

About CheckMate -205

CheckMate -205 is a Phase 2, single-arm, open-label, international, multicenter, multi-cohort study that included the evaluation of Opdivo in adult patients with cHL. All patients in cohort B had failed both auto-HSCT and subsequent brentuximab vedotin. The median number of prior lines of therapy was four, and 49% had received at least five previous lines of therapy. Patients enrolled in this trial were treated with Opdivo 3 mg/kg intravenously every two weeks until disease progression or unacceptable toxicity.

The primary endpoint was ORR by IRRC assessment. Secondary endpoints based on IRRC assessment included duration of objective response, complete and partial remission rates, duration of complete and partial remission, and based on investigator assessment, objective response and duration of objective response. Exploratory endpoints included IRRC-assessed progression-free survival (PFS), overall survival (OS), safety and tolerability, and quality of life. Investigator-assessed ORR was 72.5% (95% CI: 61.4–81.9). Best overall response was complete and partial remission in 27.5% and 45.0%. At six months, the IRRC-assessed PFS rate was 76.9% (95% CI: 65-85), and the OS rate was 98.7% (95% CI: 91.0-99.8), whereas median PFS was 10 months (95% CI: 8.41–NA). The safety profile of Opdivo in CheckMate -205 remained consistent with previously reported data in this tumor type.

Classical Hodgkin lymphoma is characterized by Reed-Sternberg cells, which exhibit 9p24.1, resulting in overexpression of PD-1 ligands PD-L1 and PD-L2 on the tumor cell surface. Increased PD-L1 and PD-L2 expression by Reed-Sternberg cells may enable these cells to evade detection by the immune system. An exploratory analysis evaluated the association between the 9p24.1 genetic alteration, programmed death 1 (PD-1) ligand expression and IRRC-assessed ORR. Responses were reported in patients with any level of 9p24.1 alteration.

The most common drug-related adverse events were fatigue (25%; 20/80), infusion-related reaction (20%; 16/80), rash (16%; 13/80), arthralgia (14%; 11/80), pyrexia (14%; 11/80), nausea (13%; 10/80), diarrhea (10%; 8/80), and pruritus (10%; 8/80). Grade 3/4 adverse events occurred in 32 patients (40%), and one Grade 5 event occurred (1%; multi-organ failure). Serious adverse events of any cause were reported in 20 patients (25%; 20/80), the most common being pyrexia (4%; 3/8), and drug-related serious adverse events in five patients (6%), the most common being infusion-related reaction (3%). Extended safety follow-up of cHL patients treated in the nivolumab clinical trial program subsequently treated with allogeneic HSCT (N=17) identified complications, including fatal events.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.

We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for overall survival and other important measures like durability of response. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents and continue to study the role of combinations in cancer.

We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.

Our collaboration with academia, as well as small and large biotech companies, to research the potential of Immuno-Oncology and non-Immuno-Oncology combinations helps achieve our goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the way patients live with cancer.

About Opdivo

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating overall survival as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014 and currently has regulatory approval in 51 countries including the United States, Japan and in the European Union.

U.S. INDICATIONS & IMPORTANT SAFETY INFORMATION
INDICATIONS

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the CheckMate trials.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in Checkmate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In Checkmate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In Checkmate 205 and 039, diarrhea or colitis occurred in 30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Dermatitis

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In Checkmate 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25), and Grade 1 (n=3). In Checkmate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 069 and 067, adrenal insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In Checkmate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In Checkmate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 205 and 039, adrenal insufficiency (Grade 2) occurred in 0.4% (1/263) of patients receiving OPDIVO. In Checkmate 069 and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In Checkmate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 205 and 039, hypothyroidism/thyroiditis occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2 (n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5% (4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1 (n=1). In Checkmate 069 and 067, diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In Checkmate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1). In Checkmate 025, hyperglycemic adverse events occurred in 9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1). In Checkmate 205 and 039, diabetes mellitus occurred in 0.8% (2/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 069 and 067, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In Checkmate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6). In Checkmate 205 and 039, nephritis and renal dysfunction occurred in 4.9% (13/263) of patients treated with OPDIVO. This included one reported case (0.3%) of Grade 3 autoimmune nephritis.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In Checkmate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In Checkmate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In Checkmate 205 and 039, rash occurred in 22% (58/263) of patients receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In Checkmate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO. In Checkmate 205 and 039, encephalitis occurred in 0.8% (2/263) of patients after allogeneic HSCT after OPDIVO.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In Checkmate 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In Checkmate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In Checkmate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In Checkmate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In Checkmate 205 and 039, hypersensitivity/infusion-related reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic SCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Embryo-fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]).

Common Adverse Reactions

In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (reported in at least 20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Checkmate Trials and Patient Populations

Checkmate 069 and 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 057 – non-squamous non-small cell carcinoma (NSCLC); Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma.

Please see U.S. Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, for YERVOY.

Please see U.S. Full Prescribing Information for OPDIVO.