On September 25, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has accepted for filing and review a supplemental Biologics License Application (sBLA) for the Opdivo (nivolumab)+Yervoy (ipilimumab) regimen to include clinical data from CheckMate -067, a landmark trial in patients with previously untreated advanced melanoma (Press release, Bristol-Myers Squibb, SEP 25, 2015, View Source [SID:1234507559]). The FDA also granted Priority Review for this application with a target action date of January 23, 2016.

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CheckMate -067 is the first Phase 3 trial evaluating the Opdivo+Yervoy regimen or Opdivo monotherapy vs. Yervoy monotherapy in patients with previously untreated advanced melanoma. Results from CheckMate -067 demonstrated superior progression-free survival (PFS) for the Opdivo+Yervoy regimen or Opdivo monotherapy vs. Yervoy monotherapy in previously untreated patients with advanced melanoma, regardless of BRAF status. If approved, this application would expand upon the initial application for the Opdivo+Yervoy regimen, which was based on tumor response rate and safety data from the Phase 2 randomized trial, CheckMate -069. The CheckMate -067 trial that serves as the basis for this submission includes comparative PFS and objective response rate data.

"Findings from CheckMate -067 provide additional evidence that the combination of two Immuno-Oncology agents, Opdivo and Yervoy, may provide improved outcomes for patients with advanced melanoma, and has the potential to become the basis for how this devastating disease is treated," said Michael Giordano, senior vice president, head of Development, Oncology, Bristol-Myers Squibb. "We saw significant clinical benefit from the Opdivo+Yervoy regimen in these patients, including an increase in the time patients lived without disease progression, and we look forward to working with the FDA to review this data."

The CheckMate -067 trial is ongoing and patients continue to be followed for the co-primary endpoint of overall survival.

About Advanced Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. The incidence of melanoma has been increasing for at least 30 years. In the United States, more than 73,000 cases of melanoma will be diagnosed this year and nearly 10,000 people are expected to die from the disease. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate has historically been just six months with a one-year survival rate of 25.5%, making it one of the most aggressive forms of cancer.

About Opdivo and Yervoy

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo and Yervoy are both monoclonal antibodies and immune checkpoint inhibitors that target separate, distinct checkpoint pathways. Inhibition of these immune checkpoint pathways results in enhanced T cell function greater than the effects of either antibody alone.

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the FDA granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy.

Opdivo was approved by the European Commission for the treatment of advanced (unresectable or metastatic) melanoma in adults, regardless of BRAF status on June 19, 2015, making it the first approval given by the European Commission for a PD-1 inhibitor in any cancer. On July 20, 2015, Nivolumab BMS was also approved for the treatment of locally advanced or metastatic squamous non-small cell lung cancer after prior chemotherapy.

On March 25, 2011, the FDA approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is now approved in more than 40 countries.

OPDIVO IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO 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 OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO 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 OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 1, 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 Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.
Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).
Please see U.S. Full Prescribing Information for OPDIVO.

YERVOY IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. 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) 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.

Recommended Dose Modifications

Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day.

Permanently discontinue YERVOY for any of the following:

Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day
Failure to complete full treatment course within 16 weeks from administration of first dose
Severe or life-threatening adverse reactions, including any of the following:
Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation
AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin >3 × the ULN
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations

Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis
Severe immune-mediated reactions involving any organ system
Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy

Immune-mediated Enterocolitis:

In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immunemediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients
Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis

Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids

Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms

Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients
Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent)
Immune-mediated Hepatitis:

In the pivotal Phase 3 study in YERVOY-treated patients, 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%

13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2)
Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution

Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids
Withhold YERVOY in patients with Grade 2 hepatotoxicity

In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID)

Immune-mediated Dermatitis:

In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., 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
There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis

Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated
Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immunemediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms

Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week

Immune-mediated Neuropathies:

In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported

Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported

Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes

Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities)

Immune-mediated Endocrinopathies:

In the pivotal Phase 3 study in YERVOY- treated patients, severe to life-threatening immunemediated 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

Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome

Median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY

Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism

Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated
Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland

Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. Long-term hormone replacement therapy may be necessary

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:

In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immunemediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia
Across the clinical development program for YERVOY, likely immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis
Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions
Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy

Pregnancy & Nursing:

YERVOY is classified as pregnancy category C. There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus
Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus
It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY

Common Adverse Reactions:

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%)
Please see Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, available at www.bms.com.

Yervoy is a registered trademark of Bristol-Myers Squibb Company.

On September 25, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported results from CheckMate -025, a Phase 3 study comparing Opdivo to everolimus in advanced renal cell carcinoma (RCC) after prior anti-angiogenic treatment, showing a significant overall survival (OS) benefit for Opdivo (Press release, Bristol-Myers Squibb, SEP 25, 2015, View Source [SID:1234507558]). In the trial, Opdivo demonstrated a median OS benefit of 25 months compared to 19.6 months for everolimus. Clinical benefit for Opdivo was observed regardless of level of PD-L1 expression. The safety profile shown in CheckMate -025 is consistent with previously reported Opdivo trials. These data will be presented Saturday, September 26, during the 2015 European Cancer Congress (ECC2015) at a Presidential Session from 4:10 – 4:20 PM CEST (Late Breaking Abstract #3). The results were also featured during the ECC2015 press program on September 25 and published in The New England Journal of Medicine (NEJM), representing the ninth publication in the NEJM for Opdivo.

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"Patients with advanced renal cell carcinoma are in need of new treatment approaches that provide improved survival, safety and tolerability," said Robert J. Motzer, M.D., medical oncologist, Memorial Sloan Kettering Cancer Center and lead author of the NEJM publication. "This is the first Phase 3 study to demonstrate the efficacy of an immune checkpoint inhibitor in advanced renal cell carcinoma. The results show meaningful clinical benefit with Opdivo treatment, producing a significant overall survival advantage and greater number of objective responses compared to everolimus, a current standard of care in the treatment of advanced kidney cancer."

Approximately 30% of patients with RCC, a common type of kidney cancer in adults, present with metastatic or advanced disease at diagnosis. Despite multiple available treatment approaches for advanced RCC, available second-line therapies are associated with limited OS, and significant toxicities and limitations in tolerability, with the majority of current treatment options providing modest progression-free survival benefit.

"We continue to see the potential of our Immuno-Oncology agent, Opdivo, to provide meaningful improvement in multiple tumor types over current standards of care in terms of overall survival," said Michael Giordano, senior vice president, head of Development, Oncology. "Results of CheckMate -025 show that Opdivo has a significant survival advantage over standard of care in patients with advanced kidney cancer who have progressed following prior treatment. These data also reinforce our Immuno-Oncology research goal to provide patients with long-term survival, and brings further confidence to the approach taken in our broader RCC development program, including the combination of Immuno-Oncology agents."

CheckMate -025 was stopped in July because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its primary endpoint, demonstrating superior OS in patients receiving Opdivo compared to the control arm. Opdivo was granted Breakthrough Therapy Designation for advanced RCC by the U.S. Food and Drug Administration based on results from this trial and the clinical need for additional treatment approaches for RCC.

About CheckMate -025

CheckMate -025 is a Phase 3 randomized, open-label study of Opdivo versus everolimus in previously treated patients with advanced clear-cell RCC after prior anti-angiogenic treatment. Patients were randomized to receive Opdivo (n=410) 3 mg/kg intravenously every two weeks or everolimus (n=411) 10 mg orally once daily. The primary endpoint was OS. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), OS by PD-L1 expression, and incidence of adverse events (AEs).

Results from CheckMate -025 mark the first and only Phase 3 study to demonstrate a significant survival advantage in previously treated patients with advanced RCC versus standard of care. Patients treated with Opdivo in this study achieved a median OS of 25 months for Opdivo and 19.6 months for everolimus (hazard ratio: 0.73; [98.5% CI, 0.57-0.93; p=0.0018]), with comparable OS benefit seen across PD-L1 expression levels.

In addition to improving overall survival, Opdivo demonstrated a superior ORR of 25% versus 5% for everolimus (p<0.0001), with one out of four patients experiencing a response. Seventeen percent of Opdivo and 7% of everolimus patients remain on treatment with a minimum follow-up of 14 months.

The safety profile of Opdivo in CheckMate -025 was consistent with prior studies and favorable versus everolimus. Fewer grade 3-4 treatment-related AEs occurred with Opdivo (19%) compared to everolimus (37%). Any grade treatment-related AEs occurred in 79% of patients treated with Opdivo and 88% of patients treated with everolimus. The most frequent treatment-related AEs were fatigue (33%), pruritus (14%), and nausea (14%) in the Opdivo arm and fatigue (34%) and stomatitis (30%) in the everolimus arm.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to 90% of all cases. RCC is approximately twice as common in men as it is in women, with the highest rates of the disease found in North America and Europe. Globally, the five-year survival rate for those diagnosed with advanced kidney cancer is 12.1%.

About Opdivo

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the FDA as a monotherapy in two cancer indications. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous (SQ) non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. On July 20, the European Commission approved Nivolumab BMS for the treatment of locally advanced or metastatic SQ NSCLC after prior chemotherapy.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO 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 OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO 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 OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 1, 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 Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

On September 25, 2015 Janssen-Cilag International NV reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has accepted its request for an accelerated assessment of the daratumumab Marketing Authorisation Application (MAA) (Press release, Johnson & Johnson, SEP 25, 2015, View Source [SID:1234507552]). This acceptance follows the earlier regulatory submission of a MAA which seeks authorisation of daratumumab as a single agent for the treatment of patients with relapsed and refractory multiple myeloma and is currently pending validation by the EMA.

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The CHMP grants accelerated assessment when a medicinal product is expected to be of major public health interest particularly from the point of view of therapeutic innovation.

Daratumumab is an investigational, human anti-CD38 monoclonal antibody that works by binding to CD38, a signalling molecule found on the surface of multiple myeloma cells.1,2,3,4 In doing so, daratumumab triggers the patient’s own immune system to attack the cancer cells, resulting in rapid tumour cell death through multiple immune-mediated and other mechanisms of action.5

The MAA includes data from the Phase 2 MMY2002 (SIRIUS) monotherapy study, presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper),6 and data from the Phase 1/2 GEN501 monotherapy study, recently published in The New England Journal of Medicine,7 and data from three additional supportive studies.

"Janssen is pleased with the CHMP’s acceptance of an accelerated regulatory review timeline for daratumumab, which reflects the high unmet need for new treatment options for patients with multiple myeloma, currently an incurable disease," said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. "We continue to work closely with European health authorities to make daratumumab available to these patients as soon as possible."

In July 2013 daratumumab was granted Orphan Drug Status by the EMA for the treatment of plasma cell myeloma.8 Furthermore, this step forward in Europe also follows the acceptance for Priority Review of the Biologics License Application for daratumumab with the U.S. FDA on September 4, 2015.

In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement which granted Janssen an exclusive worldwide license to develop, manufacture, and commercialise daratumumab.

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.9 MM is the second most common form of blood cancer, with around 39,000 new cases in Europe in 2012.10 MM most commonly affects people over the age of 65 and is more common in men than in women.11 Across Europe, five-year survival rates are 23 percent to 47 percent of people diagnosed.12 Almost 29 percent of patients with MM will die within one year of diagnosis.13 Although treatment may result in remission, unfortunately patients will most likely relapse as there is currently no cure. While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.11 Patients who relapse after treatment with standard therapies, including proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), have poor prognoses and few treatment options available.14

About Daratumumab

Daratumumab is an investigational human monoclonal antibody that binds with high affinity to the CD38 molecule, which is found on the surface of multiple myeloma cells. It is believed to induce rapid tumour cell death through multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosic and antibody-dependent cellular cytotoxicity, as well as via induction of apoptosis.5 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases in which CD38 is expressed, such as smouldering myeloma and non-Hodgkin lymphoma.

On September 25, 2015 Oncolytics Biotech Inc. ("Oncolytics") (TSX:ONC) (NASDAQ:ONCY) reported that Dr. D.W. Sborov and colleagues made a poster presentation at the 15th International Myeloma Workshop (IMW) (Press release, Oncolytics Biotech, SEP 25, 2015, View Source [SID:1234507549]). The poster presentation, entitled "Combination Carfilzomib and the Viral Oncolytic Agent REOLYSIN in Patients with Relapsed Multiple Myeloma: A Pilot Study Investigating Viral Proliferation," discloses initial findings from a pilot study (NCI-9603) in patients with relapsed or refractory multiple myeloma treated using the combination of carfilzomib and REOLYSIN. The IMW runs from September 23rd to 26th in Rome, Italy.

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Highlights of the data presented include:

100% of patients (8 of 8) experienced an objective response as measured by changes in blood monoclonal protein. Of these, 2 patients had a very good partial response (VGPR), 3 patients had a partial response (PR) and 3 patients had a minor response (MR);
Only one patient has progressed to date and five of eight remain on study;
The combination of carfilzomib and REOLYSIN produced a significant (p=0.005) increase in caspase-3, a marker associated with apoptotic (programmed) cell death; and
The treatment combination was associated with an increased infiltration of CD8+ T-cells and the significant (p=0.005) upregulation of PD-L1, suggesting that the addition of a PD-1 or PD-L1 inhibitor may further optimize the treatment regimen.
"These findings demonstrate that the combination of carfilzomib and REOLYSIN shows promise in hematological malignancies like multiple myeloma and provide compelling evidence that such drug combinations promote viral replication and cancer cell death," said Dr. Matt Coffey, Chief Operating Officer of Oncolytics. "Based on these results, we intend to move into randomized studies in this indication."

The investigators noted that this is the first time a REOLYSIN-based combination has been tested in relapsed multiple myeloma patients. A previous single-agent study conducted by the collaborators in this patient population showed that REOLYSIN was well tolerated. The collaborators and others were noted to have conducted preclinical investigations that demonstrated that the combination of REOLYSIN and carfilzomib synergistically increased the killing of multiple myeloma cells. This provided the clinical rationale for this study. In this study, the combination of carfilzomib and REOLYSIN produced a significant (p=0.005) increase in caspase-3, a marker associated with apoptotic cell death. The researchers also determined that the combination of REOLYSIN and carfilzomib increases infiltration of CD8+ T-cells and significantly (p=0.005) upregulates PD-L1. The investigators concluded that these findings necessitate continued investigation, and suggest that the addition of a PD-1 or PD-L1 inhibitor may further optimize the REOLYSIN and carfilzomib regimen.

"To this point, multiple myeloma has not responded to checkpoint inhibitor therapy," said Dr. Brad Thompson, President and CEO of Oncolytics. "The combination of REOLYSIN and carfilzomib upregulates PD-L1 and increases infiltration of CD8+ T-cells, which may make the tumor sensitive to anti-PD-L1 therapy. The follow-on randomized study we are currently planning is expected to have a patient group treated with the combination of REOLYSIN, a standard of care chemotherapy, and a checkpoint inhibitor, as well as a patient group receiving REOLYSIN and a standard of care chemotherapy."

NCI-9603 is a U.S. National Cancer Institute sponsored single-arm, open-label study of intravenously administered REOLYSIN with dexamethasone and carfilzomib to patients with relapsed or refractory multiple myeloma. Patients receive treatment on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle, to be repeated in the absence of disease progression or unacceptable toxicity. Approximately 12 patients will be enrolled in the study. The primary outcomes include measuring reovirus replication, safety, and tolerability. Secondary outcomes include examining objective response, duration of response, clinical benefit, progression-free survival, and time to progression. Other outcomes will include the measurement of immunologic correlative markers.

A copy of the poster will be available on the Oncolytics website at: View Source

About Multiple Myeloma
Multiple Myeloma is a cancer of the plasma cells and the second most common hematological malignancy. The American Cancer Society estimates there will be 26,850 new cases diagnosed in the United States and 11,240 deaths from the disease in 2015.

On September 25, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the EU Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for CotellicTM (cobimetinib), when used in combination with Zelboraf (vemurafenib), for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma (Press release, Hoffmann-La Roche , SEP 25, 2015, View Source [SID:1234507547]). Approximately 50% of melanoma skin cancers are BRAF-positive, and more than 55,000 people worldwide die every year from melanoma.1

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"Today’s CHMP positive opinion is a substantial step forward for people with BRAF-positive skin cancer in Europe and around the world," said Sandra Horning, M.D., Chief Medical Officer and Global Head of Product Development. "The Cotellic and Zelboraf combination will provide physicians with a powerful therapeutic option that can help patients live significantly longer without their disease progressing compared to Zelboraf alone."

The CHMP’s recommendation is based primarily on results of the pivotal Phase III coBRIM study. These data showed that people who received the combination of Cotellic and Zelboraf lived over a year without their disease worsening (median progression-free survival of 12.3 months, compared to 7.2 months with Zelboraf alone; hazard ratio=0.58, 95 percent confidence interval 0.46-0.72).2 The objective response rate was also higher for the combination arm compared to Zelboraf alone (70 vs. 50 percent; p<0.0001).2 The most common adverse events in the combination arm of the pivotal study were diarrhoea, rash, nausea, fever, sun sensitivity, liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and vomiting.
Supportive data early in development from the Phase Ib BRIM7 study indicated that the combination of Cotellic and Zelboraf helped people who had not been previously treated with a BRAF inhibitor live more than two years (median overall survival 28.5 months).3

Based on this CHMP recommendation, a final decision regarding the approval of the combination of Cotellic and Zelboraf is expected from the European Commission by the end of 2015.

Cotellic recently received approval in Switzerland for use in combination with Zelboraf as a treatment for patients with advanced melanoma, and the U.S. Food and Drug Administration (FDA) is expected to make a decision on Roche’s new drug application for the combination before the end of the year.

About melanoma
Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer.4,5 A V600 mutation of the BRAF protein occurs in approximately half of melanomas, and should therefore be tested to identify the best treatment option.6 When melanoma is diagnosed early, it is generally a curable disease,7,8 but most people with advanced melanoma have a poor prognosis.5 More than 232,000 people worldwide are currently diagnosed with melanoma each year.1 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.9

About Cotellic and Zelboraf in combination
Zelboraf was the first approved treatment for patients with unresectable or metastatic melanoma with BRAF V600 mutation as detected by a validated test, such as Roche’s cobas 4800 BRAF Mutation Test. Zelboraf is not indicated for use in patients with wild-type BRAF melanoma. Cotellic (cobimetinib) is designed to selectively block the activity of MEK,10 one of a series of proteins inside cells that make up the MAPK signaling pathway that helps regulate cell division and survival.11 In the majority of patients, resistance to BRAF-inhibitor monotherapy will eventually occur through re-activation of the MAPK pathway via MEK.12 Cotellic was developed to overcome resistance to BRAF-inhibition and prevent re-activation of the pathway. Cotellic binds to MEK, while Zelboraf binds to mutant BRAF, to interrupt abnormal signalling that can cause tumours to grow.13,14

Cotellic is also being investigated in combination with several investigational medicines, including immunotherapy, in several tumour types such as non-small cell lung cancer and colorectal cancer. Cotellic was discovered by Exelixis Inc. and is being developed by Roche in collaboration with Exelixis.