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Bristol-Myers Squibb Company (NYSE: BMY) today announced four- and five-year survival rates based on long-term follow up from Phase 3 and Phase 2 YERVOY^® (ipilimumab) clinical trials in patients with treatment-naïve and previously-treated metastatic melanoma. The data were presented at the ESMO 2012 Congress (European Society for Medical Oncology). (Abstract #1127 and 1116.)

In the Phase 3 trial (024), patients who had not previously received treatment for metastatic melanoma (n=502) were randomized to receive either the investigational dose of YERVOY 10 mg/kg in combination with dacarbazine (DTIC, 850 mg/m²) or DTIC alone. Long-term follow-up from this study demonstrated that treatment with YERVOY plus DTIC resulted in a four-year survival rate of 19.0% compared to 9.6% for DTIC alone. Additionally, the overall survival data appeared relatively stable between years three and four for patients treated with YERVOY plus DTIC (21.2% at three years and 19.0% at four years). The three and four-year survival rates for patients treated with placebo plus DTIC were 12.1% and 9.6%, respectively.

In three Phase 2 trials (007 [n=115], 008 [n=155] and 022 [n=217]) in which five-year follow-up data are available through a rollover study (025), patients received YERVOY at 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg. No comparator treatment arms were included in these studies. In treatment-naïve patients, the five-year estimated survival rates ranged from 38% to 49%, which was unchanged from the four-year rates. In previously-treated patients, the five-year estimated survival rates (12% to 28%) were relatively stable compared to the rates at four years (14% to 28%).

For patients who were alive after four years and who continue on therapy in study 024, few new immune-related adverse events occurred beyond two years of treatment. Overall safety data from these investigational studies have been previously presented. The types of adverse events (AEs) attributed to YERVOY in these studies were generally mechanism (immune)- based. YERVOY can result in severe and fatal immune-related adverse reactions due to T-cell activation and proliferation. Adverse events associated with YERVOY were managed with protocol-specific guidelines, including the administration of systemic corticosteroids, dose interruption/discontinuation and/or other immunosuppressants.

“Metastatic melanoma is one of the most aggressive forms of cancer with a historical five-year survival rate of less than ten percent in patients with distant metastasis. Results from these investigational studies showed a prolonged survival benefit with YERVOY at four and five years for some patients,” said Celeste Lebbe, M.D., Professor of Dermatology, Hôpital Saint-Louis. “These results add to the growing body of long-term survival data seen in some patients treated with YERVOY and further our understanding of the potential of this immunotherapy in the treatment of metastatic melanoma.”

About Study 024

Study 024 is a multi-national, randomized, double-blind Phase 3 study that evaluated the safety and efficacy of YERVOY (10 mg/kg) plus DTIC (850 mg/m²) vs. DTIC alone in treatment naive patients with Stage III unresectable or Stage IV metastatic melanoma. Patients who received prior adjuvant therapy were allowed in the trial. Patients were randomly assigned in a 1:1 ratio to receive either YERVOY plus DTIC (n=250) or DTIC plus placebo (n=252) at Weeks 1, 4, 7, 10 followed by DTIC alone every 3 weeks through Week 22 (induction phase). If drug intolerance or progressive disease (PD) was noted during Weeks 12-24, treatment was discontinued. At Week 24, patients who had stable disease (SD) or an objective response (OR) during induction with no dose-limiting toxicity could enter a maintenance phase in which they received placebo or YERVOY every 12 weeks until PD, drug intolerance or end of study. The primary endpoint of study 024 was overall survival. Results from study 024, which included three-year follow-up data, were originally published in the New England Journal of Medicine and presented at the American Society of Clinical Oncology Annual Meeting in 2011.

The combination of DTIC with YERVOY is not an FDA approved-regimen. In addition, study 024 was not designed to compare the safety and efficacy of the FDA-approved monotherapy dose of 3 mg/kg for unresectable or metastatic melanoma vs. the investigational dose of 10 mg/kg. Bristol-Myers Squibb is conducting a head-to-head Phase 3 study comparing the safety and efficacy of the currently-approved dose of 3 mg/kg vs. 10 mg/kg as monotherapy in patients with previously-treated or treatment naïve unresectable or metastatic melanoma. This study rapidly accrued patients and completed enrollment in just over four months.

About Study 025

Study 025 is a rollover Phase 2 study that includes patients from three trials who only received YERVOY: CA184-008, a single-arm study of YERVOY 10 mg/kg in previously treated patients (n=155); CA184-022, a dose-ranging study in which previously treated patients were randomized to receive YERVOY at 0.3 mg/kg (n=73), 3 mg/kg (n=72), or 10 mg/kg (n=72) with crossover from lower doses to 10 mg/kg allowed in patients whose disease progressed; and CA184-007, a randomized study of YERVOY 10 mg/kg with or without prophylactic budesonide in treatment-naïve (n=53) and previously treated patients (n=62). Treatment was administered every 3 weeks for up to four doses, at which point eligible patients could receive reinduction or maintenance YERVOY every 12 weeks starting at week 24. The analysis reported overall survival with updated last known alive date or death based on data collected through March 2012.

About Metastatic 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 other organs, such as the lymph nodes, lungs, brain or other areas of the body. Some cancer cells can actively evade surveillance by the immune system, allowing tumors to survive. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate is just 6 months with a 1-year mortality rate of 75%, making it one of the most aggressive forms of cancer. These rates are based on a meta-analysis of 42 Phase 2 trials of more than 2,100 previously-treated and treatment-naïve patients with Stage IV metastatic melanoma conducted by multiple cooperative groups from 1975-2005. The incidence of melanoma has been increasing for at least 30 years. The median age at diagnosis for melanoma is 57 and the median age at death is 67.

About YERVOY

On March 25, 2011, the FDA approved YERVOY 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. YERVOY is now approved in 41 countries. YERVOY was also added to the National Comprehensive Cancer Network^® (NCCN^®) Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Melanoma as an NCCN Category 1 FDA-approved agent for treatment of metastatic melanoma. Further details can be found at www.nccn.org.*

YERVOY, which is a recombinant, human monoclonal antibody, is the first FDA-approved cancer immunotherapy that blocks the cytotoxic T- lymphocyte antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.

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) immune-mediated 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

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 immune-mediated 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 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
• 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 immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia
• Across the clinical development program for YERVOY, 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, and autoimmune thyroiditis
• 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.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews.

* Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Melanoma V.4.2011. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed [Month and Day, year]. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.