On May 11, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported that the European Commission (EC) has approved Opdivo in combination with Yervoy for the treatment of advanced (unresectable or metastatic) melanoma in adults, representing the first and only approved combination of two Immuno-Oncology agents in the European Union (EU) (Press release, Bristol-Myers Squibb, MAY 11, 2016, View Source [SID:1234512280]).

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This approval allows for the marketing of the Opdivo + Yervoy Regimen in all 28 Member States of the EU. Approval was based on CheckMate -067, the first Phase 3, double-blind, randomized study, in which the Opdivo + Yervoy Regimen and Opdivo monotherapy demonstrated superior progression-free survival (PFS) and objective response rates (ORR) in patients with advanced melanoma, regardless of BRAF mutational status, versus Yervoy alone. The safety profile was consistent with previously reported studies evaluating the Opdivo + Yervoy Regimen, and most treatment-related adverse events were managed using established algorithms.

Dr. James Larkin, from The Royal Marsden and lead author on CheckMate – 067, the trial that led to this approval, commented, "Historically, advanced melanoma has been a very difficult-to-treat disease. Now, with this approval, patients in Europe will have a treatment option combining two Immuno-Oncology therapies, Opdivo and Yervoy, which in a Phase 3 randomized trial has shown its ability to deliver superior efficacy versus Yervoy monotherapy in progression-free survival and response. This is truly good news for healthcare providers and the patients they treat, as it represents an important new treatment option with the potential for improved outcomes."

In study CheckMate -067, the Opdivo + Yervoy Regimen demonstrated a 58% reduction in the risk of disease progression versus Yervoy monotherapy in previously untreated patients with advanced melanoma (HR=0.42 [99.5% CI: 0.32-0.56; p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk reduction versus Yervoy monotherapy (HR=0.55 [99.5% CI: 0.42-0.73; p<0.0001]). The median PFS for the Opdivo + Yervoy Regimen was 11.5 months (95% CI: 8.9-22.18) and 6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy versus 2.89 months (95% CI: 2.8-3.4) for Yervoy monotherapy, at a minimum follow-up of 18 months. The Opdivo + Yervoy Regimen and Opdivo monotherapy also demonstrated a higher ORR (ORR: 58% and 44%, p<0.0001, respectively) versus Yervoy monotherapy (19%). Median duration of response was not reached for the Opdivo + Yervoy Regimen and was 22.3 months for Opdivo monotherapy, versus 14.4 months for Yervoy alone.

Based on a pre-planned, descriptive analysis of data from CheckMate -067, the EC adopted the Committee for Medicinal Products for Human Use (CHMP) recommendation to add an informative statement to the broad indication that relative to Opdivo monotherapy, an increase in PFS for the combination of Opdivo with Yervoy is established only in patients with low tumor PD-L1 expression. In the study, overall response rates were higher for the combination of Opdivo and Yervoy relative to Opdivo monotherapy across tumor PD-L1 expression levels.

The approval was also based on supportive data from the Phase 2 study, CheckMate -069, in which the Opdivo + Yervoy Regimen demonstrated an ORR, the primary endpoint, of 61% (95% CI: 48.9-72.4) in patients with BRAF wild-type advanced melanoma, versus 11% (95% CI: 3-25.4) ORR in the Yervoy monotherapy arm, with a minimum follow-up of 11 months. The estimated 12- and 18-month overall survival (OS) rates were 79% (95% CI: 67, 87) and 73% (95% CI: 61, 82), respectively, for the Opdivo + Yervoy Regimen, and 62% (95% CI: 44, 75) and 56% (95% CI: 39, 70), respectively, for Yervoy monotherapy. The OS data are based on an exploratory, pre-planned analysis of patients with BRAF wild-type advanced melanoma.

Emmanuel Blin, senior vice president, Head of Commercialization, Policy and Operations, Bristol-Myers Squibb, commented, "Today’s approval of the Opdivo + Yervoy Regimen for advanced melanoma patients supports our goal of developing innovative treatment approaches that have the potential to improve patient outcomes. The Opdivo + Yervoy Regimen is the first and only approved Immuno-Oncology combination, and only Regimen to deliver superior efficacy compared to Yervoy, and we are thrilled to make this novel combination treatment available to patients with advanced melanoma in Europe."

Approval Based on Superior Efficacy Demonstrated Versus Yervoy In Pivotal Phase 3 Study

CheckMate -067 is a Phase 3, double-blind, randomized study that evaluated the Opdivo + Yervoy Regimen or Opdivo monotherapy versus Yervoy alone in patients with previously untreated advanced melanoma, including both BRAF V600 mutation positive or BRAF wild-type advanced melanoma. A total of 945 patients were randomized to receive the Opdivo + Yervoy Regimen (Opdivo 1 mg/kg plus Yervoy 3 mg/kg every 3 weeks for 4 doses followed by Opdivo 3 mg/kg every 2 weeks thereafter; n=314), Opdivo monotherapy (Opdivo 3 mg/kg every 2 weeks; n=316) or Yervoy monotherapy (Yervoy 3 mg/kg every 3 weeks for 4 doses followed by placebo every 2 weeks; n=315). Randomization was stratified by PD-L1 expression (≥5% vs. <5%), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging system. Patients were treated until progression or unacceptable toxicity. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS); the study is ongoing and patients continue to be followed for OS. Objective response rate (ORR) and the duration of response were also assessed.

Results from the trial demonstrated a statistically significant improvement in PFS in patients with advanced melanoma treated with the Opdivo + Yervoy Regimen (p<0.0001) and with Opdivo as a single agent (p<0.0001) versus Yervoy monotherapy. At a minimum follow-up of 18 months, the Opdivo + Yervoy Regimen demonstrated a 58% reduction in the risk of disease progression versus Yervoy monotherapy in previously untreated patients with advanced melanoma (HR=0.42 [99.5% CI: 0.32-0.56; p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk reduction versus Yervoy monotherapy (HR=0.55 [99.5% CI: 0.42-0.73; p<0.0001]). The median PFS for the Opdivo + Yervoy Regimen was 11.5 months (95% CI: 8.9-22.18) and 6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy versus 2.89 months (95% CI: 2.8-3.4) for Yervoy monotherapy, at a minimum follow-up of 18 months.

The Opdivo + Yervoy Regimen and Opdivo monotherapy also demonstrated a higher ORR (ORR: 58% and 44%, p<0.0001, respectively) versus Yervoy monotherapy (19%). There were 38 (12%) complete responses and 143 (46%) partial responses seen in patients treated with the Opdivo + Yervoy Regimen, and 31 (10%) complete responses and 107 (34%) partial responses seen in patients treated with Opdivo monotherapy, versus 7 (2%) complete responses and 53 (17%) partial responses seen in patients treated with Yervoy alone. Median duration of response was not reached (0+ – 24+ months) for the Opdivo + Yervoy Regimen and was 22.3 months (0+ – 23+) for Opdivo monotherapy, versus 14.4 months (1.4 – 22.3+) for Yervoy alone.

CheckMate -069 is a Phase 2, double-blind, randomized study evaluating the Opdivo + Yervoy Regimen versus Yervoy monotherapy in 142 patients with previously untreated unresectable or metastatic melanoma. The trial included patients with BRAF V600 mutation positive and BRAF wild-type advanced melanoma, and randomization was stratified by BRAF mutation status. The primary endpoint was ORR in patients with BRAF wild-type tumors. Secondary endpoints included PFS in patients with BRAF wild-type tumors, ORR in patients with BRAF V600 mutation positive tumors and safety. Overall survival was an exploratory endpoint. Treatment was continued until progression or unacceptable toxicity. In this study, the Opdivo + Yervoy Regimen demonstrated a response rate of 61% (95% CI: 48.9-72.4) in patients with BRAF wild-type advanced melanoma, versus 11% (95% CI: 3-25.4) ORR in the Yervoy monotherapy arm, with a minimum follow-up of 11 months. The estimated 12- and 18-month OS rates were 79% (95% CI: 67, 87) and 73% (95% CI: 61, 82), respectively, for the Opdivo + Yervoy Regimen, and 62% (95% CI: 44, 75) and 56% (95% CI: 39, 70), respectively, for Yervoy.

In a pooled dataset of the Opdivo + Yervoy Regimen, based on three studies of the combination, the most frequent adverse reactions (≥10%) were rash (51%), fatigue (43%), diarrhea (42%), pruritus (35%), nausea (25%), pyrexia (19%), decreased appetite (15%), hypothyroidism (15%), vomiting (14%), colitis (14%), abdominal pain (13%), anthralgia (11%) and headache (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). Among the patients treated with Opdivo in combination with Yervoy in CheckMate -067, 151/313 (48%) had the first onset of Grade 3 or 4 adverse reactions during the initial combination phase. Among the 147 patients in this group who continued treatment in the single-agent phase, 37 (25%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase.

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. Melanoma is the ninth most common cancer in Europe, with an estimated 100,000 new cases diagnosed annually and more than 20,000 deaths.

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 modality alongside surgery, radiation and chemotherapy 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. 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.

Our collaboration with academia, as well as small and large biotech companies is responsible for researching the potential of Immuno-Oncology and non-Immuno-Oncology combinations, with the goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to changing 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 50 countries including the United States, Japan, and in the European Union.

U.S. FDA APPROVED 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.

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).

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 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 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 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 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 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).

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).

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.

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, 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.

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.

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 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%).

About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd (Ono) Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

On May 11, 2016 Bristol-Myers Squibb Company (NYSE:BMY) and AbbVie (NYSE:ABBV) reported that the European Commission has approved Empliciti (elotuzumab) for the treatment of multiple myeloma as combination therapy with Revlimid (lenalidomide) and dexamethasone in patients who have received at least one prior therapy (Press release, Bristol-Myers Squibb, MAY 11, 2016, View Source [SID:1234512279]). Empliciti is now the first and only immunostimulatory antibody approved for multiple myeloma in the European Union (EU).

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The approval is based on data from the randomized, open-label, Phase 3 ELOQUENT-2 study, which evaluated Empliciti in combination with lenalidomide and dexamethasone (ERd) versus lenalidomide and dexamethasone (Rd) alone. The co-primary endpoints of this study, progression-free survival (PFS) as assessed by hazard ratio (HR) and overall response rate (ORR), were achieved, with extended follow-up data showing a 53% relative improvement in PFS rate at three years (23% versus 15%). Additionally, a pre-specified interim analysis for overall survival (OS) found a positive trend favoring the Empliciti combination versus Rd alone (HR=0.77 [95% CI: 0.61, 0.97, p=0.0257]), though at the time of the interim analysis, the OS endpoint had not reached the pre-determined threshold for statistical significance. Patients will continue to be followed for survival, and the final analysis is pending. Empliciti with lenalidomide and dexamethasone is associated with the following Warnings and Precautions: infusion reactions, infections, second primary malignancies, hepatotoxicity, interference with determination of complete response, pregnancy/females and males of reproductive potential, and adverse reactions. Please see detailed Important Safety Information below.

"At Bristol-Myers Squibb, we are committed to delivering pioneering medicines with the goal of revolutionizing the way cancer is treated for patients who inspire our work each and every day," said Emmanuel Blin, senior vice president and head of Commercialization, Policy and Operations, Bristol-Myers Squibb. "With the approval of Empliciti in the EU, we are proud to extend our Immuno-Oncology science to multiple myeloma patients in Europe who have received at least one prior therapy."

In ELOQUENT-2, Empliciti was evaluated in patients who had received one to three prior therapies. The study demonstrated that the ERd regimen resulted in a 32% reduction in the risk of disease progression or death compared to Rd alone (HR=0.68 [97.61% CI: 0.55, 0.85, p=0.0001]). The ERd regimen also showed a 21% relative improvement in PFS rate at one year (68% versus 56%) and a 50% relative improvement in PFS rate at two years (39% versus 26%) compared to Rd alone. The ERd regimen demonstrated a significant improvement in ORR of 78.5% (95% CI: 73.6-82.9; p=0.0002) versus 65.5% in the Rd arm (95% CI: 60.1-70.7). The extended follow-up analysis also showed ERd had a median delay of one year in the time to next treatment compared to Rd alone: 33.35 months (95% CI: 26.15, 40.21) versus 21.22 months (95% CI: 18.07, 23.20) (HR=0.62 [95% CI: 0.50, 0.77]). These data were initially reported at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2015.

The most common adverse reactions (all grades) in ERd and Rd (>10%), respectively, were diarrhea (59.2%, 49.3%), pyrexia (43.0%, 27.7%), fatigue (40.0%, 34.7%), cough (33.2%, 20.3%), nasopharyngitis (29.5%, 27.7%), upper respiratory tract infection (25.2%, 22.7%), lymphopenia (17.6%, 13.6%), headache (17.2%, 9.6%), pneumonia (15.6%, 12.9%) and herpes zoster (10.0%, 5.7%).

"Today’s decision of the European Commission is excellent news for relapsed and refractory multiple myeloma patients," said Sarper Diler, President of Myeloma Patients Europe. "Multiple myeloma has had a difficult-to-treat history, and at Myeloma Patients Europe, we are committed to ensuring these patients living in any European country are able to access new, innovative medicines, like Empliciti."

"Empliciti represents an important new treatment option for patients with multiple myeloma and healthcare providers who are treating this cancer in Europe," said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "AbbVie is proud to be part of the team that developed Empliciti and pleased to be partnering with Bristol-Myers Squibb to bring this new therapy to previously treated multiple myeloma patients."

About ELOQUENT-2

ELOQUENT-2 (CA204-004) is a Phase 3, open-label, randomized study evaluating Empliciti in combination with Rd versus Rd alone in patients with relapsed or refractory multiple myeloma. The trial randomized 646 patients who had received one to three prior therapies. Patients were randomized 1:1 to receive either Empliciti 10 mg/kg in combination with Rd or Rd alone in 4-week cycles until disease progression or unacceptable toxicity. Baseline patient demographics and disease characteristics were well balanced between treatment arms and included a meaningful portion of patients who were ≥ 65 years old, had high-risk cytogenetics and/or were refractory to the most recent line of therapy. The minimum follow-up for all study subjects was 24 months. The co-primary endpoints were PFS, as assessed by hazard ratio, and ORR, as determined by a blinded Independent Review Committee using the European Group for Blood and Marrow Transplantation response criteria.

"As multiple myeloma is largely incurable and is often characterized by a cycle of remission and relapse, there is a critical need for new therapies for patients that work in unique and innovative ways," said Antonio Palumbo, M.D., study investigator and chief of the Myeloma Unit, Department of Oncology, University of Torino in Torino, Italy. "In clinical trials, Empliciti in combination with lenalidomide and dexamethasone delivered a significant benefit in progression-free survival compared to lenalidomide and dexamethasone alone, which could make a meaningful difference in the lives of patients struggling with this serious disease."

Discontinuation rates due to adverse reactions were similar across the ERd and Rd arms (8.7%, 12.9%). The most frequent serious adverse reactions (Grade 3-4) in ERd and Rd were lymphopenia (12.7%, 7.4%), pneumonia (10.5%, 8.1%), fatigue (6.4%, 6.2%), diarrhea (3.7%, 3.1%) and deep vein thrombosis (3.5%, 1.7%). The most common adverse reactions in ERd and Rd (>20%), respectively, were diarrhea (59.2%, 49.3%), pyrexia (43.0%, 27.7%), fatigue (40.0%, 34.7%), cough (33.2%, 20.3%), nasopharyngitis (29.5%, 27.7%) and upper respiratory tract infection (25.2%, 22.7%).

Infusion reactions occurred in 10% of patients treated with ERd; these adverse reactions were Grade 3 or lower (Grade 3, 1%; Grade 4, 0%). In the trial, 1% of patients discontinued due to infusion reactions, and 5% of patients required interruption of the administration of Empliciti for a median of 25 minutes.

About Multiple Myeloma

Multiple myeloma is a hematologic, or blood, cancer that develops in the bone marrow. It occurs when a plasma cell, a type of cell in the soft center of bone marrow, becomes cancerous and multiplies uncontrollably. Common symptoms of multiple myeloma include bone pain, fatigue, kidney impairment and infections.

Despite advances in multiple myeloma treatment over the last decade, less than half of patients survive for five or more years after diagnosis. Patients often experience a cycle of remission and relapse, and once a patient first relapses, their prognosis worsens with progressively faster relapses through each subsequent line of therapy. It is estimated that annually, more than 114,200 new cases of multiple myeloma are diagnosed, and more than 80,000 people die from the disease globally.

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 modality alongside surgery, radiation and chemotherapy 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. 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.

Our collaboration with academia, as well as small and large biotech companies, is responsible for researching the potential Immuno-Oncology and non-Immuno-Oncology combinations, with the 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 Empliciti

Empliciti is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 also is expressed on Natural Killer cells, plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Empliciti has a dual mechanism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.

Empliciti in combination with lenalidomide and dexamethasone is approved in the United States, and the safety and efficacy of Empliciti is being evaluated by other health authorities.

Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities.

U.S. INDICATION

EMPLICITI (elotuzumab) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

U.S. IMPORTANT SAFETY INFORMATION

Infusion Reactions

EMPLICITI can cause infusion reactions. Common symptoms include fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose. If a Grade 2 or higher infusion reaction occurs, interrupt the EMPLICITI infusion and institute appropriate medical and supportive measures. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.
Premedicate with dexamethasone, H1 Blocker, H2 Blocker, and acetaminophen prior to infusing with EMPLICITI.
Infections

In a clinical trial of patients with multiple myeloma (N=635), infections were reported in 81.4% of patients in the EMPLICITI with lenalidomide/dexamethasone arm (ERd) and 74.4% in the lenalidomide/dexamethasone arm (Rd). Grade 3-4 infections were 28% (ERd) and 24.3% (Rd). Opportunistic infections were reported in 22% (ERd) and 12.9% (Rd). Fungal infections were 9.7% (ERd) and 5.4% (Rd). Herpes zoster was 13.5% (ERd) and 6.9% (Rd). Discontinuations due to infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5% (ERd) and 2.2% (Rd). Monitor patients for development of infections and treat promptly.
Second Primary Malignancies

In a clinical trial of patients with multiple myeloma (N=635), invasive second primary malignancies (SPM) were 9.1% (ERd) and 5.7% (Rd). The rate of hematologic malignancies were the same between ERd and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd). Monitor patients for the development of SPMs.
Hepatotoxicity

Elevations in liver enzymes (AST/ALT greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were 2.5% (ERd) and 0.6% (Rd). Two patients experiencing hepatotoxicity discontinued treatment; however, 6 out of 8 patients had resolution and continued treatment. Monitor liver enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered.
Interference with Determination of Complete Response

EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.
Pregnancy/Females and Males of Reproductive Potential

There are no studies with EMPLICITI with pregnant women to inform any drug associated risks.
There is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide and it is contraindicated for use in pregnancy. Refer to the lenalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information.
Adverse Reactions

Infusion reactions were reported in approximately 10% of patients treated with EMPLICITI with lenalidomide and dexamethasone. All reports of infusion reaction were Grade 3 or lower. Grade 3 infusion reactions occurred in 1% of patients.
Serious adverse reactions were 65.4% (ERd) and 56.5% (Rd). The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15.4%, 11%), pyrexia (6.9%, 4.7%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).
The most common adverse reactions in ERd and Rd, respectively (>20%) were fatigue (61.6%, 51.7%), diarrhea (46.9%, 36.0%), pyrexia (37.4%, 24.6%), constipation (35.5%, 27.1%), cough (34.3%, 18.9%), peripheral neuropathy (26.7%, 20.8%), nasopharyngitis (24.5%, 19.2%), upper respiratory tract infection (22.6%, 17.4%), decreased appetite (20.8%, 12.6%), and pneumonia (20.1%, 14.2%).
Please see the full Prescribing Information for Empliciti.