Bristol-Myers Squibb's Opdivo (nivolumab) + Yervoy (ipilimumab) Regimen Receives Expanded FDA Approval in Unresectable or Metastatic Melanoma Across BRAF Status1

Opdivo + Yervoy Regimen now indicated for unresectable or metastatic melanoma patients, regardless of BRAF mutational status, based on accelerated approval1

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Demonstrated significantly superior progression-free survival vs. Yervoy alone in CheckMate -067 with the first and only FDA-approved combination of immune checkpoint inhibitors1,2

FDA also expands use of Opdivo as single-agent to include previously untreated BRAF mutation-positive advanced melanoma patients, based on accelerated approval1

With this seventh approval for Opdivo in just over a year, and the fourth for late-stage melanoma, more patients fighting cancer now have access to Immuno-Oncology treatment options1

Saturday, January 23, 2016 6:36 pm EST
"To make this treatment option available to more patients is truly a milestone in the fight against this deadly disease."
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced that the U.S. Food and Drug Administration (FDA) has approved Opdivo (nivolumab) in combination with Yervoy (ipilimumab) for the treatment of patients with BRAF V600 wild-type and BRAF V600 mutation-positive unresectable or metastatic melanoma.1 This indication is approved under accelerated approval based on progression-free survival (PFS).1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1 This approval expands the original indication for the Opdivo + Yervoy Regimen for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma to include patients, regardless of BRAF mutational status, based on data from the Phase 3 CheckMate -067 trial, in which PFS and overall survival (OS) were co-primary endpoints.1,2

Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, other adverse reactions; infusion reactions; and embryofetal toxicity.1 Please see the Important Safety Information section below, including Boxed WARNING for Yervoy regarding immune-mediated adverse reactions.

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"For nearly a decade, our researchers have worked tirelessly to find treatment options that could improve outcomes for patients with late-stage melanoma, a particularly aggressive cancer, and we are incredibly proud of today's approval to expand the use of the Opdivo + Yervoy Regimen to include patients with BRAF mutation-positive unresectable or metastatic melanoma. CheckMate -067 is the first Phase 3 study to observe the efficacy and safety of both Opdivo as a single-agent as well as in combination with Yervoy versus Yervoy alone," said Chris Boerner, Head of U.S. Commercial, Bristol-Myers Squibb. "To make this treatment option available to more patients is truly a milestone in the fight against this deadly disease."

The FDA also expanded the use of Opdivo as a single-agent to include previously untreated BRAF mutation-positive advanced melanoma patients.1 The use of Opdivo as a single-agent in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma is approved under accelerated approval based on progression-free survival.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1 Opdivo was approved by the FDA in November 2015, for use in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.1

"Patients with metastatic melanoma historically have a very challenging disease. Recent advances in our understanding of the immune response to cancer has yielded therapies which provide meaningful responses and hope. The combination of two Immuno-Oncology treatments, nivolumab and ipilimumab, has been shown to provide these patients with a much needed improvement in progression-free survival and response rates," said Jedd D. Wolchok, MD, PhD, Chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center. "This expanded approval for the nivolumab and ipilimumab regimen provides more advanced melanoma patients with an Immuno-Oncology combination treatment, and the potential for improved outcomes."

Expanded Approval Based on Efficacy Demonstrated in a Phase 3 Trial

CheckMate -067 is a Phase 3, double-blind, randomized study that evaluated the Opdivo + Yervoy Regimen or Opdivo monotherapy vs. Yervoy monotherapy in patients with previously untreated advanced melanoma.1, 2 The trial evaluated previously untreated patients, including both BRAF V600 mutant and wild-type advanced melanoma, and enrolled 945 patients who 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).1 Patients were treated until progression or unacceptable toxic effects.1 The median duration of exposure was 2.8 months (range: 1 day to 18.8 months) for patients in the Opdivo + Yervoy Regimen arm with a median of four doses (range: 1 to 39 for Opdivo; 1 to 4 for Yervoy), and 6.6 months (range: 1 day to 17.3 months) duration for the Opdivo monotherapy arm with a median of 15 doses (range: 1 to 38).1,2 The co-primary endpoints were PFS and OS; the study is ongoing and patients continue to be followed for OS.2

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) vs. Yervoy monotherapy.1 Median PFS was 11.5 months (95% CI: 8.9-16.7) for the Opdivo + Yervoy Regimen and 6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy, vs. 2.9 months (95% CI: 2.8-3.4) for Yervoy monotherapy.1 The Opdivo + Yervoy Regimen demonstrated a 58% reduction in the risk of disease progression vs. Yervoy (HR: 0.42; 95% CI: 0.34-0.51; p<0.0001), while Opdivo monotherapy demonstrated a 43% risk reduction vs. Yervoy monotherapy (HR: 0.57; 95% CI: 0.47-0.69; p<0.0001).1

In addition, the Opdivo + Yervoy Regimen and Opdivo monotherapy demonstrated higher confirmed objective response rates (ORR; 50% and 40%; p<0.0001, respectively) vs. Yervoy monotherapy (14%).1 The percentage of patients with a complete response was 8.9%, 8.5% and 1.9%, favoring the Regimen and Opdivo monotherapy over Yervoy monotherapy.1 Partial responses were seen in 41% of patients treated with the Opdivo + Yervoy Regimen, 31% of patients treated with Opdivo monotherapy, and 12% of patients treated with Yervoy monotherapy. The Opdivo + Yervoy Regimen delivered durable responses, with three of four (76%) patients experiencing an ongoing response of at least six months (range: 1.2+ to 15.8+).1 Of patients in the Opdivo monotherapy and Yervoy monotherapy arms, 74% and 63% experienced an ongoing response of at least six months, respectively (ranges: 1.3+ to 14.6+; 1.0+ to 13.8+).1

"The melanoma community is excited to see the ongoing developments in research from the pharmaceutical industry, including Bristol-Myers Squibb, who made the first approved combination of two Immuno-Oncology treatments available to more patients fighting this disease," said Tim Turnham, Executive Director, Melanoma Research Foundation. "Today's expanded approvals continue to bring new treatment options to patients, and demonstrate the ongoing impact of Immuno-Oncology research."

In CheckMate -067, serious adverse reactions (73% and 37%), adverse reactions leading to 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 + Yervoy arm relative to the Opdivo arm.1 No overall differences in safety or efficacy were reported between elderly and younger patients.1 The most common adverse reactions leading to discontinuation of the Opdivo + Yervoy Regimen relative to Opdivo as a single-agent were diarrhea (8% and 1.9%), colitis (8% and 0.6%), increased ALT (4.8% and 1.3%), increased AST (4.5% and. 0.6%), and pneumonitis (1.9% and 0.3%).1 The most frequent (≥10%) serious adverse reactions in the Opdivo + Yervoy arm and the Opdivo arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%) and pyrexia (10% and 0.6%).1 The most common adverse reactions (≥20%) reported in patients receiving the Opdivo + Yervoy Regimen relative to Opdivo as a single-agent were fatigue (59% and 53%), rash (53% and 40%), diarrhea (52% and 31%), and nausea (40% and 28%).1 Pyrexia (37%), vomiting (28%) and dyspnea (20%) were also reported in ≥20% of patients receiving the Opdivo + Yervoy Regimen.1

About the Opdivo + Yervoy Regimen

The scientific rationale for targeting the immune system via dual immune checkpoint inhibition in cancer has formed the basis of a novel approach to the treatment of metastatic melanoma.2

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack.2 Opdivo and Yervoy are immune checkpoint inhibitors that target separate, distinct and complementary checkpoint pathways (PD-1 and CTLA-4).1 The mechanism of action involves dual immune checkpoint inhibition resulting in increased anti-tumor activity.1 Yervoy blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, while Opdivo restores the active T-cell response directed at the tumor.1,3 This may affect healthy cells and result in immune-mediated adverse reactions, which can be severe and potentially fatal.1

Bristol-Myers Squibb has a broad, global development program to study the combination of Opdivo and Yervoy consisting of more than 14 trials in which more than 2,000 patients have been enrolled worldwide through September 2015.

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.3 Opdivo's broad global development program is based on Bristol-Myers Squibb's understanding of the biology behind Immuno-Oncology. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials across a variety of tumor types. 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 46 countries including the United States, Japan, and in the European Union.

About Metastatic Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin.3 Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to other organs.3 The incidence of melanoma has been increasing for at least 30 years.3 Approximately 73,870 melanoma cases were estimated to be diagnosed in the U.S. in 2015.3 Melanoma is mostly curable when treated in its early stages.3 However, in its late stages, 5-year and 10-year survival rates in the U.S. average 15-20% and 10-15%, respectively.3

About Bristol-Myers Squibb's Patient Support Programs

Bristol-Myers Squibb remains committed to helping patients through treatment with our medicines. For support and assistance, patients and physicians may call 1-855-OPDIVO-1. This number offers one-stop access to a range of support services for patients and healthcare professionals alike.

About Bristol-Myers Squibb's Access Support

Bristol-Myers Squibb is committed to helping patients access the Opdivo + Yervoy Regimen and offers BMS Access Support® to support patients and providers in gaining access. BMS Access Support, the Bristol-Myers Squibb Reimbursement Services program, is designed to support access to BMS medicines and expedite time to therapy through reimbursement support including Benefit Investigations, Prior Authorization Facilitation, Appeals Assistance, and assistance for patient out-of-pocket costs. BMS Access Support assists patients and providers throughout the treatment journey – whether it is at initial diagnosis or in support of transition from a clinical trial. More information about our reimbursement support services can be obtained by calling 1-800-861-0048 or by visiting www.bmsaccesssupport.com. For healthcare providers seeking specific reimbursement information, please visit the BMS Access Support Product section by visiting www.bmsaccesssupportopdivo.com.

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 demonstration 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 demonstration of clinical benefit in 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.

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