On October 31, 2016 Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK) reported that the U.S. Food and Drug Administration (FDA) has accepted for review the Abbreviated New Drug Application (ANDA) for generic doxorubicin hydrochloride (HCI) liposome injection submitted by its partner Actavis LLC (an indirect, wholly owned subsidiary of Teva Pharmaceuticals USA, Inc.) (Press release, Merrimack, OCT 31, 2016, View Source [SID1234516115]). This is the first product developed by Merrimack under a partnership agreement with Actavis LLC pursuant to which Merrimack is responsible for the development and commercial supply of bulk drug product and Actavis LLC is responsible for fill/finish activities, regulatory approvals and commercialization in the United States.

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Doxorubicin HCl liposome injection is marketed as DOXIL in the United States by Janssen Products LP, a Johnson & Johnson company. The approved indications for the product are ovarian cancer, AIDS-related Kaposi’s sarcoma and multiple myeloma. DOXIL generated approximately $600 million annually in global revenue prior to Johnson & Johnson’s 2011 manufacturing disruption, which resulted in the placement of DOXIL on the FDA’s drug shortage list. While DOXIL was on the drug shortage list, the FDA approved a generic version of doxorubicin HCl liposome injection marketed by Sun Pharma Global FZE, and both products now share the U.S. market. If approved, Merrimack is eligible to receive a royalty rate in the mid-twenties of net profits on sales of doxorubicin HCl liposome injection under the agreement with Actavis.

"We are pleased to have achieved this important milestone with our partner, Actavis," said Gary Crocker, Chairman of Merrimack’s Board of Directors and interim President and CEO. "This collaboration leverages Merrimack’s proven expertise in the development of liposomal products and provides the opportunity to maximize the use of our state-of-the-art commercial liposomal manufacturing facility. It also could allow us, if the product is approved, to generate an additional revenue stream to not only offset costs but meaningfully improve earnings. We look forward to the FDA’s review of Actavis’s ANDA filing and providing further support as Actavis navigates the regulatory approval process."

Merrimack is a leader in the development and manufacturing of nanoliposomal products. In addition to the generic doxorubicin HCl liposome injection for which the ANDA was just accepted, Merrimack has developed or is developing several novel therapeutic candidates. Merrimack’s first commercial product, ONIVYDE (irinotecan liposome injection), is a novel liposomal formulation of irinotecan that was approved by the FDA in the United States in October 2015.

On October 31, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for ARIAD’s investigational oral anaplastic lymphoma kinase (ALK) inhibitor, brigatinib, in patients with metastatic ALK-positive (ALK+) non-small cell lung cancer (NSCLC) who have progressed on crizotinib (Press release, Ariad, OCT 31, 2016, View Source [SID1234516110]). The FDA granted ARIAD’s request for Priority Review and has set an action date of April 29, 2017 under the Prescription Drug User Fee Act (PDUFA).

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"The FDA acceptance of our application is an important milestone in our ongoing efforts to discover, develop and deliver highly innovative treatments for patients with rare cancers," said Paris Panayiotopoulos, president and chief executive officer of ARIAD. "We are pleased that our significant R&D investments in brigatinib and our work with the FDA are bringing us closer to potentially offering a treatment option for patients with ALK+ NSCLC who are refractory to crizotinib. We look forward to continuing to work closely with the FDA during the brigatinib NDA review and remain committed to developing critical therapies for unserved and underserved small patient populations suffering from rare cancers."

ARIAD’s NDA submission includes clinical data from its Phase 1/2 and pivotal Phase 2 ALTA trials of brigatinib. The FDA’s Priority Review status accelerates the review time from 10 months to a goal of six months from the filing of the application. Brigatinib received Breakthrough Therapy designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib, and was granted orphan drug designation by the FDA for the treatment of ALK-positive, ROS1-positive, and EGFR-positive NSCLC. ARIAD plans to submit a Marketing Authorization Application (MAA) for brigatinib to the European Medicines Agency (EMA) in early 2017.

ARIAD is a small, research-driven biotechnology company. ARIAD has invested more than $1.3 billion in R&D since the Company was founded. In 2015, ARIAD generated $119 million in total revenue and invested $171 million, or 143 percent of revenue, in R&D.

About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). The global Phase 2 ALTA trial, in patients with locally advanced or metastatic ALK+ NSCLC who were previously treated with crizotinib, is the primary basis for brigatinib’s initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy and safety of brigatinib in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor. More information on brigatinib clinical trials, including the expanded access program (EAP) for ALK+ NSCLC can be found here.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 228,190 new cases of lung cancer diagnosed each year in the United States, according to the American Cancer Society. Anaplastic lymphoma kinase (ALK) was first identified as a chromosomal rearrangement in anaplastic large-cell lymphoma (ALCL). Genetic studies indicate that chromosomal rearrangements in ALK are key drivers in a subset of NSCLC patients as well. Approximately three to eight percent of patients with NSCLC have a rearrangement in the ALK gene.

On October 31, 2016 Epizyme, Inc. (NASDAQ:EPZM), a clinical-stage biopharmaceutical company creating novel epigenetic therapies, reported that it has entered into two Cooperative Research and Development Agreements (CRADAs) with the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) (Press release, Epizyme, OCT 31, 2016, View Source [SID1234516109]). The CRADAs will evaluate tazemetostat, Epizyme’s first-in-class EZH2 inhibitor, and pinometostat, the Company’s first-in-class DOT1L inhibitor. Both investigational medicines target proteins implicated in the development and regulation of cancer.

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"This collaboration reflects Epizyme’s strategy to enhance our development programs through impactful partnerships," said Peter Ho, M.D., Ph.D., Chief Medical Officer, Epizyme. "These CRADAs broaden the scope of our ongoing tazemetostat clinical program to explore its potential benefit in a wider range of cancer indications. We are also excited to continue the exploration of pinometostat’s potential utility in treating acute leukemias in combination regimens. We look forward to generating additional data to advance our epigenetic pipeline of novel therapies for patients with cancer."

As part of the CRADA for tazemetostat, CTEP will collaborate with Epizyme in clinical trials to evaluate the safety and efficacy of tazemetostat in patients with hematologic malignancies and solid tumors. The initial NCI-sponsored study will evaluate tazemetostat in a phase 2 clinical trial in patients with ovarian cancer. External publications and Epizyme preclinical data indicate that inhibition of EZH2 could be beneficial in subsets of ovarian cancer.

Under the second CRADA, the safety and efficacy of pinometostat will be evaluated in patients with acute leukemias. Initial studies will evaluate the combination of pinometostat with standard-of-care therapies or targeted agents in acute myeloid leukemia, acute lymphoid leukemia, or mixed lineage leukemia characterized by a rearrangement in the mixed lineage leukemia gene (MLL-r). Preclinical studies of pinometostat in MLL-r cell line models have shown synergy with chemotherapies, including acute leukemia standard-of-care agents and select targeted therapies.

As part of both agreements, additional clinical trials will be considered. NCI will predominantly fund the studies and manage study operations.

About the Tazemetostat Clinical Program
Tazemetostat, a first-in-class EZH2 inhibitor, is being evaluated as a monotherapy and in combination with other agents in multiple cancer indications. Phase 2 studies of tazemetostat as a monotherapy are currently ongoing in patients with non-Hodgkin lymphoma; in adults and children with certain genetically defined solid tumors, including INI1-negative and SMARCA4-negative tumors and synovial sarcoma; and in patients with mesothelioma characterized by BAP1 loss-of-function. Tazemetostat has been granted orphan drug status by the U.S. Food and Drug Administration, for the treatment of malignant rhabdoid tumors.

Additionally, tazemetostat is being evaluated in two combination studies in patients with diffuse large B-cell lymphoma (DLBCL). A first-line Phase 1b/2 trial of tazemetostat in combination with R-CHOP, an immunochemotherapy regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, is being conducted as part of Epizyme’s collaboration with the Lymphoma Study Association. A Phase 1b study evaluating tazemetostat in combination with Tecentriq (atezolizumab), an anti-PD-L1 cancer immunotherapy approved by the U.S. Food and Drug Administration, is being conducted as part of a collaboration with Genentech, a member of the Roche Group, in relapsed and refractory patients with DLBCL. For more information on tazemetostat clinical trials, please visit www.epizymeclinicaltrials.com.

About Pinometostat
Pinometostat, a small molecule inhibitor of DOT1L, is under clinical evaluation for the treatment of children with acute leukemias, including a genetically defined leukemia characterized by MLL-r. Pinometostat is being developed in collaboration with Celgene. Epizyme retains all U.S. rights to pinometostat and has granted Celgene an exclusive license to pinometostat outside of the U.S.

On October 31, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported new data presentations from studies evaluating Opdivo (nivolumab) as monotherapy or in combination with Yervoy (ipilimumab) in the treatment of melanoma, including new research on the efficacy and safety of the combination in melanoma patients with high unmet need including those with elevated serum lactate dehydrogenase (LDH) and brain metastases (Press release, Bristol-Myers Squibb, OCT 31, 2016, View Source [SID1234516108]). Additional presentations will also highlight new data on health economics and real-world outcomes in patients living with the disease.

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The data, to be presented at the Society for Melanoma Research (SMR) 2016 Congress in Boston, MA from November 6-9, underscore the Company’s continued leadership in advancing melanoma treatment research and deepening our scientific understanding of the potential of Immuno-Oncology as a treatment option including the potential survival impact of combination therapies.

"Bristol-Myers Squibb continues to advance the scientific understanding of Immuno-Oncology as an innovative approach to the treatment of multiple tumor types, including melanoma," said Fouad Namouni, M.D., head of development, Oncology, Bristol-Myers Squibb. "We remain focused on studying the use of Opdivo, both as single-agent therapy and in combination with Yervoy, in patients with advanced melanoma and to enhancing our understanding of the potential benefits and risks of the Opdivo and Yervoy combination regimen, including in patient sub-groups in need of new options."

The SMR 2016 Congress will feature eight separate data presentations from Bristol-Myers Squibb. The full set of data to be presented by Bristol-Myers Squibb are as follows:

Opdivo and Yervoy Combination

CheckMate -067, -069, -066: Efficacy of nivolumab plus ipilimumab combination in patients with advanced melanoma and elevated serum lactate dehydrogenase: a pooled analysis
Presenter: J. Larkin
Plenary Session 10: Melanoma and the Immune System ‐ Therapy and Biomarkers Wednesday, November 9, 8:00 a.m. ET, salon F-K
CheckMate -204: Phase II study evaluating the safety of nivolumab plus ipilimumab in patients with advanced melanoma metastatic to the brain
Presenter: H. Tawbi
Poster Session
CheckMate -038: Efficacy and safety of nivolumab alone or combined with ipilimumab in patients with melanoma metastatic to the brain in a phase 1 study
Presenter: TBD
Poster Session
Opdivo Monotherapy

Overall survival in patients with advanced melanoma who received nivolumab vs investigator’s choice chemotherapy in the phase 3 CheckMate -037 trial
Presenter: M. Smylie
Plenary Session 10: Melanoma and the Immune System ‐ Therapy and Biomarkers Wednesday, November 9, 8:40 a.m. ET, salon F-K
Health Economics and Real-World Outcomes Research

Differences in the value patients and physicians place on durable survival: Implications for the treatment of advanced melanoma
Presenter: J. Shafrin
Poster Session
Cost comparison analysis of nivolumab + ipilimumab regimen and dabrafenib + trametinib utilizing clinical trial and real world data
Presenter: R. Potluri
Poster Session
Patient and provider relationships and perceptions regarding melanoma treatment decisions
Presenter: D. Stenehjem
Poster Session
OPTIMIzE: a US multi-site observational study in patients with unresectable and metastatic melanoma
Presenter: J.M. Kirkwood
Poster Session
Posters will be displayed throughout the congress during normal congress hours. Key viewing times are:
Sunday, November 6, 2016: Opening Reception – 7:30 p.m. to 9:30 p.m.
Monday, November 7, 2016: Poster Reception – 6:00 p.m. – 8:00 p.m.
Wednesday, November 9, 2016: Refreshment Break and Poster Viewing – 9:35 a.m. to 10:00 a.m.
Bristol-Myers Squibb: At the Forefront of Immuno-Oncology Science & Innovation

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines that will raise survival expectations in hard-to-treat cancers and will change the way patients live with cancer.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents, including the first combination of two I-O agents in metastatic melanoma, and our differentiated clinical development program, which is studying broad patient populations across more than 20 types of cancers with 11 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and inform which patients will benefit most from I-O therapies.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part, but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 57 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 47 countries, including the United States and the European Union.

U.S. FDA APPROVED INDICATIONS FOR OPDIVO

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 the confirmatory trials.

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

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

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

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

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

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

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

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

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

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

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

OPDIVO can cause immune-mediated hepatitis. 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 patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

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 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

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and 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. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

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

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

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 Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. 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 patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

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. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. 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 patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic HSCT after OPDIVO

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

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

Embryo-Fetal Toxicity

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

Lactation

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

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). 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 (n=206). 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 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 (n=313) relative to the OPDIVO arm (n=313). 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 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) 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 (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (≥20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).

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

CHECKMATE Trials and Patient Populations

CheckMate 067 – advanced melanoma alone or in combination with YERVOY; CheckMate 037 and 066 – advanced melanoma; CheckMate 017 – squamous non-small cell lung cancer (NSCLC); CheckMate 057 – non-squamous NSCLC; CheckMate 025 – renal cell carcinoma; CheckMate 205/039 – classical Hodgkin lymphoma.

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

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