On December 5, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported that an anti-CD27 antibody developed by Aduro Biotech Europe and derived from its proprietary B-select technology has been selected to be advanced into clinical development by Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the U.S. and Canada), through a subsidiary (Press release, Aduro BioTech, DEC 5, 2016, View Source [SID1234516924]). CD27 has been recognized as having a critical role in activating a productive anti-cancer immune response and has demonstrated the potential to be combined with checkpoint inhibitors in pre-clinical studies.

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"Pre-clinical studies have shown that an anti-CD27 agonist can induce a T cell-mediated anti-cancer immune response, and in combination with PD-1 immune checkpoint inhibitors complete tumor eradication can be achieved," said Hans van Eenennaam, Ph.D., chief operational officer, Aduro Biotech Europe.

The CD27 antibody was licensed by MSD to advance as a part of their successful immunotherapy development program and was identified in close collaboration with Prof. Jannie Borst, Ph.D., professor at the University of Amsterdam and division head at the Netherlands Cancer Institute, through Aduro’s B-select monoclonal antibody technology. This technology includes a proprietary ultra-selective functional screening process to identify antibodies with unique binding properties against a broad repertoire of targets that can modulate the innate and adaptive arms of the immune system.

"In 2014, prior to the acquisition by Aduro Biotech, BioNovion entered into a worldwide license agreement with MSD that covers the product candidate’s development and advancement through commercialization," said Andrea van Elsas, Ph.D., chief scientific officer of Aduro Biotech Europe. "Both companies recognized the significant potential of targeting CD27 as a new and distinct mechanism in cancer immunotherapy, especially in the context of PD-1 checkpoint inhibitors, and were strongly committed to accelerate a quality candidate into the clinic."

Conference Call with Management
Aduro’s management will host a conference call to review this announcement and provide a program update, including STELLAR, today at 5:30 a.m. PT/ 8:30 a.m. ET. To participate in the conference call, please dial (844) 309-0604 (domestic) or (574) 990-9932 (international) and refer to conference ID 31336163. Live audio of the conference call will be simultaneously webcast and will be available to members of the news media, investors and the general public at View Source

About the Aduro – MSD Collaboration
BioNovion B.V. and MSD, through a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, entered into a worldwide license agreement in 2014 for the development and commercialization of CD27 antibody agonists, and BioNovion received an up-front payment of $15 million. In 2015, BioNovion was acquired by Aduro Biotech and became its subsidiary, Aduro Biotech Europe B.V.

Under the agreement, a Joint Research Committee was formed to advance the program. Aduro has been reimbursed for certain research activities and is eligible to receive future development, commercial and net sales milestone payments. In addition, Aduro is eligible to receive royalties in the mid-single digits to low teens based on any net sales of the product, if it is approved for marketing.

On December 5, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that it has initiated a study of its NY‑ESO SPEAR T‑cells in myxoid/round cell liposarcoma (MRCLS) (Press release, Adaptimmune, DEC 5, 2016, View Source [SID1234516923]). Patient screening is underway, and the results from this study in up to 15 patients will inform a potential future registration trial. The initiation of screening in this study meets a milestone set forth in the Company’s strategic collaboration agreement with GlaxoSmithKline plc (LSE/NYSE: GSK).

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This is an open-label pilot study in patients to assess preliminary safety and efficacy in this new indication. Initially, 10 patients will be enrolled. If further characterization of the treatment is required, up to 5 additional patients may be enrolled. Eligible patients will be HLA-A*02:01, HLA‑A*02:05 and/or HLA-A*02:06 with advanced (metastatic or inoperable) high grade MRCLS whose tumor shows positive NY-ESO-1 expression defined as ≥30 percent of cells that are 2+ or 3+ by immunohistochemistry. Patients will receive preconditioning with fludarabine and cyclophosphamide at the same dose that is being used in Cohort 4 of the Company’s ongoing synovial sarcoma study.

About MRCLS
Soft tissue sarcomas can develop from tissues like fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues. There are approximately 50 types of soft tissue sarcomas, including MRCLS. Myxoid/round cell liposarcoma is associated with specific chromosomal translocations and represents about 30 to 35 percent of liposarcomas and 5 to 10 percent of all adult soft tissue sarcomas. Myxoid/round cell liposarcoma commonly presents at an age ranging from 35 to 55 years.

On December 5, 2016 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported the presentation of results from the Company’s Phase 1A study in healthy volunteers evaluating oral non-covalent reversible BTK inhibitor SNS-062 (Press release, Sunesis, DEC 5, 2016, View Source [SID1234516922]). The results were presented in a poster session titled "CLL: Therapy, excluding Transplantation: Poster I" on Saturday, December 3, at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California. The presentation, titled "First-in-Human Phase 1a Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the Noncovalent Bruton’s Tyrosine Kinase (BTK) Inhibitor SNS-062 in Healthy Subjects," is available at www.sunesis.com.

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"These final results from the Phase 1A Healthy Volunteer study suggest that SNS-062, with a favorable safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile, and its improved PK properties over ibrutinib and acalabrutinib, has significant potential to become a new treatment option for patients with B-cell malignancies," said Linda Neuman, M.D., Vice President, Clinical Development of Sunesis. "Additionally, as a non-covalent BTK inhibitor with a distinct reversible binding profile, SNS-062 may overcome the acquired resistance to ibrutinib and other covalent clinical-stage BTK inhibitors resulting from a point mutation (C481S) in the active site."

"The safety profile, extent of SNS-062 exposure, and duration of BTK inhibition from these study results are encouraging and support our plans for a Phase 1B/2 study to assess safety and efficacy in patients with advanced B-cell malignancies after prior ibrutinib exposure, both with and without a BTK C481 mutation," said Daniel Swisher, President and Chief Executive Officer of Sunesis. "We are preparing an IND filing for this year as we work closely with our identified clinical sites for this study, and expect to begin dosing patients within the first half of 2017."

The reported data from this Phase 1A randomized, double-blind, placebo-controlled, single-dose study are from four sequential cohorts of 8 subjects each who were randomly assigned to receive progressively higher single oral administrations of SNS-062 at doses of 25, 50, 100, 200, and 300 mg (n=6 per cohort) or placebo (n=2 per cohort).

For the primary endpoint of safety in stage 1, investigators were blinded to treatment arm for assessment of relatedness. Overall, AEs were reported for 8 (33%) subjects who received SNS-062 and for 3 (38%) subjects who received placebo. In the unblinded stages 2 and 3 of the trial, a similar pattern and rate of AEs were observed. Overall, no obvious pattern of dose-dependent toxicity was observed. All AEs were transient and low grade. None of the AEs, laboratory abnormalities, or ECG or telemetry findings were considered clinically meaningful. No SAEs were reported.

SNS-062 was rapidly absorbed and had mean plasma half-life values across all dose cohorts of 6.9 to 17 hours. SNS-062 demonstrated rapid, profound (~100%), and prolonged inhibition of BTK at all dose levels support investigation of a twice-daily dosing regimen in B-cell malignancies with or without an acquired BTK resistance mutation.

Furthermore in stage 2, food had no impact on the extent of absorption or elimination of SNS-062, suggesting that it may be administered to patients without regard to food. In stage 3, SNS-062, similar to ibrutinib, is a sensitive substrate of CYP3A4 and administration with moderate/strong CYP3A4 inhibitors or inducers is not recommended.

About SNS-062

SNS-062 is a novel, second-generation BTK inhibitor, a class of kinase inhibitors that selectively inhibits the enzyme Bruton’s tyrosine kinase (BTK). This target mediates signaling through the B-cell receptor, which is critical for adhesion, migration, proliferation and survival of normal and malignant B-lineage lymphoid cells. Unlike other drugs in its class, SNS-062 binds non-covalently and reversibly to the BTK enzyme. Its binding profile along with improved PK/PD properties potentially provide SNS-062 an opportunity to address the leading acquired resistance to ibrutinib, a mutation in the enzyme’s binding site required for covalent binding. In preclinical studies, SNS-062 demonstrated potent activity against C481S mutated B-cell malignancies, and has been studied in healthy subjects in a completed Phase 1A, randomized, double-blind, placebo-controlled dose-ranging study to investigate the drug’s safety, pharmacokinetics, and pharmacodynamics. With the reported successful study outcome, SNS-062 is proceeding to a Phase 1B/2 study in patients with B-cell malignancies.

On December 5, 2016 Omeros Corporation (NASDAQ: OMER) reported that its small-molecule inhibitors against GPR174, an orphan G protein-coupled receptor (GPCR) narrowly expressed in immune cells and linked to cancers, substantially and statistically significantly boost levels of cytokines and reduce the population of a subset of T cells known as regulatory T cells (Tregs), both activities known to be important in cancer immunotherapy (Press release, Omeros, DEC 5, 2016, View Source [SID1234516917]). Based on these findings, the compounds being advanced by Omeros hold potential advantages over both chimeric antigen receptor (CAR) T-cell therapy and checkpoint inhibitors, each highly touted immunotherapies in development for the treatment of multiple cancers. Part of its orphan GPCR program, Omeros believes that the company alone has identified compounds that inhibit GPR174, and Omeros is establishing a broad patent position directed to any GPR174 inhibitor for the treatment of cancer.

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In assays with human peripheral blood mononuclear cells (PBMCs) evaluating T-cell proliferation and survival following T-cell stimulation, Omeros discovered that small-molecule GPR174 inhibitors increase, with statistical significance, the levels of cytokines interleukin 2 (IL-2) and interferon gamma (IFN-γ) multiple-fold and nearly doubled interleukin 10 (IL-10). Moreover, GPR174 inhibition statistically significantly reduced by approximately 40 percent the population of Tregs, a subset of T-cells elevated in a large number of cancers. Data from GPR174 inhibition in mouse PBMCs are consistent with the human PBMC findings. Importantly, the compound effects were not observed in PBMCs derived from mice genetically lacking GPR174, indicating that the robust Omeros compound effects are the result of "on-target" interaction with the orphan receptor.

These results demonstrate that GPR174 inhibition potentiates the activity of effector T cells, which produce cytokines and are known to be integral to combatting cancer. Also, reducing the level of Tregs is a key objective in cancer immunotherapy, and high levels of Tregs in solid tumors frequently correlates with poor patient outcomes. In addition, signaling and mechanistic studies support that GPR174 suppresses anti-tumor activity, and inhibitors of GPR174 are expected to counteract that detrimental suppression.

"The data from Omeros’ GPR174 program are exciting, as they may lead to a new approach to increase immune function through simultaneous modulation of multiple immune cell subsets," stated Marc Gavin, Ph.D., Research Associate Member, Benaroya Research Institute. "GPR174 inhibition represents a wholly new mechanism in cancer immunotherapy, one that may offer the combined effects of cytokine stimulation and Treg reduction across a wide variety of cancers. This unique mechanism together with Omeros’ development of small-molecule inhibitors targeting GPR174 could provide meaningful benefits over other cancer immunotherapies and a significant advance for patients."

Based on the collective data, small-molecule inhibitors of GPR174 could provide a significant advance in cancer immunotherapy with meaningful potential advantages over current cancer immunotherapies in development, including CAR-T cell therapy and checkpoint inhibitors. Small molecules, unlike antibodies, can be formulated for oral, intravenous, intralesional and topical delivery, addressing some of the administration and procedural limitations of other immunotherapies. Small-molecule compounds, because of their shorter half-life than antibodies, should not have the same safety concerns (e.g., acute, life-threatening immune reactions due to extended duration of drug activity) associated with CAR-T cell and checkpoint therapies. GPR174 inhibitors act on both CD4 (helper) and CD8 (cytotoxic) T-cells and should not rely on the presence of specific tumor cell-surface receptors to be effective as do checkpoint inhibitors. GPR174 inhibitors represent a class of agents that could treat a broad range of cancers – the primary mechanistic limitation of a GPR174 inhibitor is expected to be a cancer cell that is recognized by the body’s immune system as fully "self," i.e., a cancer cell without mutation, which is quite rare.

"Omeros’ proprietary orphan GPCR program continues to generate new drug targets, and GPR174 is one of our current areas of focus," stated Gregory A. Demopulos, M.D., chairman and chief executive officer of Omeros Corporation. "The company’s development of GPR174 inhibitors and related target-based intellectual property position expands our therapeutic assets to oncology and, specifically, to the rapidly progressing and high-interest field of cancer immunotherapy."

About Omeros’ GPCR Program

Omeros uses its proprietary high-throughput CRA to identify small-molecule agonists and antagonists for orphan GPCRs, or GPCRs without known functionally active compounds (i.e., ligands), unlocking them to drug development. Omeros believes that it is the first to possess the capability to unlock orphan GPCRs in high-throughput, and that currently there is no other comparable technology. Omeros has screened a large number of orphan GPCRs against its small-molecule chemical libraries using its proprietary, high-throughput CRA technology. The CRA detects receptor antagonists, agonists and inverse agonists. Omeros has identified and confirmed sets of compounds that interact selectively with 54 of the 81 Class A orphan receptors linked to metabolic, cardiovascular and immunologic disorders, oncology, and disorders of the central nervous system. Omeros has also demonstrated that the CRA is effective in identifying ligands for Class B GPCRs.

GPCRs, which mediate key physiological processes in the body, are one of the most valuable families of drug targets. According to Insight Pharma Reports, GPCR-targeting drugs represent 30 to 40 percent of marketed pharmaceuticals. Examples include Claritin (allergy), Zantac (ulcers and reflux), OxyContin (pain), Lopressor (high blood pressure), Imitrex (migraine headache), Reglan (nausea) and Abilify (schizophrenia, bipolar disease and depression) as well as all other antihistamines, opioids, alpha and beta blockers, and compounds acting through serotonin and dopamine receptors.

The industry focuses its GPCR drug discovery efforts mostly on non-sensory GPCRs. Of the 363 total non-sensory GPCRs, approximately 240 have known ligands with nearly half of those targeted either by marketed drugs (46 GPCRs) or by drugs in development (about 82 GPCRs). There are approximately 120 orphan GPCRs, which have no known ligands. Without a known ligand, drug development for a given receptor is extremely difficult.

On December 5, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported updated findings from the Phase 1b trial, CheckMate -012, in chemotherapy-naïve advanced non-small cell lung cancer patients evaluating Opdivo monotherapy, or in combination with Yervoy, at different doses and schedules (Press release, Bristol-Myers Squibb, DEC 5, 2016, View Source [SID1234516912]). Data from this trial have been previously reported. These updated results, with a median follow-up of 16 months, include pooled efficacy findings for the Opdivo and Yervoy combination cohorts (Opdivo 3 mg/kg every two weeks plus Yervoy 1 mg/kg every six [Q6W] or 12 weeks [Q12W]).

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In the pooled combination cohorts, the median progression-free survival in patients with PD-L1 expression ≥1% (n=46) was 12.7 months (95% CI: 7.8, 23.0) and was not reached in patients with PD-L1 expression ≥50% (n=13; 95% CI: 7.8, NR). For patients with ≥50% PD-L1 expression (n=13), the one-year overall survival rate was 100% in the pooled combination cohorts. In addition, the confirmed objective response rates in all treated patients (n=77) was 43%, nearly double the response rate reported with Opdivo monotherapy (23%; n=52), with six patients (8%) achieving a complete response, three of which were in patients with PD-L1 expression <1%. The Grade 3/4 treatment-related adverse events were 42% and 31% for the Q12W and Q6W combination cohorts, respectively.

Scott N. Gettinger, M.D., associate professor of medicine, Yale Cancer Center, New Haven, Conn., commented, "With longer follow-up in the CheckMate -012 trial, we observe that the Opdivo and Yervoy combination resulted in encouraging progression-free survival. We are also excited to see the consistent near doubling of response rates with the combination relative to Opdivo alone in both PD-L1 expressors and non-expressors, and the previously reported response rates of over 50% and 90%, respectively, among patients with at least 1% and 50% tumor PD-L1 expression. We look forward to further evaluating Opdivo plus Yervoy in the first line treatment setting for advanced lung cancer."

Results from CheckMate -012 will be presented today at the International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer (WCLC) in Vienna, Austria, during an Oral Session at 11:00 a.m. CET.

Nick Botwood, M.D., development lead, Lung, Bristol-Myers Squibb, commented, "The updated results from CheckMate -012 continue to be promising, and we look forward to advancing the Opdivo and Yervoy combination in the ongoing CheckMate -227 Phase 3 trial for first-line advanced lung cancer, with the hope of confirming these findings."

About CheckMate -012

CheckMate -012 is a multi-arm Phase 1b trial evaluating the safety and tolerability (primary endpoints) of Opdivo as monotherapy or in combination with Yervoy at different doses and schedules in patients with chemotherapy-naïve advanced non-small cell lung cancer. The secondary endpoints include confirmed objective response rate (ORR) and progression-free survival (PFS) rates at 24 weeks. Exploratory endpoints include overall survival (OS) and efficacy by PD-L1 expression.

The updated data presented at WCLC include a median follow-up of 16 months for the two combination cohorts – Opdivo 3 mg/kg every two weeks plus Yervoy 1 mg/kg every six weeks (Q6W) (n=39) and 12 weeks (Q12W) (n=38). In the study, both PD-L1 expressors >1% and non-expressors <1% were enrolled. The majority of patients with quantifiable baseline PD-L1 expression in each cohort had PD-L1 tumor expression of ≥1%, including 72% in the Q6W cohort and 70% in the Q12W cohort.

The pooled PFS and OS findings for the combination cohorts in all-treated patients and by tumor PD-L1 expression are reported below.

Nivo 3 Q2W +
Ipi 1 Q6/12W All-Treated (n=77) PD-L1 >1% (n=46) PD-L1 >50% (n=13)
Median PFS, mo (95%, CI) 8.0 (4.1, 13.2) 12.7 (7.8, 23.0) NR (7.8, NR)
1-year OS rate, % 76 87 100
Additional efficacy findings were reported for the Q6W and Q12W cohorts in patients with tumor PD-L1 expression ≥1% at WCLC. These findings are summarized below.

Q12W (n = 23) Q6W (n = 23)
ORR, % (n/N) 57 (13/23) 57 (13/23)
Median PFS, mo (95%, CI) 10.4 (6.4, NR) 13.2 (3.5, 23.0)
1-year OS rate, % 91 83
The rates of treatment-related adverse events (AEs) with Opdivo plus Yervoy remained similar to those previously reported. Treatment related AEs of any grade were 84% and 74% for the Q12W and Q6W combination cohorts, respectively. The Grade 3/4 AEs were 42% and 31% for the Q12W and Q6W combination cohorts, respectively. Treatment-related AEs of any grade led to discontinuation in 18% of patients in Q12W and Q6W combination cohorts. Treatment-related Grade 3/4 AEs led to discontinuation in 8% of patients in the Q12W and Q6W combination cohorts.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. Non-small cell lung cancer (NSCLC) is one of the most common types of the disease and accounts for approximately 85% of cases. About 25% to 30% of all lung cancers are squamous cell carcinomas, and non-squamous NSCLC accounts for approximately 50% to 65% of all lung cancer cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47% and 50%; for Stage IV NSCLC, the five-year survival rate drops to 2%.

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 + Yervoy combination 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.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based 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

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]). In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infections, and sepsis.

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 Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice.

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; Checkmate 141 – squamous cell carcinoma of the head and neck.

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