On March 1, 2017 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company focused on bringing novel immuno-oncology therapies to patients with cancer, reported that two abstracts on the company’s indoximod program will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2017 Annual Meeting in Washington, D.C (Press release, NewLink Genetics, MAR 1, 2017, View Source [SID1234517927]).

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Clinical Trials Plenary Session: Abstract CT117 – Interim analysis of the Phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma, to be presented during the Novel Immuno-Oncology Agent Clinical Trials session, Tuesday April 4, 2017 10:30 a.m. – 12:45 p.m. ET.

Poster Session: Abstract 4076 – A novel prodrug of indoximod with enhanced pharmacokinetic properties, to be presented during poster session PO.ET05.01 – Mechanistic Understanding of Novel Anticancer Therapies, April 4, 2017 1 p.m. – 5 p.m. ET .
The complete text of Clinical Plenary Session abstracts that have not been selected for the press program will be posted online at 4:30 p.m. ET on Friday, March 31. The text of clinical trials abstracts that have been selected for inclusion in the press program will not be posted online until the date and time of presentation.

"We are honored to have been selected by the AACR (Free AACR Whitepaper) review committee for the Clinical Trials Plenary Session at the upcoming AACR (Free AACR Whitepaper) meeting," said Nicholas Vahanian, M.D., President and Chief Medical Officer. "We look forward to sharing the data from both of these abstracts."

On March 2, 2017 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that data on monalizumab will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, April 1 – 5, 2017, in Washington, D.C (Press release, Innate Pharma, MAR 1, 2017, View Source [SID1234517926]). Abstracts are available on the AACR (Free AACR Whitepaper) website. Monalizumab is Innate Pharma’s investigational first-in-class anti-NKG2A antibody partnered with AstraZeneca.

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These data support the rationale for the development of monalizumab:

Preclinical data will be presented in a mini-symposium and show NKG2A expression on tumor-infiltrating CD8+ T cells in patients with head and neck cancer as well as synergy between treatment with a HPV vaccine and NKG2A blockade in a mouse tumor model;
During a poster session, safety data from the dose-escalation part of a Phase Ib/II study evaluating monalizumab in combination with cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck will be presented. In this study, monalizumab plus cetuximab were well tolerated with no additional safety concerns compared to monalizumab or cetuximab alone.
Monalizumab is currently being tested in five Phase I and I/II clinical trials in various cancer as a single agent and in combination with other therapies.



Presentation and poster details:

NKG2A checkpoint receptor expression on tumor-infiltrating CD8+ T cells restrains efficacy of immunotherapy
Abstract Number: 2999
Session Type: Mini-symposium, webcast
Session Title: Innate Immune Mechanisms in Cancer Treatment
Session Date and Time: Monday April 3, 2017 4:35 – 4:50 PM EST
Location: Washington Convention Center, Room 152, Level 1
Presented by Thorbald van Hall, Department of Clinical Oncology, Leiden University Medical Centre, The Netherlands
Safety of the first-in-class anti-NKG2A monoclonal antibody monalizumab in combination with cetuximab: a phase Ib/II study in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN)
Abstract Number: 5666/20
Session Type: Poster Session
Session Title: Innate Immunity to Generate Adaptive Immunity
Session Date and Time: Wednesday April 5, 2017 8:00 AM – 12:00 PM EST
Location: Washington Convention Center, Halls A-C, Poster Section 28
Presented by Roger B. Cohen M.D., Abramson Cancer Center, Philadelphia, USA

On March 1, 2017 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported that new preclinical data showing the broad anti-tumor activity on its "prime-pull" approach, as well as the ability of its ZVex vectors to activate dendritic cells potently, will be presented at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2017 Annual Meeting, being held from April 1-5, 2017 in Washington D.C (Press release, Immune Design, MAR 1, 2017, View Source [SID1234517925]).

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"These AACR (Free AACR Whitepaper) data illustrate the significant local and systemic immune responses that the combination of ZVex vectors with G100 may generate. We observed complete eradication of large, established B16 tumors in animal models, which previously has been achieved only with complex regimens," said Jan ter Meulen, MD, PhD, Chief Scientific Officer at Immune Design. "In addition, we will present additional data supporting the ability of ZVex vectors to generate potent activation of human dendritic cells."

Immune Design will present data showing the "Prime-Pull" concept that involves the (i) intradermal administration of the dendritic cell (DC)-targeting ZVex vector expressing a tumor-associated antigen and (ii) intratumoral injection of G100, a formulated, potent synthetic toll-like receptor-4 (TLR-4) agonist, in the difficult to treat B16 melanoma model. Antigen-specific CD8 T-cells are induced ("primed") by a ZVex vector, and subsequent injection of G100 leads to pro-inflammatory changes in the tumor microenvironment (TME), which induces the trafficking of T-cells into the tumor (the "pull"). This inflamed TME and recruitment of ZVex-induced CD8 T cells eradicated large, established B16 tumors. Also importantly, treated mice rejected re-challenge with a tumor lacking the antigen used for immunization, indicating antigen spreading induced by the immunotherapeutic regimen. Immune Design is evaluating this immunotherapy approach in an ongoing Phase 1 trial in patients with soft tissue sarcoma who are receiving G100 and CMB305, its prime-boost approach that is being evaluated in multiple clinical trials as both a monotherapy and in combination with atezolizumab, Genentech’s anti-PD-L1 antibody.

In addition, Immune Design will present separate data highlighting the ability of its ZVex vectors to induce potent, innate immune activation in human DCs. Company researchers studied the effect of human DC transduction with ZVex vectors by gene expression profiling. Human DCs transduced with ZVex vectors displayed statistically significant up-regulation of genes involved in antigen presentation and anti-viral defense pathways, highlighting that ZVex is sufficient to activate transduced DCs and facilitate antigen presentation to T cells.

The details for the poster presentations are as follows:

Large established B16 tumors in mice are eradicated by ZVex (dendritic cell-targeting lentiviral vector) and G100 (TLR4 agonist) combination immunotherapy through increasing tumor-infiltrating effector T cells and inducing antigen spreading

Abstract #: 5673

Session Category: Clinical Research

Session Title: Innate Immunity to Generate Adaptive Immunity

Date and Time: Wednesday, April 5, 2017, 8:00 a.m. — 12:00 p.m.

Location: Convention Center, Halls A-C, Poster Section 28

Poster Board: 27

Authors: Tina C. Albershardt, Andrea J. Parsons, Jardin Leleux, Peter Berglund, Jan ter Meulen. Immune Design

The poster presentation will be made available at Immune Design’s website on or after April 5, 2017.

ZVex lentiviral vector strongly activates pro-inflammatory, antigen processing, and anti-viral defense response pathways in monocyte-derived dendritic cells

Abstract #: 5092

Session Category: Experimental and Molecular Therapeutics

Session Title: Gene- and Vector-based Therapy

Date and Time: Wednesday, April 5, 2017, 8 a.m. — 12 p.m.

Location: Convention Center, Halls A-C, Poster Section 3

Poster Board: 8

Authors: Anshika Bajaj, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen. Immune Design

The poster presentation will be made available at Immune Design’s website on or after April 5, 2017.

About ZVex

ZVex is Immune Design’s discovery platform designed to activate and expand the immune system’s natural ability to create tumor-specific cytotoxic T cells (CTLs) in vivo. ZVex uses a re-engineered virus to carry genetic information of a tumor antigen selectively to dendritic cells in the skin or lymph nodes. This ultimately results in the creation of CTLs designed to kill tumor cells bearing that same specific tumor antigen. ZVex is also designed to carry the genetic information for, and therefore potentially cause dendritic cells to express, multiple antigens and/or selected epitopes of interest (including neoantigens), as well as cytokines or other immunomodulatory molecules.

About G100

G100 is a product candidate from Immune Design’s GLAAS discovery platform. It contains a potent synthetic small molecule toll-like receptor-4 (TLR-4) agonist, Glucopyranosyl Lipid A (GLA), and is the lead product candidate in Immune Design’s Antigen Agnostic approach. It leverages the activation of both innate and adaptive immunity, including Dendritic Cells, in the tumor microenvironment to create an immune response against the tumor’s preexisting diverse set of antigens. A growing set of clinical and preclinical data have demonstrated the ability of G100 to activate tumor-infiltrating lymphocytes, macrophages and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor. The ensuing induction of local and systemic immune responses has been shown to result in local and abscopal (shrinking of tumors outside the scope of the localized treatment) tumor control in preclinical studies. G100 was evaluated in a Phase 1 study in Merkel cell carcinoma patients and produced a 50% overall response rate per protocol and a favorable safety profile. Currently, G100 is being evaluated as both a monotherapy with local radiation and in combination with Merck’s anti-PD-1 agent, pembrolizumab, pursuant to a clinical collaboration with Merck, in a randomized Phase 1/2 trial in patients with follicular non-Hodgkin lymphoma.

On March 1, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY), the Breast International Group (BIG), Breast European Adjuvant Study Team (BrEAST) and Frontier Science Foundation (FS) reported positive results from the phase III APHINITY study (Press release, Hoffmann-La Roche, MAR 1, 2017, View Source [SID1234517924]). The study met its primary endpoint and showed that adjuvant (after surgery) treatment with the combination of Perjeta (pertuzumab), Herceptin (trastuzumab) and chemotherapy (the Perjeta-based regimen) achieved a statistically significant reduction in the risk of recurrence of invasive disease or death (invasive disease-free survival; iDFS) in people with HER2-positive early breast cancer (eBC) compared to Herceptin and chemotherapy alone. The safety profile of the Perjeta-based regimen was consistent with that seen in previous studies1, and no new safety signals were identified. Full results from the APHINITY trial will be presented at an upcoming medical meeting in 2017.

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"These results from the positive APHINITY study represent an important addition to the body of data for Perjeta in the treatment of people with HER2-positive early breast cancer," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development at Roche. "We look forward to discussing these adjuvant results with global regulatory authorities."

Gunter von Minckwitz, MD, study coordinator from the Breast International Group and academic study partners, added, "APHINITY provides yet another example of the importance of industry-academic collaborations and their value in advancing cancer care for people affected by this challenging disease."

HER2-positive breast cancer is an aggressive form of the disease, which affects approximately one in five people with breast cancer2 and is associated with a poor prognosis if left untreated.3 Despite advancements in the treatment of HER2-positive eBC, up to one in three people treated with Herceptin and chemotherapy may eventually see their cancer return.4,5 Treatment options are needed to improve the outcomes of people with this aggressive disease. Treating breast cancer early, before it has spread, may improve the chance of preventing the disease from returning and potentially reaching an incurable stage.6 Adjuvant therapy is given after surgery and is aimed at killing any remaining cancer cells to reduce the risk of the cancer returning.6

The combination of Perjeta, Herceptin and chemotherapy is licenced as a neoadjuvant (before surgery) treatment for people with HER2-positive eBC in more than 75 countries worldwide following approvals by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).1,7 In the US, the regimen is currently available under the FDA accelerated approval programme. The APHINITY trial reflects the commitment to evaluate the Perjeta-based regimen as part of a complete treatment approach for eBC. These data will be discussed with health authorities across the world, including the US FDA with the hope to convert the current US accelerated approval to a full approval.

About APHINITY8
APHINITY (Adjuvant Pertuzumab and Herceptin IN Initial TherapY in Breast Cancer, NCT01358877/ BO25126/ BIG 4-11) is an international, phase III, randomised, double-blind, placebo-controlled, two-arm study evaluating the efficacy and safety of Perjeta plus Herceptin and chemotherapy compared to Herceptin and chemotherapy as an adjuvant therapy in 4,805 people with operable HER2-positive eBC.

People enrolled in the study underwent surgery and were randomised to one of two arms (1:1) to receive either:
Six to eight cycles of chemotherapy (anthracycline or non-anthracycline-containing regimen) with Perjeta and Herceptin, followed by Perjeta and Herceptin every three weeks for a total of one year (52 weeks) of treatment.
Six to eight cycles of chemotherapy (anthracycline or non-anthracycline-containing regimen) with placebo and Herceptin, followed by placebo and Herceptin every three weeks for a total of one year (52 weeks) of treatment.
Radiotherapy and/or endocrine therapy could be initiated at the end of adjuvant chemotherapy. The APHINITY study allowed for a range of standard chemotherapy regimens to be used and both lymph node-positive and lymph node-negative participants were eligible for enrolment. The primary efficacy endpoint of the APHINITY study is iDFS, which is the time a patient lives without return of invasive breast cancer at any site or death from any cause after adjuvant treatment. Secondary endpoints include cardiac and overall safety, overall survival, disease-free survival and health-related quality of life.

About Perjeta
Perjeta is a medicine that targets the HER2 receptor, a protein found on the outside of many normal cells and in high quantities on the outside of cancer cells in HER2-positive cancers.9,10 Perjeta is designed specifically to prevent the HER2 receptor from pairing (or ‘dimerising’) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumour growth and survival. Binding of Perjeta to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Perjeta and Herceptin are believed to complement each other, as both bind to the HER2 receptor, but to different places. The combination of Perjeta and Herceptin is thought to provide a more comprehensive, dual blockade of HER signalling pathways, thus preventing tumour cell growth and survival.11,12

On March 1, 2017 Bristol-Myers Squibb Company (NYSE: BMY) reported that new clinical data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 in Washington, D.C., from April 1-5 (Press release, Bristol-Myers Squibb, MAR 1, 2017, View Source [SID1234517923]).

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Research to be presented represents the company’s ongoing commitment to investigating long-term survival and safety data in advanced cancers, and to exploring the interaction between biomarkers and Immuno-Oncology (I-O) therapy across multiple tumor types. Results will be disclosed for Opdivo (nivolumab), as a single-agent and in combination with Yervoy (ipilimumab), as well as an investigational, optimized, once-daily IDO1 inhibitor alone or in combination with Opdivo. IDO is part of Bristol-Myers Squibb’s robust early clinical development pipeline and one of 21 oncology compounds in clinical study. Bristol-Myers Squibb will also share data generated as part of the International Immuno-Oncology Network (II-ON), a global peer-to-peer collaboration with academia established in 2012 and focused on advancing the science of I-O through a series of preclinical, translational and biology-focused research objectives.

"At Bristol-Myers Squibb, we are committed to translational research as we advance the development of next-generation Immuno-Oncology therapies and conduct biomarker research that will help us determine which patients are most likely to benefit from our treatments," said Fouad Namouni, M.D., head of development, Oncology, Bristol-Myers Squibb. "In all of our research efforts, we are driven by our overarching goal of changing the way patients live with cancer."

The full set of data to be presented by Bristol-Myers Squibb includes:

Melanoma / Skin Cancer

Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-naïve patients with advanced melanoma (CheckMate -067)
Author: James Larkin
Abstract # CT075
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials
Monday, April 3, 2017, 3:35 – 3:50 p.m., Ballroom C, Level 3
Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab in patients with virus-associated tumors (CheckMate -358): Efficacy and safety in Merkel cell carcinoma
Author: Suzanne Topalian
Abstract # CT074
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials
Monday, April 3, 2017, 3:05 – 3:20 p.m. Ballroom C, Level 3
Overall survival and safety experience from an expanded access program of nivolumab for patients with advanced melanoma who progressed after prior ipilimumab treatment (CheckMate -168)
Author: Milton Barros e Silva
Abstract # LB-055
Late-Breaking Poster Session: Clinical Research 1
Monday, April 3, 2017, 8:00 a.m. – 12:00 p.m., Poster Section 34; Poster Board #18
Lung

Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage IV or recurrent non-small cell lung cancer: an exploratory analysis of CheckMate -026
Author: Solange Peters
Abstract # CT082
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials
Monday, April 3, 2017, 5:20 – 5:30 p.m., Ballroom C, Level 3
Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer: Clinical characteristics of long-term survivors
Author: Julie Renee Brahmer
Abstract # CT077
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials Monday, April 3, 2017, 4:05 – 4:20 p.m., Ballroom C, Level 3
An Open-label Phase 3b/4 Safety Trial of Flat-Dose Nivolumab in Combination With Ipilimumab in Patients With Advanced Non-Small Cell Lung Cancer
Author: Rathi N. Pillai
Abstract # CT070
Poster Session: Phase II/III Clinical Trials in Progress
Monday, April 3, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster Section 33, Poster Board #20
Head and Neck Cancer

Treatment Beyond Progression With Nivolumab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck in the Phase 3 Checkmate -141 Study
Author: Robert Haddad
Abstract # CT157
Poster Session: Phase II/III Clinical Trials in Progress
Monday, April 3, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster Section 33
Pipeline

BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic activity, alone and in combination with nivolumab in advanced cancers in a phase 1/2a trial
Author: Lillian L. Siu
Abstract # CT116
Plenary Session: Novel Immuno-oncology Agent Clinical Trials
Tuesday, April 4, 2017, 11:13 – 11:28 a.m., Ballroom C, Level 3
Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical stage IDO1 inhibitor
Author: John T. Hunt
Abstract # 4964
Minisymposium: Novel Approaches for Experimental Therapeutics
Tuesday, April 4, 2017, 3:20 – 3:35 p.m. ET, Room 144, Level 1
Biomarkers and Dosing

Evaluation of oral microbiome profiling as a response biomarker in squamous cell carcinoma of the head and neck: Analyses from CheckMate -141
Author: Robert L. Ferris
Abstract # CT022
Clinical Trials Plenary Session: Immuno-oncology Biomarkers in Clinical Trials
Sunday, April 2, 2017, 4:48 – 5:03 p.m., Hall D-E, Level 2
Tumor-associated immune cell PD-L1 expression and peripheral immune profiling: Analyses from CheckMate -141
Author: Robert L. Ferris
Abstract # CT021
Clinical Trials Plenary Session: Immuno-oncology Biomarkers in Clinical Trials
Sunday, April 2, 2017, 4:33 – 4:48 p.m., Hall D-E, Level 2
Immunogenomic analyses of tumor cells and microenvironment in patients with advanced melanoma before and after treatment with nivolumab
Author: Timothy A. Chan
Abstract # 2988
Minisymposium: Clinical Biomarkers
Monday, April 3, 2017, 3:35 – 3:50 p.m. ET, Room 151, Level 1
Immunomodulatory effects of nivolumab and ipilimumab in combination or nivolumab monotherapy in advanced melanoma patients: CheckMate -038
Author: Antoni Ribas
Abstract # CT073
Minisymposium: Update, Novel Indication, and New Immuno-oncology Clinical Trials
Monday, April 3, 2017, 3:20 – 3:35 p.m., Ballroom C, Level 3
A model-based exposure-response assessment of a nivolumab 4-weekly (Q4W) dosing schedule across multiple tumor types
Author: Xiaochen Zhao
Abstract # CT101
Poster Session: Phase I Clinical Trials
Tuesday, April 4, 2017, 8:00 a.m. – 12:00 p.m. ET, Halls A-C, Poster Section 33
A Comparative Study of PD-L1 IHC 22C3 and 28-8 FDA-Approved Diagnostic Assays in Cancer
Author: Cory Batenchuk
Abstract # 4015
Poster Session: Assay Technology
Tuesday, April 4, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster section 1
Soluble HLA-G and -E (sHLA-G/E) as potential biomarkers of clinical outcomes in patients with advanced, refractory squamous (SQ) NSCLC treated with nivolumab: CheckMate -063
Author: Vera Rebmann
Abstract # CT126
Poster Session: Phase I-III Clinical Trials and Pediatric Clinical Trials
Tuesday, April 4, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster Section 33
Pooled analysis of PD-L1 expression across 6 tumor types in the nivolumab clinical program
Author: Gabriel Krigsfeld
Abstract # CT143
Poster Session: Phase I-III Clinical Trials and Pediatric Clinical Trials
Tuesday, April 4, 2017, 1:00 – 5:00 p.m. ET, Halls A-C, Poster Section 33
II-ON

RNA-sequencing of tumor-educated platelets enables nivolumab immunotherapy response prediction
Author: Mirte Muller
Abstract # LB-248
Poster Session: Lake-Breaking Clinical Research 2 / Endocrinology
Tuesday, April 4, 2017,1:00 – 5:00 p.m. ET, Poster Section 34
Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

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 35 types of cancers with 13 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 60 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 50 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.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory 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]). 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. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

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 Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).

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; Checkmate 275 – urothelial carcinoma.

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