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Oncodesign presents its latest scientific developments at the AACR annual global meeting on oncology

On April 3, 2017 ONCODESIGN (FR0011766229 – ALONC), a biotechnology company serving the pharmaceutical industry in the discovery of new therapeutic molecules to fight cancer and other serious illnesses with no known effective treatment, reported that it will present its latest scientific developments at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 held on April 1-5, in Washington DC, USA (Press release, Oncodesign, APR 3, 2017, View Source [SID1234518433]).

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The AACR (Free AACR Whitepaper) is the largest global organisation that brings together public and private actors involved in cancer research. Its annual meetings attract every year over 18,000 researchers from the industry and academia.

On this occasion, Oncodesign will present several of its recent scientific developments:

As part of the IMODI project, Oncodesign will present a poster on one of the more important collections of extensively characterised predictive models for pancreatic cancer in the world. The collection of breast cancer models, particularly documented and representative of the human disease, caught the attention of the organisers of the AACR (Free AACR Whitepaper) meeting and will be presented during a dedicated conference on April 4, 2017. According to the INCA study, breast cancer is the cancer with highest incidence in women, with over 54,000 new cases each year in France.
As part of the IMAkinib project, Oncodesign will present the preclinical, cellular and in vivo imaging results obtained with its first PET-tracer generated by the Nanocyclix technology, currently in phase 1 of its development in patients with non-small cell lung cancer.
Oncodesign will also present the results of its Experimentation’s research activities on a new immunotherapy formulation conducted for the US company Checkmate Pharmaceuticals (Cambridge, MA). Remarkable efficacy results have been obtained, in combination with immune checkpoint modulators, in several cancer indications.
Finally, Oncodesign will describe in a fourth poster Experimentation’s internal research conducted on the resistance to PD-11 blockade. Antibodies targeting PD-1 have been recently approved as second line treatments for several types of cancer (urethra, kidney, head and neck, Hodgkin’s lymphoma), or as first line treatment for metastatic melanoma and metastatic non-small cell lung cancer. In spite of the positive response rates and increased survival in the majority of treated patients, a resistance phenomenon develops in certain patients. The Oncodesign research presented at the AACR (Free AACR Whitepaper) meeting aims to develop combination strategies to overcome such resistance and to identify biomarkers. This research showcases complex data analyses, such as cytokine profiles studied in syngeneic models.
Jan Hoflack, Ph.D., Chief Scientific Officer of Oncodesign, said: "Being represented in this way in one of the largest global medical meetings on oncology is a privilege, which provides unparalleled visibility to Oncodesign. This reinforces further the reputation of Oncodesign in terms of its research quality, upheld by the commitment of all our teams to promote the discovery of more effective new drugs."

Full details on Oncodesign presentations during the AACR (Free AACR Whitepaper) meeting:

Abstract n°5169: "Overcoming pd1 targeting antibody resistance using combination strategies"
Presentation: Dr. Jean-François Mirjolet (Oncodesign, Dijon, France)
Poster session/Section: Poster Section 28
Date: April 3, 2017
Time: 8:00am – 12:00pm EDT
Venue: Convention Center, Halls A-C

Abstract n°52217: "Preclinical proof of concept for the first Nanocyclix TKI-PET radiotracer targeting activated EGFR positive lung tumors"
Presentation: Dr. Francis Bichat (Oncodesign, Dijon, France)
Poster session/Section: Poster Section 39
Date: April 3, 2017
Time: 8:00am – 12:00pm EDT
Venue: Convention Center, Halls A-C

Abstract n°28: "Antitumor activity of the CMP-001 (TLR9 agonist) alone or combined with immune modulators in syngeneic tumor models"
Presentation: Dr. Aaron Morris (Checkmate Pharmaceuticals, Boston, US) and
Dr Sylvie Maubant (Oncodesign, Dijon, France)
Poster session/Section: Poster Section 26
Date: April 3, 2017
Time:
1:00pm – 5:00pm EDT
Venue: Convention Center, Halls A-C

Abstract n°3846: "Imodi initiative: A novel holistic and integrative approach with patient-derived tumor models against pancreatic cancer"
Presentation: Dr. Juan Iovanna (Inserm U1068, Marseille, France)
Poster session/Section: Poster Section 37
Date: April 4, 2017
Time: 8:00am – 12:00pm EDT
Venue: Convention Center, Halls A-C

Abstract n°5015: "Innovative and predictive models against breast cancer"
Presentation: Dr. S. Tabonne (Leon Berard clinical center, Lyon, France)
Section: Tumor biology Minisymposium session
Date: April 4, 2017
Time:
3:00pm – 5:00pm EDT

OncoSec Presents Preclinical Data Demonstrating Improved Systemic Anti-Tumor Response Following Modifications to IL-12 Gene Delivery Therapy at AACR Annual Meeting

On April 3, 2017 OncoSec Medical Incorporated ("OncoSec") (NASDAQ: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, reported a poster titled "Intratumoral Delivery of a P2A-linked Bicistronic IL-12 Construct Leads to High Intratumoral Expression and Systemic Anti-tumor Response" (Abstract ID # 1614) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, in Washington, D.C (Press release, OncoSec Medical, APR 3, 2017, View Source [SID1234518431]). The poster included preclinical data demonstrating the latest developments of OncoSec’s gene delivery platform in a murine melanoma model.

Previous studies have shown the use of immunomodulatory cytokines is effective in the regression of a wide range of tumors. However, systemic delivery of recombinant cytokines has often resulted in life-threatening adverse effects. Intratumoral gene electrotransfer of plasmid encoded interleukin-12 (IL-12) has shown acceptable safety and efficacy profiles in regressing tumors, both preclinically and clinically.

"We sought to optimize the anti-tumor immune response of our IL-12 immunotherapy platform that combines intratumoral injection of plasmid DNA coding for IL-12 and electroporation. Using a mouse model of melanoma, we were able to demonstrate that the changes made to plasmid design and to electroporation parameters can significantly increase production of IL-12, leading to an improved anti-tumor effect," said Punit Dhillon, OncoSec President and CEO. "The new IL-12 construct is the backbone of our next generation combination molecules."

Copies of the abstract are available and can be viewed on the AACR (Free AACR Whitepaper) website at View Source!/4292/presentation/6375. The poster is available in the Publications section of OncoSec’s website.

Seattle Genetics Presents Data Advancing Antibody-Drug Conjugate and Novel Immuno-Oncology Programs at the American Association for Cancer Research (AACR) Annual Meeting

On April 3, 2017 Seattle Genetics, Inc. (Nasdaq: SGEN), a global biotechnology company, reported multiple data presentations that support the company’s advancing antibody-drug conjugate (ADC) and immuno-oncology programs at the upcoming 108th Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) being held April 1-5, 2017, in Washington, D.C (Press release, Seattle Genetics, APR 3, 2017, View Source [SID1234518430]). The presentations describe the ability of ADCETRIS (brentuximab vedotin) to activate antitumor immune responses, supporting continued clinical evaluation in combination with checkpoint inhibitors. Additionally, preclinical data feature two immuno-oncology agents, SEA-CD40 and SGN-2FF, both of which are in phase 1 trials. Seattle Genetics and Unum Therapeutics are presenting preclinical data evaluating combination treatment with Antibody-Coupled T cell Receptor (ACTR) engineered autologous T cells and an antibody targeting B-cell maturation antigen (BCMA), SEA-BCMA, for multiple myeloma. Further data highlight clinical biomarker analyses for vadastuximab talirine (SGN-CD33A; 33A), an ADC under evaluation in the global phase 3 CASCADE trial for acute myeloid leukemia (AML).

"Our expertise in empowered-antibody innovation drives a substantial, advancing pipeline of more than a dozen clinical and preclinical programs, both ADCs and immuno-oncology agents," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development, at Seattle Genetics. "Preclinical data presented at AACR (Free AACR Whitepaper) support multiple ongoing clinical studies evaluating combination treatment of ADCETRIS and nivolumab (Opdivo) in relapsed Hodgkin and non-Hodgkin lymphoma and phase 1 trials of two proprietary immuno-oncology agents, SEA-CD40 and SGN-2FF, in solid tumors. Seattle Genetics is transforming into a global, multi-product oncology company through dedication to scientific innovation and the needs of patients."

Multiple presentations are being featured at AACR (Free AACR Whitepaper) that highlight advances with Seattle Genetics’ ADC and empowered antibody pipeline programs. Abstracts can be found at www.aacr.org and include the following:

Preclinical data evaluating the ability of brentuximab vedotin (ADCETRIS) to induce immunogenic cell death will be presented in a poster presentation on Wednesday, April 5, 2017 (Abstract #5588). These data demonstrate that ADCETRIS-treated tumor cells initiate an antitumor immune response alone and, to a greater extent, in combination with anti-PD-1 agents, and support combination strategies with immuno-oncology regimens, such as the ongoing phase 1/2 clinical trials evaluating ADCETRIS and nivolumab (Opdivo) in relapsed Hodgkin and non-Hodgkin lymphoma.
Preclinical data supporting the ongoing phase 1 study of SGN-2FF for patients with advanced solid tumors, including non-small cell lung cancer, were highlighted in an oral presentation at the New Drugs on the Horizon symposium on Sunday, April 2, 2017 (Session #DDT02-02). SGN-2FF is an oral, small molecule immuno-oncology agent that has been shown in preclinical models to inhibit fucosylation of proteins and thereby stimulate the immune system to slow the growth and spread of cancer cells.
SEA-CD40 preclinical data will be presented in a poster on Tuesday, April 4, 2017 (Abstract #3647), focusing on mechanism of action through activation of antitumor immune response and potential for combination with checkpoint inhibitors. This innovative immuno-oncology agent being developed by Seattle Genetics targets the protein CD40 using Seattle Genetics’ proprietary sugar-engineered antibody (SEA) technology to produce a non-fucosylated antibody. SEA-CD40 is under evaluation in a phase 1 trial for the treatment of blood cancers and solid tumors.
An analysis of CD33 target binding by vadastuximab talirine from a phase 1 monotherapy study in AML will be highlighted in a poster presentation on Tuesday, April 4, 2017 (Abstract #CT120). Vadastuximab talirine is being broadly evaluated across multiple lines of therapy in patients with myeloid malignancies, including the ongoing global phase 3 CASCADE study in newly diagnosed, older AML patients and phase 1/2 trial in patients with newly diagnosed myelodysplastic syndrome (MDS).
A novel preclinical program evaluating SEA-BCMA antibody in combination with ACTR T cells in multiple myeloma, developed in collaboration with Unum Therapeutics, will be highlighted in a poster presentation on Tuesday, April 4, 2017 (Abstract #4605). The ACTR engineered T cell technology enables programming of a patient’s immune system to attack tumor cells when co-administered with tumor-specific therapeutic antibodies. The cell surface protein BCMA is expressed on cells of several cancer types, including multiple myeloma and other B cell malignancies. The preclinical data support clinical evaluation of SEA-BCMA and ACTR T cell combination treatment in multiple myeloma patients.

Celgene Notified of ANDA Filing for POMALYST®

On April 3, 2017 Celgene Corporation (NASDAQ:CELG) reported that it has received a Paragraph IV Notice Letter advising that Teva Pharmaceuticals USA, Inc. submitted an Abbreviated New Drug Application (ANDA) to the U.S. Food and Drug Administration (FDA) seeking authorization from the FDA to manufacture and market a generic version of POMALYST (pomalidomide) 1 mg, 2 mg, 3 mg and 4 mg in the United States (Press release, Celgene, APR 3, 2017, View Source [SID1234518427]).

The Notice Letter contains Paragraph IV certifications against certain patents related to POMALYST. Celgene is assessing the notice. Celgene intends to vigorously defend its extensive intellectual property rights related to POMALYST.

About POMALYST

In the U.S., POMALYST (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Five-Year Survival Observed With Opdivo (nivolumab) in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC), in Phase 1 Study CA209-003

On April 3, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported the first report of five-year overall survival (OS) data from the Phase 1 dose-ranging study CA209-003 evaluating Opdivo in patients with previously treated advanced non-small cell lung cancer (NSCLC; n=129) (Press release, Bristol-Myers Squibb, APR 3, 2017, View Source [SID1234518426]). Overall survival was an exploratory endpoint in this study. The estimated OS rate at five years was 16% in heavily pre-treated NSCLC patients; survival was observed across PD-L1 expression levels and tumor histologies. The safety profile of Opdivo from this study was previously reported; no new safety signals were identified in this analysis. These data were featured today during the official press program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 in Washington, D.C.

Scott N. Gettinger, M.D., a senior author of CA209-003 and associate professor of medicine, Yale Cancer Center, New Haven, Conn., commented, "Historically, five-year survival rates for patients with advanced NSCLC have been less than 5%. With new data emerging from the NSCLC cohort of CA209-003, we observe that the estimated five-year overall survival rate in Opdivo-treated patients in the study was 16%. In addition, based on investigator assessments, the majority of these patients showed no evidence that their lung cancer had progressed at the time of their last follow-up. These findings offer important new insights into the long-term clinical profile of Opdivo in this patient population."

These results also will be presented today at AACR (Free AACR Whitepaper) from 4:05 – 4:20 p.m. during the Update, Novel Indication, and New Immuno-Oncology Clinical Trials session (Late-Breaking Abstract CT077).

Nick Botwood, M.D., development lead, Lung, Bristol-Myers Squibb, commented, "Opdivo is a standard of care for second-line NSCLC and has been an important treatment option for these patients. CA209-003 represents the longest follow-up analysis of data from a clinical trial testing an anti-PD-1 immunotherapy, and it is encouraging to observe that a subset of these heavily pre-treated patients experienced, at minimum, five years of survival. We look forward to further evaluating our Immuno-Oncology agents, including Opdivo-based combinations, with the goal of improving long-term survival for lung cancer patients."

About CA209-003

CA209-003 (NCT00730639) is a Phase 1b, open-label, multicenter, multidose, dose-escalation study of Opdivo in patients with select advanced or recurrent malignancies, including previously treated non-small cell lung cancer (NSCLC). In this study, patients received one to five prior systemic therapies for advanced NSCLC (n=129) and were treated with Opdivo (1, 3 or 10 mg/kg) intravenously once every two weeks for less than 96 weeks. The primary objectives were measures of safety and tolerability. Secondary objectives include antitumor activity. Overall survival (OS) and analysis by PD-L1 expression levels were exploratory objectives. The data reported at AACR (Free AACR Whitepaper) 2017 represent pooled data across the three doses for the NSCLC cohort.

At five years, the estimated OS rate for patients treated with Opdivo at all doses was 16%, and the median OS was 9.9 months (95% CI: 7.8, 12.4), with a minimum follow-up of 58 months. The five-year OS rates were consistent across histologies (squamous = 16% [n=54]; non-squamous = 15% [n=74]). In patients with evaluable PD-L1 expression (n=68/129), five-year OS rates increased as the PD-L1 expression level increased. Five-year OS rates were 20%, 23% and 43% in patients with PD-L1 expression <1%, ≥1% and ≥50%, respectively. PD-L1 status was not evaluable in 47% of patients (n=61/129); the estimated five-year OS rate in patients with unknown PD-L1 status was 10%. Based on investigators’ assessment, 75% (n=12/16) of patients remained without evidence of progressive disease at their last follow-up. In the study, five-year survivors had variable length of time and disease course from diagnosis to Opdivo treatment initiation. The median time from initial diagnosis to start of Opdivo was 1.2 years (range, 0.4 to 6.1 years).

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.