On April 19, 2016 Oncothyreon Inc. (NASDAQ:ONTY), a clinical-stage biopharmaceutical company, reported the presentation of data highlighting the preclinical development of orally bioavailable, potent and selective checkpoint kinase 1 (Chk1) inhibitors (Press release, Oncothyreon, APR 19, 2016, View Source [SID:1234511061]).

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Results were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans.

Chk1 is a protein kinase that plays a major role in the ability of cancer cells to respond to DNA damage and DNA replication stress. As a single agent, Chk1 inhibitors may selectively target cancer cells that have high replication stress, which can be caused by activation of oncogenic signaling and loss of tumor suppressor functions. Chk1 inhibitors may also be used in combination with chemotherapy, potentially enhancing cell death and increasing the efficacy of these agents.

"The research presented at AACR (Free AACR Whitepaper) describes the results of our efforts to identify highly potent and selective, orally bioavailable Chk1 inhibitors with compelling single-agent and combinatorial anti-tumor activity," said Scott Peterson, Ph.D, Chief Scientific Officer of Oncothyreon. "We believe the Chk1 program warrants further study as part of our strategy to develop a pipeline of novel, orally available, targeted agents designed to improve the lives and outcomes of patients with cancer."

The Oncothyreon presentation, titled "Discovery and development of orally available subnanomolar potent checkpoint kinase 1 inhibitors as potential anticancer therapies" (Abstract #2721), highlights preclinical data demonstrating that select Chk1 inhibitors display subnanomolar biochemical and single-digit nanomolar cellular potency against Chk1. In addition, Oncothyreon Chk1 inhibitors are active against a diverse range of cancer cell lines derived from leukemias, lymphomas and solid tumors, and demonstrate synergistic activity in combination with the chemotherapeutic drugs gemcitabine or cytarabine. The pharmaceutical properties of the Chk1 inhibitors also indicate good metabolic stability and pharmacokinetic properties, with good oral bioavailability in preclinical models, which may allow for the development of optimized dosing schedules.

The research was conducted pursuant to a research collaboration agreement with Sentinel Oncology.

On April 19, 2016 Johnson & Johnson (NYSE: JNJ) reported sales of $17.5 billion for the first quarter of 2016, an increase of 0.6% as compared to the first quarter of 2015 (Press release, Johnson & Johnson, APR 19, 2016, View Source [SID:1234511056]).

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Operational sales results increased 3.9% and the negative impact of currency was 3.3%. Domestic sales increased 7.2%. International sales decreased 6.0%, reflecting operational growth of 0.6% and a negative currency impact of 6.6%. Excluding the net impact of acquisitions, divestitures and hepatitis C sales, on an operational basis, worldwide sales increased 6.9%, domestic sales increased 9.8% and international sales increased 3.8%.* The currency devaluation in Venezuela negatively impacted worldwide operational sales growth by 60 basis points, and international sales growth by 120 basis points.

Net earnings and diluted earnings per share for the first quarter of 2016 were $4.3 billion and $1.54, respectively. First quarter 2016 net earnings included after-tax intangible amortization expense of approximately $0.2 billion and a charge for after-tax special items of approximately $0.2 billion. First quarter 2015 net earnings included after-tax intangible amortization expense of approximately $0.2 billion and a net gain for after-tax special items of approximately $0.1 billion. A reconciliation of non-GAAP financial measures is included as an accompanying schedule. Excluding after-tax intangible amortization expense and special items, adjusted net earnings for the current quarter were $4.7 billion and adjusted diluted earnings per share were $1.68, representing increases of 6.1% and 7.7%, respectively, as compared to the same period in 2015.* On an operational basis, adjusted diluted earnings per share increased 10.3%.*

"We are off to a strong start to the year, supported by our first quarter underlying sales growth," said Alex Gorsky, Chairman and Chief Executive Officer. "Our Pharmaceuticals business continues to deliver impressive levels of growth, we have steady improvement in our Consumer business, and we are seeing momentum in our Medical Devices businesses, all of which are fueling our optimism for the full-year ahead."

Mr. Gorsky continued, "I am proud of our global teams for their contributions to these results and their commitment to developing innovative solutions that address the unmet health care needs of people around the world."

The Company updated its sales guidance for the full-year 2016 to $71.2 billion to $71.9 billion reflecting current foreign currency exchange rates. Additionally, the Company increased its adjusted earnings guidance for full-year 2016 to $6.53 – $6.68 per share.

Worldwide Consumer sales of $3.2 billion for the first quarter 2016 represented a decrease of 5.8% versus the prior year, consisting of an operational decrease of 0.2% and a negative impact from currency of 5.6%. Domestic sales decreased 0.1%; international sales decreased 9.6%, which reflected an operational decrease of 0.3% and a negative currency impact of 9.3%. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales increased 1.9%, domestic sales increased 4.1% and international sales increased 0.5%*. The currency devaluation in Venezuela negatively impacted worldwide Consumer operational sales growth by 200 basis points, and international sales growth by 320 basis points.

Primary contributors to Consumer operational sales results were over-the-counter products including TYLENOL and MOTRIN analgesics, upper respiratory products including ZYRTEC allergy medications, digestive health products, domestic LISTERINE oral care products and international anti-smoking aids.

Worldwide Pharmaceutical sales of $8.2 billion for the first quarter 2016 represented an increase of 5.9% versus the prior year with an operational increase of 8.5% and a negative impact from currency of 2.6%. Domestic sales increased 12.9%; international sales decreased 3.4%, which reflected an operational increase of 2.6% and a negative currency impact of 6.0%. Excluding the net impact of acquisitions, divestitures and hepatitis C sales, on an operational basis, worldwide sales increased 12.3%, domestic sales increased 16.2% and international sales increased 7.1%.*

Worldwide operational sales growth was driven by new products and the strength of core products. New product sales growth was negatively impacted by lower sales of OLYSIO/SOVRIAD (simeprevir) due to competitive entrants. Strong growth in new products include IMBRUVICA (ibrutinib), an oral, once-daily therapy approved for use in treating certain B-cell malignancies, a type of blood or lymph node cancer; XARELTO (rivaroxaban), an oral anticoagulant; DARZALEX (daratumumab), for the treatment of patients with multiple myeloma; and INVOKANA/INVOKAMET (canagliflozin), for the treatment of adults with type 2 diabetes.

Additional contributors to operational sales growth include REMICADE (infliximab) and SIMPONI/SIMPONI ARIA (golimumab), biologics approved for the treatment of a number of immune-mediated inflammatory diseases; STELARA (ustekinumab), a biologic approved for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis; and INVEGA SUSTENNA/XEPLION/TRINZA (paliperidone palmitate), long-acting, injectable atypical antipsychotics for the treatment of schizophrenia in adults.

During the quarter, the U.S. Food and Drug Administration (FDA) approved an additional indication for IMBRUVICA (ibrutinib) for first-line treatment of chronic lymphocytic leukemia. The Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending a conditional marketing authorization in the European Union for first-in-class CD38 immunotherapy DARZALEX (daratumumab), for the treatment of patients with multiple myeloma, as well as a positive opinion recommending marketing authorization for TREVICTA (paliperidone palmitate a 3-monthly injection) for the maintenance treatment of schizophrenia.

In April, subsequent to the first quarter, a worldwide collaboration and license agreement was entered into with TESARO, Inc. for exclusive rights to the investigational compound niraparib in prostate cancer.

Worldwide Medical Devices sales of $6.1 billion for the first quarter 2016 represented a decrease of 2.4% versus the prior year consisting of an operational increase of 0.5% and a negative currency impact of 2.9%. Domestic sales increased 2.2%; international sales decreased 6.5%, which reflected an operational decrease of 1.0% and a negative currency impact of 5.5%. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales increased 3.0%, domestic sales increased 3.3% and international sales increased 2.8%.*

Primary contributors to operational sales growth were electrophysiology products in the Cardiovascular business; joint reconstruction products in the Orthopaedics business; endocutters, energy and biosurgical products in the Advanced Surgery business; and international ACUVUE contact lenses in the Vision Care business.

In April, subsequent to the quarter, the acquisition of NeuWave Medical, Inc., a privately held medical device company that manufactures and markets minimally invasive soft tissue microwave ablation systems, was completed.

On April 19, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported the results of comprehensive preclinical studies on its investigational tyrosine kinase inhibitor (TKI), AP32788, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (Press release, Ariad, APR 19, 2016, View Source [SID:1234511048]). AP32788 is a TKI designed to target specific mutations in EGFR or HER2 present in a subset of patients with non-small cell lung cancer (NSCLC), for whom there are currently no targeted therapies available. The Phase 1/2 clinical trial of AP32788 is expected to begin patient enrollment in the second quarter of 2016.

The data presented were included in an oral presentation entitled, “AP32788, a potent, selective inhibitor of EGFR and HER2 oncogenic mutants, including exon 20 insertions, in preclinical models.” The research conducted by ARIAD scientists showed that in a matched set of engineered cell lines, AP32788 inhibited all tested EGFR and HER2 mutants, including exon 20 insertion mutants, with selectivity over wild-type (WT) EGFR. Inhibition of WT EGFR in non-tumor cells has been associated with dose-limiting toxicities of EGFR inhibitors in patients. Enzymatic analysis confirmed that AP32788 irreversibly inactivated EGFR exon 20 with 20-fold selectivity over WT EGFR, in contrast to other tested EGFR TKIs. AP32788 also induced tumor regressions in a mouse EGFR exon 20 model at doses that were well tolerated.

“These preclinical data on AP32788 demonstrate its potential to potently inhibit exon 20 mutant forms of EGFR and HER2, that are not addressed by currently available TKI treatments,” said Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. “The selectivity data suggest that efficacious levels of exposure to AP32788 may be achievable in patients with these challenging mutations —a hypothesis we will be testing in the Phase 1/2 trial. We believe AP32788 is the first TKI that has been designed and optimized to inhibit the underlying mutation present in these orphan oncology disease subsets.”

About Non-Small Cell Lung Cancer, EGFR and HER2

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 221,200 new cases of lung cancer diagnosed in 2015 in the United States, according to the American Cancer Society. EGFR mutations represent the largest known, targetable subset of NSCLC. While the most common types of EGFR mutation are addressed by approved TKI therapies, there are no targeted treatment options available for the approximately 4 to 9 percent of EGFR-mutated lung tumors with exon 20 insertion mutations1. In addition, patients with HER2 mutations, mostly exon 20 insertion mutations, comprise approximately 2 percent of NSCLC patients2 and also have no current treatment options. ARIAD estimates that there are approximately 6,000 patients in the United States living with EGFR exon 20 or HER2 point mutations, based on available data from 2014 on the number of Stage IIIB or IV NSCLC and the estimated percentage of patients with these mutations.

About AP32788

AP32788 is an investigational oral tyrosine kinase inhibitor (TKI) of activating mutations in EGFR and HER2. The molecule was designed to address the unmet need in patients with non-small cell lung cancer (NSCLC) driven by exon 20 insertion mutations in EGFR and HER2, and is ARIAD’s fourth internally discovered oncology IND to be cleared for clinical development.

On April 19, 2016 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported the publication of a manuscript in the online edition of the journal Pediatric Blood and Cancer describing a confirmed RECIST partial response in the first patient enrolled in the recently opened pediatric Phase 1 dose-escalation trial of LOXO-101 (Press release, Loxo Oncology, APR 19, 2016, View Source [SID:1234511041]).

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The manuscript was co-authored with Nemours Children’s Hospital, Northwestern University and St. Jude Children’s Research Hospital.

The peer-reviewed manuscript describes a 16-month old female patient with advanced infantile fibrosarcoma (IFS), a rare pediatric cancer. Genetic testing revealed an ETV6-NTRK3 fusion, which is frequently found in IFS. Following multiple unsuccessful surgeries and courses of chemotherapy, the patient was enrolled in the pediatric Phase 1 trial of LOXO-101, which employs a liquid formulation of the drug designed specifically for pediatric patients unable to swallow capsules. Her disease involved the neck, face, skull, mastoids and cervical vasculature. Throughout the first cycle of treatment with LOXO-101, the parents noted improved engagement and playfulness. At the end of cycle 1 (day 28), imaging of the brain and neck showed tumor regression of more than 90 percent from baseline. Repeat scans at the end of cycle 2 showed a continued decrease in tumor volume. During the preparation of the manuscript, the patient was in study cycle 5, with a RECIST confirmed partial response, and was beginning to achieve normal developmental milestones. The patient experienced no adverse events related to LOXO-101.

"Most infants and children with infantile fibrosarcoma can be cured through surgery and chemotherapy. When our patient’s disease progressed in spite of these treatments, the only other viable treatment option was radiation therapy, which posed devastating long-term consequences for our patient," said Dr. Ramamoorthy Nagasubramanian M.D., first author of the manuscript, Division Chief, Pediatric Hematology-Oncology at Nemours Children’s Hospital and Assistant professor of Pediatrics at the University of Central Florida College of Medicine. "The rapid, dramatic reduction in tumor size shows early but promising evidence of the potential for LOXO-101 to provide significant benefit for pediatric patients harboring NTRK gene fusions."

"Although some genetic drivers of cancer are found in both pediatric and adult patients, there are few targeted therapies available to children with cancer," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "We’ve known that NTRK fusions play an important role in many pediatric cancers, and this case study is a first step in demonstrating that a selective TRK inhibitor can provide benefit to these children. We are dedicated to the rapid development of LOXO-101 in pediatric cancer patients."

The Phase 1 clinical trial is a multicenter, open-label trial in pediatric patients with advanced solid or primary CNS tumors. In order to meet the criteria for enrollment, patients must be between one year of age and 21 years of age with a locally advanced or metastatic solid tumor or primary CNS tumor that has progressed, or was nonresponsive to available therapies, and for which no standard or available curative therapy exists. Patients as young as one month old are eligible for enrollment if they have a diagnosis of infantile/congenital fibrosarcoma, with a documented NTRK fusion that has progressed, or was nonresponsive to available therapies, and for whom no standard or available curative therapy exists. For more information on this Phase 1 trial, including study sites and eligibility criteria, visit clinicaltrials.gov (study identifier NCT02637687), or contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123. Loxo Oncology’s Policy for Access to Investigational Agents can be found on the Loxo Oncology website.

About LOXO-101
LOXO-101 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an ongoing Phase 1 clinical trial, LOXO-101 has demonstrated encouraging preliminary efficacy. LOXO-101 is also being evaluated in a global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions and a Phase 1 trial in pediatric patients. For additional information about the LOXO-101 clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123.

On April 19, 2016 Bristol-Myers Squibb Company (NYSE: BMY) reported the first presentation of data from CheckMate -141, a Phase 3 open-label, randomized trial, evaluating Opdivo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) after platinum therapy compared to investigator’s choice of therapy (methotrexate, docetaxel, or cetuximab) (Press release, Bristol-Myers Squibb, APR 19, 2016, View Source [SID:1234511040]).

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In the trial, which evaluated overall survival (OS) as the primary endpoint, patients treated with Opdivo experienced a 30% reduction in the risk of death, with a median OS of 7.5 months (95% CI: 5.5-9.1) compared to 5.1 months (95% CI: 4.0-6.0) for investigator’s choice (HR=0.70 [97.73% CI: 0.51-0.96] p=0.0101). The one-year survival rate for Opdivo was 36% compared to 16.6% for investigator’s choice. The safety profile of Opdivo in CheckMate -141 was consistent with prior studies, with no new safety signals identified.

These data were featured today, Tuesday, April 19, during the 2016 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) official press program at 8:30 A.M. CT and will be presented during the Immuno-Oncology Clinical Trials II Plenary Session from 10:30 A.M. – 12:15 P.M. CT.

Maura Gillison, M.D., Ph.D., lead investigator, Jeg Coughlin Chair of Cancer Research, The Ohio State University Wexner Medical Center, commented, "Squamous cell carcinoma of the head and neck that progresses after platinum-therapy is a devastating disease with a very poor prognosis. There are no systemic therapies that improve survival, and therefore, there is a tremendous unmet need for new treatment options for this patient population. In CheckMate -141, Opdivo demonstrated an improvement in survival compared to three standard of care options in this overall patient population, regardless of PD-L1 expression levels and HPV status."

Based on a planned interim analysis, this trial was stopped early in January 2016 because an assessment conducted by the independent Data Monitoring Committee concluded the study met its primary endpoint of OS in patients receiving Opdivo compared to the control arm.

Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb, commented, "We are excited to share, for the first time, data from the CheckMate -141 trial with the oncology community at the 2016 AACR (Free AACR Whitepaper) Annual Meeting. We are encouraged by the overall survival results seen with this investigational use of Opdivo versus three standard of care options for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, who often face poor survival rates. These findings are supportive of our Immuno-Oncology research goal to study potential treatment options for their ability to help patients with difficult-to-treat cancers achieve long-term survival."

About CheckMate -141

CheckMate -141 is a Phase 3, open-label, randomized trial evaluating Opdivo versus investigator’s choice of therapy in patients with recurrent or metastatic SCCHN with tumor progression within six months of platinum therapy in the adjuvant, primary, recurrent or metastatic setting. Patients were randomized 2:1 to receive Opdivo 3 mg/kg intravenously over 60 minutes every two weeks, or one of the following single agents: methotrextate 40 mg/m2 intravenously weekly, docetaxel 30 mg/m2 intravenously weekly, or cetuximab 400 mg/m2 intravenously once then 250 mg/m2 weekly. Therapies chosen for the control arm represent the most commonly used therapies in the platinum refractory setting. The primary endpoint was OS. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Additional endpoints included safety.

In the trial, patients treated with Opdivo experienced a significant reduction (30%) in the risk of death, with a median OS of 7.5 months (95% CI: 5.5-9.1) compared to 5.1 months (95% CI: 4.0-6.0) for the control arm (HR=0.70 [97.73% CI: 0.51-0.96] p=0.0101). The one-year OS rate was 36% for Opdivo compared to 16.6% for the control arm.

CheckMate -141 also evaluated the efficacy of Opdivo by HPV status and PD-L1 expression compared to investigator’s choice of therapy. HPV testing was performed for patients identified by investigators with oropharyngeal tumors. In the study, Opdivo demonstrated improved survival in this overall population, regardless of HPV status. HPV-positive status was associated with greater magnitude of effect with Opdivo versus investigator’s choice. In HPV-positive patients treated with Opdivo, median OS was 9.1 months vs. 4.4 months for patients treated with investigator’s choice of therapy (HR=0.56 [95% CI: 0.32-0.99]). In HPV-negative patients treated with Opdivo, median OS was 7.5 months vs. 5.8 months for patients treated with investigator’s choice of therapy (HR=0.73 [95% CI: 0.42-1.25])

Of randomized patients, 72% (260) were evaluable for PD-L1 expression. Rates of PD-L1 expression were balanced between subgroups. Opdivo demonstrated improved survival in the overall population, regardless of PD-L1 expression level (chart below).


Efficacy Summary: Median Overall Survival by PD-L1 Expression

Hazard Ratio (HR) for Opdivo vs. Investigator’s Choice Therapy
(Median OS, mos)
>1% PD-L1 expression level HR=0.55 [95% CI: 0.36-0.83]
8.7 mos vs. 4.6 mos
(95% CI: 5.7-9.1) (95% CI: 3.8-5.8)
<1% PD-L1 expression level HR=0.89 [95% CI: 0.54-1.45]
5.7 mos vs. 5.8 mos
(95% CI: 4.4-12.7) (95% CI: 4.0-9.8)

The safety profile of Opdivo in CheckMate -141 was consistent with prior studies with no new safety signals identified. Treatment-related adverse events (TRAEs) of any grade occurred in 58.9% of patients on Opdivo vs. 77.5% of patients on investigator’s choice. Grade 3-4 TRAEs were reported in 13.1% of patients on Opdivo vs. 35.1% of patients on investigator’s choice. Two drug-related deaths were reported as related to Opdivo (pneumonitis and hypercalcemia), and one Grade 5 event of lung infection on the investigator’s choice arm.

About Head & Neck Cancer

Head and neck cancer is the seventh most common cancer globally, with an estimated 400,000 to 600,000 new cases per year and 223,000 to 300,000 deaths per year. The five-year survival rate is reported as less than 4% for metastatic Stage IV disease. Squamous cell carcinoma of the head and neck (SCCHN) accounts for approximately 90% of all head and neck cancers with global incidence expected to increase by 17% between 2012 and 2022. Risk factors for SCCHN include tobacco and alcohol consumption, and the increasing role of Human Papilloma Virus (HPV) infection leading to rapid increase in oropharyngeal SCCHN in Europe and North America. Quality of life is often impacted for SCCHN patients as physiological function (breathing, swallowing, eating, drinking), personal characteristics (appearance, speaking, voice), sensory function (taste, smell, hearing), and psychological/social function can be affected.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.

We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for overall survival and other important measures like durability of response. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents, and continue to study the role of combinations in cancer.

We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.

Our collaboration with academia, as well as small and large biotech companies, to research the potential Immuno-Oncology and non-Immuno-Oncology combinations, helps achieve our goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the way patients live with cancer.

About Opdivo

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating overall survival as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 50 countries including the United States, Japan, and in the European Union.

U.S. FDA APRPOVED INDICATIONS

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

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1).

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1).

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In Checkmate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In Checkmate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1). In Checkmate 025, hyperglycemic adverse events occurred in 9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1).

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6).

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In Checkmate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. 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 Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO.

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. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. 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 Checkmate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In Checkmate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In Checkmate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus.

Embryo-fetal Toxicity

Based on its mechanism of action, OPDIVO 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- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO 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.

Serious Adverse Reactions

In Checkmate 067, serious adverse reactions (37%), adverse reactions leading to permanent discontinuation (14%) or to dosing delays (28%), and Grade 3 or 4 adverse reactions (72%) occurred in the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO arm were diarrhea (2.6%), colitis (1.6%), and pyrexia (0.6%). In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. 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. 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 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

Common Adverse Reactions

In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus 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%).