On September 8, 2015 AstraZeneca and The University of Manchester reported a collaboration harnessing clinical bioinformatics to deliver personalised healthcare for cancer patients (Press release, AstraZeneca, SEP 7, 2015, View Source;astrazeneca-in-new-clinical-collaboration [SID:1234507406]). The five-year agreement will see the organisations apply clinical trial bioinformatics to better identify the right cancer treatment for the right patient at the right time.

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As part of the collaboration, AstraZeneca will provide a total of £11.5 million to support clinical bioinformatics research led by a dedicated team of investigators within the recently established Centre for Cancer Biomarker Sciences at the Manchester Cancer Research Centre. The research will be carried out in partnership with the state-of-the-art clinical trials unit of The Christie NHS Foundation Trust, which is at the forefront of experimental cancer medicine in the UK.

Projects will include the development of a new bioinformatics system to capture and integrate clinical trial safety, efficacy, biomarker and drug distribution data in real time, presenting the information in the form of graphs that can be easily interpreted by clinicians to help tailor the treatment for patients. The collaboration will also support new training programmes in clinical research and pharmacokinetic and pharmacodynamic modelling for investigators to understand the distribution and clinical effects of medicines within the body.

Mene Pangalos, Executive Vice President, Innovative Medicines & Early Development, said: "This collaboration is exciting because it will eventually allow us to incorporate important data from clinical trials into a format that can be reviewed in real time by healthcare professionals and matched with information about cancer medicines. We will be able to modify clinical trial programmes accordingly and support clinicians to offer more accurate, personalised and rapid decision making to patients about their treatment."

Professor of Experimental Cancer Medicine, Andrew Hughes, from the University’s Institute of Cancer Sciences said: "Patient insight is key to our understanding of new cancer drugs. The information we get from patients about their experiences of taking new drugs is key to shaping our risk and benefit assessment. AstraZeneca has long supported the UK science base and this latest collaboration with the Manchester Cancer Research Centre will enable the patients to share their insights with investigators and sponsors more effectively and efficiently than today, enabling a more informed assessment."

This collaboration builds on existing scientific collaborations between AstraZeneca and The University of Manchester, ranging from research into novel cancer medicines to progressing treatments for lung cancer, advancing inflammatory research and developing new drug delivery systems.

On September 7, 2015 Endocyte, Inc. (Nasdaq:ECYT), today presented the final overall survival (OS) analysis from the Phase 2b TARGET trial evaluating its small molecule drug conjugate (SMDC) vintafolide in combination with docetaxel in patients with FR positive recurrent NSCLC at the World Conference on Lung Cancer in Denver, Colorado (Press release, Endocyte, SEP 7, 2015, View Source [SID:1234507405]).

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Vintafolide plus docetaxel improved overall survival by 2.7 months in NSCLC regardless of histology (Median OS 11.5 vs. 8.8 months, OS HR=0.86, 95% CI [0.58, 1.26]). In the predefined subset analysis of patients with adenocarcinoma, which expresses higher levels of folate receptor, vintafolide plus docetaxel improved OS by 5.9 months (12.5 vs. 6.6 months, HR=0.72, 95% CI [0.44, 1.16]). OS for vintafolide as single agent was similar to docetaxel (OS 8.4 vs. 8.8 months, HR=1.02, 95% CI [0.70, 1.50]).

The study previously reported that the PFS primary endpoint was met, (HR=0.75, 95% CI [0.52, 1.09]) regardless of histology and in the adenocarcinoma subgroup (HR=0.73, 95% CI [0.46, 1.16]). The safety profile of the combination arm was consistent with those observed with docetaxel alone and vintafolide alone, though a higher rate of hematologic and peripheral neuropathy adverse events were observed in the combination arm.

"The final OS results are consistent with the biology of the folate receptor target, with higher expression levels in the adenocarcinoma subgroup. These data are important in guiding our future studies in NSCLC," said Ron Ellis, president and CEO at Endocyte.

"Based on the results to date from the ongoing Phase 1 dose escalation trial of EC1456, we are optimistic that this agent will represent an important improvement in the treatment landscape for NSCLC," said Alison Armour, chief medical officer.

EC1456 is a second generation folate-targeted SMDC, which delivers a more potent drug payload at higher doses than vintafolide.

About Vintafolide and Etarfolatide

Vintafolide is an investigational, proprietary, injectable SMDC consisting of folate (vitamin B9) linked to a potent vinca alkaloid cytotoxic agent, desacetylvinblastine hydrazide (DAVLBH). Vintafolide is designed to selectively target the folate receptor to deliver the anti-cancer agent to the cancerous tissue. Tumors that have high concentrations of the folate receptor are identified by etarfolatide, a non-invasive imaging diagnostic agent.

About EC1456

EC1456 is a second generation SMDC consisting of folate (vitamin B9) linked to a potent cytotoxic agent, tubulysin B hydrazide (TubBH). EC1456 includes an advanced spacer/linker to allow for potentially higher dosing in spite of a more potent payload than vintafolide. EC1456 is currently being evaluated in a Phase 1 study in patients with advanced solid tumors (ClinicalTrials.gov Identifier: NCT01999738).

On September 7, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported updated results from the Opdivo (nivolumab)+Yervoy (ipilimumab) arms in CheckMate -012, a multi-arm Phase 1b trial evaluating Opdivo in patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC) (Press release, Bristol-Myers Squibb, SEP 7, 2015, View Source [SID:1234507404]). In this study, Opdivo was administered as monotherapy or as part of a combination with other agents, including Yervoy, at different doses and schedules. Results from other cohorts in CheckMate -012 have been previously-unreported.

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These updated results include findings from the administration of four new dosing schedules of Opdivo+Yervoy (n=148), which resulted in confirmed objective response rates (ORR) ranging from 13% to 39% depending on the administered regimen. Median duration of response was not reached in any of these arms with a median follow-up of 6.2 months to 16.6 months, and median progression-free survival (PFS) ranged from 4.9 months to 10.6 months.

The types of treatment-related serious adverse events (SAEs) reported in these cohorts for CheckMate -012 were consistent with other previously-reported Opdivo+Yervoy cohorts of this trial. The new dosing schedules in this study resulted in less toxicity than previously-reported dosing schedules, and were characterized by low frequency of treatment-related adverse events (AEs) leading to discontinuation (3% to 10%) and no treatment-related deaths. These data will be presented today at the 16th World Conference on Lung Cancer (WCLC) (Abstract #786).

"Clinical results from Opdivo+Yervoy have already been reported in previously untreated metastatic melanoma, showing the potential of dual immune checkpoint blockade targeting both PD-1 and CTLA-4," said Naiyer Rizvi, M.D., director of Thoracic Oncology and Immunotherapeutics for the Division of Hematology and Oncology at Columbia University Medical Center. "The preliminary results from this trial in advanced non-small cell lung cancer similarly push the envelope of benefit with an immunotherapy combination strategy in the first-line treatment of advanced non-small cell lung cancer which warrants further studies."

Non-small cell lung cancer accounts for approximately 85% of all lung cancer cases. Five year survival rates vary globally depending on the stage and type of lung cancer.

"The results we are reporting today for Opdivo+Yervoy in non-small cell lung cancer are very promising as they further expand our scientific rationale and clinical data for combining Immuno-Oncology agents," said Michael Giordano, senior vice president, head of Development, Oncology. "Overall survival data for Opdivo in the second-line treatment of squamous non-small cell lung cancer marked great progress in Immuno-Oncology; yet an unmet need remains for first-line treatments that offer durable, long-term survival and greater tolerability. We are hopeful that as we continue to advance Phase 3 clinical research of Opdivo-based combinations in the first-line setting that we will be able to offer lung cancer patients an option that fills this unmet need."

About CheckMate -012

CheckMate -012 is a multi-arm Phase 1b trial evaluating the safety and tolerability of Opdivo in patients with chemotherapy-naïve advanced NSCLC, as either a monotherapy or in combination with other agents, including Yervoy, at different doses and schedules. The results presented at WCLC include 148 squamous (SQ) and non-SQ patients who received Opdivo+Yervoy at one of the following new dosing schedules. Across the studied regimens and doses, Opdivo+Yervoy showed confirmed ORR ranging from 13% to 39% while median PFS ranged from 4.9 months to 10.6 months.

The safety profile of Opdivo+Yervoy in this trial was consistent with previously-reported studies. There were low frequency of treatment-related grade 3-4 AEs leading to discontinuation (3%–10%) and no treatment-related deaths. Discontinuation rates were comparable to the Opdivo monotherapy arm of this study.

Data from these dosing schedules, along with previously reported data from CheckMate -012, informed the ongoing Phase 3 trial comparing Opdivo or Opdivo+Yervoy versus platinum doublet chemotherapy in chemotherapy-naïve patients with advanced NSCLC (CheckMate -227).

About Opdivo and Yervoy

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo and Yervoy are both monoclonal antibodies and immune checkpoint inhibitors that target separate, distinct checkpoint pathways. Inhibition of these immune checkpoint pathways is thought to result in enhanced T-cell function greater than the effects of either antibody alone.

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous (SQ) non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. On July 20, the European Commission approved Nivolumab BMS for the treatment of locally advanced or metastatic SQ NSCLC after prior chemotherapy.

On March 25, 2011, the FDA approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is now approved in more than 40 countries.

Indication and Important Safety Information for OPDIVO (nivolumab)

INDICATION

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 3. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO including five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal 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 OPDIVO 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 OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).
Please see U.S. Full Prescribing Information for OPDIVO at www.bms.com.

YERVOY Important Safety Information

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. 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) 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.

Recommended Dose Modifications

Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day.

Permanently discontinue YERVOY for any of the following:

Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day
Failure to complete full treatment course within 16 weeks from administration of first dose

Severe or life-threatening adverse reactions, including any of the following:
Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation
AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin >3 × the ULN
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations

Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis

Severe immune-mediated reactions involving any organ system

Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy

Immune-mediated Enterocolitis:

In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immunemediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients
Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis

Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids

Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms

Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients
Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent)

Immune-mediated Hepatitis:

In the pivotal Phase 3 study in YERVOY-treated patients, 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%

13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2)

Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution

Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids

Withhold YERVOY in patients with Grade 2 hepatotoxicity

In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID)

Immune-mediated Dermatitis:

In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., 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
There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated

Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immunemediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms

Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week

Immune-mediated Neuropathies:

In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported

Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported

Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes

Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities)

Immune-mediated Endocrinopathies:

In the pivotal Phase 3 study in YERVOY- treated patients, severe to life-threatening immunemediated 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

Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome

Median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY

Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism

Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated
Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland

Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. Long-term hormone replacement therapy may be necessary

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:

In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immunemediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia
Across the clinical development program for YERVOY, likely immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis
Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions
Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy

Pregnancy & Nursing:

YERVOY is classified as pregnancy category C. There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus
Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus
It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY

Common Adverse Reactions:

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%)
Please see Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, available at www.bms.com.

On September 7, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported longer term survival and safety data from CheckMate -017 and -063, two pivotal trials evaluating Opdivo in previously treated squamous (SQ) non-small cell lung cancer (NSCLC), showing sustained survival benefit across these studies (Press release, Bristol-Myers Squibb, SEP 7, 2015, View Source [SID:1234507403]). In both trials, Opdivo showed an estimated 18 month overall survival (OS) rate of 27% (CheckMate -063) to 28% (CheckMate -017); survival benefit was independent of PD-L1 expression.

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The safety profile of Opdivo is consistent with previously-reported trials, and in CheckMate -017, is also favorable compared to docetaxel. These data will be presented today at the 16th World Conference on Lung Cancer (Abstract #736, CheckMate -017 and #828, CheckMate -063).

"Immuno-Oncology agents like Opdivo provide a novel approach to treating cancer. The improvement in survival observed in advanced squamous non-small cell lung cancer represents an important step forward for our patients," said Suresh S. Ramalingam, M.D., director, Division of Medical Oncology, Winship Cancer Institute of Emory University. "These updated results demonstrate the ability to achieve longer term survival outcomes in this patient population. In fact, the Kaplan-Meier curve from this study suggests a prolonged survival benefit for a subset of patients."

Previously-reported one year results from CheckMate -017 showed a significantly superior OS rate of 42% versus 24% for docetaxel. In CheckMate -063, the estimated one-year survival rate was 39%.

"Our approach to Immuno-Oncology research is intended to show meaningful improvement over the traditional standard of care on the benchmark endpoint of overall survival," said Michael Giordano, senior vice president, head of Development, Oncology. "We have taken a comprehensive research approach in lung cancer, one focused on a commitment to providing the first major advancement in squamous non-small cell lung cancer in more than a decade – Opdivo – that offers the potential to replace chemotherapy. With the data presented today, we remain confident in our Immuno-Oncology strategy, including fulfilling our goal in showing the survival benefit for Opdivo, not only in non-small cell lung cancer, but similar to the data already observed in advanced melanoma and other tumor types."

About CheckMate -017 & CheckMate -063

CheckMate -017 and CheckMate -063 demonstrated the efficacy and safety of Opdivo in patients with advanced or metastatic SQ NSCLC who had progressed following previous chemotherapy treatment. Together, the trials investigated Opdivo monotherapy at a dose of 3 mg/kg every two weeks, which has been well-established across the Phase 3 Opdivo clinical development programs for various tumors. These trials also formed the basis for Opdivo’s approvals in the U.S. and European Union, and helped to establish the agent as standard of care for previously treated SQ NSCLC.

CheckMate -017 is a landmark Phase 3, open-label, randomized clinical trial that evaluated Opdivo (n=135) 3mg/kg intravenously over 60 minutes every two weeks versus standard of care, docetaxel (n=137) 75 mg/m2 intravenously administered every three weeks in patients with advanced SQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The study’s primary endpoint was OS and secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). The trial included patients regardless of their PD-L1 expression status.

CheckMate -017 showed a doubling in 18 month OS benefit with an estimated 28% of patients alive at 18 months for Opdivo versus 13% for docetaxel. The median OS for the Opdivo arm was 9.2 months and 6.0 months for docetaxel (hazard ratio: 0.62 [95% CI, 0.48, 0.81; P = 0.0004]). In addition, Opdivo showed a statistically significant improvement in PFS and ORR. The PFS rate at 18 months was 17% for the Opdivo arm versus 2.7% for docetaxel. Median PFS was 3.5 months for patients administered Opdivo versus 2.8 months for docetaxel (hazard ratio: 0.63; [95% CI, 0.48, 0.83; P = 0.0008]). The ORR was 20% for the Opdivo arm versus 9% for docetaxel for an estimated odds ratio of 2.6 (95% CI, 1.3, 5.5; P = 0.0083), with an ongoing response seen in 63% of patients treated with Opdivo. In the trial, 28 patients were treated with Opdivo beyond initial progression, and nine demonstrated a non-conventional pattern of benefit (7%). The safety profile of Opdivo continued to be favorable versus docetaxel and treatment-related AEs occurred less frequently with Opdivo (n=131; any grade, 59%; grade 3–5, 8%; no grade 5 events) than docetaxel (n=129; any grade, 87%; grade 3–5, 58%), including both hematologic and non-hematologic toxicities. The majority of treatment-related select AEs in patients receiving Opdivo occurred within the first three months of treatment.

CheckMate -063 is a Phase 2, single-arm, open-label trial that included patients with metastatic SQ NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic treatment regimen (n=117). In this trial, Opdivo showed an estimated 18-month OS rate of 27%. At 18 months, confirmed objective response rate, the study’s primary endpoint, was 15% (95% CI: 9, 22). Median OS was 8.1 months (95% CI: 6.1, 10.9). Most treatment-related AEs were of low grade (any grade, 75%; grade 3-4, 17%) and managed using established treatment algorithms.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. Lung cancer results in more deaths worldwide than colorectal, breast and prostate cancers combined. Non-small cell lung cancer (NSCLC) is one of the most common types of the disease and accounts for approximately 85% of cases. Squamous cell NSCLC accounts for approximately 25% to 30% of all lung cancer cases. Five year survival rates vary globally depending on the stage and type of lung cancer.

About Opdivo

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as a monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the FDA as a monotherapy in two cancer indications. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous (SQ) non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. On July 20, the European Commission approved Nivolumab BMS for the treatment of locally advanced or metastatic SQ NSCLC after prior chemotherapy.

INDICATION

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal 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 OPDIVO 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 OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 1, 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 Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).