1stOncology™: Cancer Intelligence Service – Page 16000 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Presentation of IPH4102 rationale and phase I design at the cutaneous lymphoma task force meeting of the EORTC

On September 26, 2015 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that Professor Martine Bagot, Head of the Dermatology Department at the Saint-Louis Hospital in Paris and co-discoverer of the target KIR3DL2, today presented the rationale of IPH4102 for the treatment of CTCL as well as the protocol of the upcoming Phase I trial at the EORTC Cutaneous Lymphoma Task Force meeting in Turin, Italy (Press release, Innate Pharma, SEP 25, 2015, View Source [SID:1234507572]). IPH4102 is a first-in-class cytotoxic antibody against KIR3DL2, a tumor marker specifically expressed in most subtypes of CTCL.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

Professor Martine Bagot, principal investigator of the Phase I trial, said: "The unmet need in CTCL, notably in Sézary syndrome and transformed mycosis fungoides, the most aggressive forms of CTCL, is very large. Thanks to its novel target specifically expressed by the tumor cells, IPH4102 has a unique potential for being both very effective and well tolerated". She added: "This Phase I trial includes cohort expansions aiming at an early detection of antitumor activity. We hope that this approach will accelerate the development of IPH4102".

The Phase I trial is an open label, multicenter study of IPH4102 in patients with relapsed/refractory cutaneous T-cell lymphomas which will be performed in Europe (France, the Netherlands, and the United Kingdom) and in the US. Participating institutions will include several hospitals with internationally recognized expertise: the Saint-Louis Hospital (Paris, France), the MD Anderson Cancer Center (Houston, Texas), the Stanford University Medical Center (Stanford, CA), the Ohio State University (Columbus, OH), the Leiden University Medical Center (Netherlands), and the Guy’s and St Thomas’ Hospital (United Kingdom). Approximately 60 patients with KIR3DL2-positive CTCL having failed at least two prior lines of treatment are expected to be enrolled in a dose-escalation / cohort expansion study. The cohort expansion is expected to be performed in 2 CTCL subtypes displaying the highest expression of KIR3DL2, transformed mycosis fungoides and Sézary syndrome, depending on the findings during the dose escalation part of the study.

Exelixis Announces Positive Results from METEOR Phase 3 Pivotal Trial of Cabozantinib in Advanced Renal Cell Carcinoma Presented at European Cancer Congress 2015

On September 25, 2015- Exelixis, Inc. (NASDAQ:EXEL) reported positive results from METEOR, the phase 3 pivotal trial comparing cabozantinib to everolimus in 658 patients with renal cell carcinoma (RCC) who have experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor (TKI) (Press release, Exelixis, SEP 25, 2015, View Source;p=RssLanding&cat=news&id=2090565 [SID:1234507565]). In July 2015, Exelixis disclosed that the trial met its primary endpoint, demonstrating a statistically significant increase in progression-free survival for patients in the cabozantinib arm. Principal investigator Toni K. Choueiri, M.D. will present detailed data from the late-breaking METEOR abstract (#4-LBA) on Saturday, September 26, during the Presidential Session I at the European Cancer Congress (ECC) 2015, which is being held September 25-29 in Vienna. The METEOR data and an accompanying editorial were also published today in The New England Journal of Medicine.

As announced in July, the METEOR trial met its primary endpoint of demonstrating a statistically significant increase in progression-free survival (PFS) for cabozantinib as compared to everolimus, as determined by an independent radiology committee. Per the trial protocol, the primary analysis was conducted among the first 375 patients randomized to ensure sufficient follow up and a PFS profile that would not be primarily weighted toward early events. The median PFS was 7.4 months for the cabozantinib arm versus 3.8 months for the everolimus arm, corresponding to a 42% reduction in the rate of disease progression or death for cabozantinib as compared to the everolimus arm (hazard ratio [HR]=0.58, 95% confidence interval [CI] 0.45-0.75, p<0.001). Cabozantinib effects were favorable across patient stratification subgroups including the number of prior VEGF receptor TKI therapies and commonly applied RCC risk criteria developed by Motzer et al.

In a post-hoc subset analysis of patients who had received sunitinib, the most commonly used first-line therapy, as their only prior VEGF receptor TKI, the median PFS for cabozantinib-treated patients (n=76) was 9.1 months versus 3.7 months for everolimus-treated patients (n=77). This corresponds to a 59% reduction in the rate of disease progression or death for patients treated with cabozantinib (HR=0.41, 95% CI 0.28-0.61).

"In the METEOR trial, cabozantinib significantly improved progression-free survival as compared to everolimus, a commonly-used standard of care, in both the full study population for the primary endpoint analysis as well as in the subgroup of patients previously treated with sunitinib only. Cabozantinib was also associated with a safety profile similar to other VEGF receptor TKIs used to treat renal cell carcinoma," said Toni K. Choueiri, M.D., clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and METEOR’s principal investigator. "Uniquely, treatment with cabozantinib resulted in a strong trend towards improving overall survival, which is unprecedented as compared with other studies to date evaluating TKIs. The totality of the data support cabozantinib as a potential new treatment option for RCC patients whose disease has progressed following VEGF receptor-targeting therapy."

Data pertaining to overall survival (OS) in the entire study population of 658 patients, a secondary endpoint of the trial, were immature at the data cutoff. As previously announced, a pre-specified interim analysis triggered by the primary analysis for PFS showed a strong trend in OS favoring cabozantinib (HR=0.67, 95% CI 0.51-0.89, p=0.005) At the time of the interim analysis, the p-value of 0.0019 to achieve statistical significance was not reached, and the trial will continue to the final analysis of OS anticipated in 2016. Objective response rate, another secondary endpoint, was significantly higher with cabozantinib (21%) as compared with everolimus (5%; p < 0.001). Treatment discontinuations for adverse events unrelated to progressive disease were 9% and 10% for cabozantinib and everolimus, respectively.

"These results from the METEOR trial suggest that cabozantinib has the potential to become a new and differentiated treatment option for patients with renal cell carcinoma who have progressed following VEGF receptor tyrosine kinase therapy, the most commonly-utilized treatment in the first-line setting," said Michael M. Morrissey, Ph.D., Exelixis’ president and chief executive officer. "Exelixis is working quickly to share the data with regulators in the United States and European Union. We are on track to complete our U.S. NDA filing by the end of this year, where cabozantinib has received Breakthrough Therapy Designation, and expect a European filing to follow in early 2016. We look forward to advancing these regulatory processes in hopes of bringing cabozantinib to the renal cell carcinoma community as soon as possible."

653 patients were evaluable for safety. Median duration of exposure was 7.6 months for cabozantinib and 4.4 months for everolimus. Investigators employed dose reductions to manage adverse events (AE), and 60% of patients on the cabozantinib arm and 25% of patients on the everolimus arm had dose reductions. The median average daily dose was 44 mg for cabozantinib and 9 mg for everolimus. The incidence of adverse events (any grade), regardless of causality, was 100% with cabozantinib and more than 99% with everolimus. Serious adverse events occurred in 40% of cabozantinib patients and 43% of everolimus patients. The most common AEs regardless of causality, grade 3 or higher, for cabozantinib were: hypertension (15%), diarrhea (11%), fatigue (9%), and hand-foot syndrome (8%). The most common AEs regardless of causality, grade 3 or higher, for everolimus were: anemia (16%), fatigue (7%), hyperglycemia (5%), and dyspnea (4%). Grade 5 adverse events occurred in 6.6% of patients in the cabozantinib arm and in 7.8% of patients in the everolimus arm, and were primarily related to disease progression. Treatment-related grade 5 events occurred in one patient (0.3%; death not otherwise specified) in the cabozantinib arm and 2 patients (0.6%; aspergillus infection and aspiration pneumonia) in the everolimus arm.

Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. COMETRIQ is not indicated for patients with advanced RCC or any other form of the disease. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the COMETRIQ capsule form.

Webcast for the Investment Community

Exelixis will host a live webcast on Saturday, September 26, 2015, following the METEOR presentation at ECC 2015. The webcast will begin at 12:30 p.m. EDT / 9:30 a.m. PDT (18:30 local Vienna time). During the webcast, Exelixis management and Dr. Toni Choueiri, principal investigator of the METEOR trial, will review and provide context for the data presented at the Congress.

To access the webcast link, log onto www.exelixis.com and proceed to the Event Calendar page under Investors & Media. Please connect to the company’s website at least 15 minutes prior to the webcast to ensure adequate time for any software download that may be required to listen to the webcast. Alternatively, you may access the webcast at this address: View Source

An archived replay of the webcast will be available on the Event Calendar page under Investors & Media at www.exelixis.com for one year. An audio-only phone replay will be available until 11:59 p.m. EDT on September 28, 2015. Access numbers for the phone replay are: (855) 859-2056 (domestic) and (404) 537-3406 (international); the passcode is 47549145.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the United States.1 Clear cell renal cell carcinoma is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3

Treatments for advanced RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon) until the introduction of targeted therapies into the RCC setting a decade ago. In the second and later-line setting, which encompasses approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two therapies have been approved for the treatment of patients who have received prior VEGF receptor TKIs. However, despite the availability of several therapeutic options, currently approved agents have shown little differentiation in terms of efficacy and have demonstrated only modest PFS benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau (VHL) protein function, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) and consequent up-regulation of VEGF, MET, and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype, and reduced overall survival. 6 Up-regulation of MET in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET in the development of resistance to these therapies.7

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL, and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

COMETRIQ (cabozantinib capsules) is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.
Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.
COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.
Wound complications have been reported with COMETRIQ.
COMETRIQ treatment results in an increase in hypertension.
Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.
The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.

Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.
Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.
COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.
COMETRIQ can cause fetal harm when administered to a pregnant woman.

Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Bristol-Myers Squibb Announces U.S. Food and Drug Administration Regulatory Filing Update for the Opdivo+Yervoy Regimen in Patients with Previously Untreated Advanced Melanoma

On September 25, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has accepted for filing and review a supplemental Biologics License Application (sBLA) for the Opdivo (nivolumab)+Yervoy (ipilimumab) regimen to include clinical data from CheckMate -067, a landmark trial in patients with previously untreated advanced melanoma (Press release, Bristol-Myers Squibb, SEP 25, 2015, View Source [SID:1234507559]). The FDA also granted Priority Review for this application with a target action date of January 23, 2016.

CheckMate -067 is the first Phase 3 trial evaluating the Opdivo+Yervoy regimen or Opdivo monotherapy vs. Yervoy monotherapy in patients with previously untreated advanced melanoma. Results from CheckMate -067 demonstrated superior progression-free survival (PFS) for the Opdivo+Yervoy regimen or Opdivo monotherapy vs. Yervoy monotherapy in previously untreated patients with advanced melanoma, regardless of BRAF status. If approved, this application would expand upon the initial application for the Opdivo+Yervoy regimen, which was based on tumor response rate and safety data from the Phase 2 randomized trial, CheckMate -069. The CheckMate -067 trial that serves as the basis for this submission includes comparative PFS and objective response rate data.

"Findings from CheckMate -067 provide additional evidence that the combination of two Immuno-Oncology agents, Opdivo and Yervoy, may provide improved outcomes for patients with advanced melanoma, and has the potential to become the basis for how this devastating disease is treated," said Michael Giordano, senior vice president, head of Development, Oncology, Bristol-Myers Squibb. "We saw significant clinical benefit from the Opdivo+Yervoy regimen in these patients, including an increase in the time patients lived without disease progression, and we look forward to working with the FDA to review this data."

The CheckMate -067 trial is ongoing and patients continue to be followed for the co-primary endpoint of overall survival.

About Advanced Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. The incidence of melanoma has been increasing for at least 30 years. In the United States, more than 73,000 cases of melanoma will be diagnosed this year and nearly 10,000 people are expected to die from the disease. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate has historically been just six months with a one-year survival rate of 25.5%, making it one of the most aggressive forms of cancer.

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 results 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 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. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy.

Opdivo was approved by the European Commission for the treatment of advanced (unresectable or metastatic) melanoma in adults, regardless of BRAF status on June 19, 2015, making it the first approval given by the European Commission for a PD-1 inhibitor in any cancer. On July 20, 2015, Nivolumab BMS was also approved for the treatment of locally advanced or metastatic squamous non-small cell lung cancer 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.

OPDIVO 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%).
Please see U.S. Full Prescribing Information for OPDIVO.

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.

Yervoy is a registered trademark of Bristol-Myers Squibb Company.

Opdivo (nivolumab) Demonstrates Superior Overall Survival in a Phase 3 Trial Compared to Standard of Care in Patients with Previously Treated Advanced Renal Cell Carcinoma

On September 25, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported results from CheckMate -025, a Phase 3 study comparing Opdivo to everolimus in advanced renal cell carcinoma (RCC) after prior anti-angiogenic treatment, showing a significant overall survival (OS) benefit for Opdivo (Press release, Bristol-Myers Squibb, SEP 25, 2015, View Source [SID:1234507558]). In the trial, Opdivo demonstrated a median OS benefit of 25 months compared to 19.6 months for everolimus. Clinical benefit for Opdivo was observed regardless of level of PD-L1 expression. The safety profile shown in CheckMate -025 is consistent with previously reported Opdivo trials. These data will be presented Saturday, September 26, during the 2015 European Cancer Congress (ECC2015) at a Presidential Session from 4:10 – 4:20 PM CEST (Late Breaking Abstract #3). The results were also featured during the ECC2015 press program on September 25 and published in The New England Journal of Medicine (NEJM), representing the ninth publication in the NEJM for Opdivo.

"Patients with advanced renal cell carcinoma are in need of new treatment approaches that provide improved survival, safety and tolerability," said Robert J. Motzer, M.D., medical oncologist, Memorial Sloan Kettering Cancer Center and lead author of the NEJM publication. "This is the first Phase 3 study to demonstrate the efficacy of an immune checkpoint inhibitor in advanced renal cell carcinoma. The results show meaningful clinical benefit with Opdivo treatment, producing a significant overall survival advantage and greater number of objective responses compared to everolimus, a current standard of care in the treatment of advanced kidney cancer."

Approximately 30% of patients with RCC, a common type of kidney cancer in adults, present with metastatic or advanced disease at diagnosis. Despite multiple available treatment approaches for advanced RCC, available second-line therapies are associated with limited OS, and significant toxicities and limitations in tolerability, with the majority of current treatment options providing modest progression-free survival benefit.

"We continue to see the potential of our Immuno-Oncology agent, Opdivo, to provide meaningful improvement in multiple tumor types over current standards of care in terms of overall survival," said Michael Giordano, senior vice president, head of Development, Oncology. "Results of CheckMate -025 show that Opdivo has a significant survival advantage over standard of care in patients with advanced kidney cancer who have progressed following prior treatment. These data also reinforce our Immuno-Oncology research goal to provide patients with long-term survival, and brings further confidence to the approach taken in our broader RCC development program, including the combination of Immuno-Oncology agents."

CheckMate -025 was stopped in July because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its primary endpoint, demonstrating superior OS in patients receiving Opdivo compared to the control arm. Opdivo was granted Breakthrough Therapy Designation for advanced RCC by the U.S. Food and Drug Administration based on results from this trial and the clinical need for additional treatment approaches for RCC.

About CheckMate -025

CheckMate -025 is a Phase 3 randomized, open-label study of Opdivo versus everolimus in previously treated patients with advanced clear-cell RCC after prior anti-angiogenic treatment. Patients were randomized to receive Opdivo (n=410) 3 mg/kg intravenously every two weeks or everolimus (n=411) 10 mg orally once daily. The primary endpoint was OS. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), OS by PD-L1 expression, and incidence of adverse events (AEs).

Results from CheckMate -025 mark the first and only Phase 3 study to demonstrate a significant survival advantage in previously treated patients with advanced RCC versus standard of care. Patients treated with Opdivo in this study achieved a median OS of 25 months for Opdivo and 19.6 months for everolimus (hazard ratio: 0.73; [98.5% CI, 0.57-0.93; p=0.0018]), with comparable OS benefit seen across PD-L1 expression levels.

In addition to improving overall survival, Opdivo demonstrated a superior ORR of 25% versus 5% for everolimus (p<0.0001), with one out of four patients experiencing a response. Seventeen percent of Opdivo and 7% of everolimus patients remain on treatment with a minimum follow-up of 14 months.

The safety profile of Opdivo in CheckMate -025 was consistent with prior studies and favorable versus everolimus. Fewer grade 3-4 treatment-related AEs occurred with Opdivo (19%) compared to everolimus (37%). Any grade treatment-related AEs occurred in 79% of patients treated with Opdivo and 88% of patients treated with everolimus. The most frequent treatment-related AEs were fatigue (33%), pruritus (14%), and nausea (14%) in the Opdivo arm and fatigue (34%) and stomatitis (30%) in the everolimus arm.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to 90% of all cases. RCC is approximately twice as common in men as it is in women, with the highest rates of the disease found in North America and Europe. Globally, the five-year survival rate for those diagnosed with advanced kidney cancer is 12.1%.

About Opdivo

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. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 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.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Immune-Mediated Colitis

Immune-Mediated Hepatitis

Immune-Mediated Nephritis and Renal Dysfunction

Immune-Mediated Hypothyroidism and Hyperthyroidism

Other Immune-Mediated Adverse Reactions

Embryofetal Toxicity

Lactation

Serious Adverse Reactions

Common Adverse Reactions

Janssen’s daratumumab accepted for accelerated CHMP assessment for treatment of European patients with heavily pre-treated multiple myeloma

On September 25, 2015 Janssen-Cilag International NV reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has accepted its request for an accelerated assessment of the daratumumab Marketing Authorisation Application (MAA) (Press release, Johnson & Johnson, SEP 25, 2015, View Source [SID:1234507552]). This acceptance follows the earlier regulatory submission of a MAA which seeks authorisation of daratumumab as a single agent for the treatment of patients with relapsed and refractory multiple myeloma and is currently pending validation by the EMA.

The CHMP grants accelerated assessment when a medicinal product is expected to be of major public health interest particularly from the point of view of therapeutic innovation.

Daratumumab is an investigational, human anti-CD38 monoclonal antibody that works by binding to CD38, a signalling molecule found on the surface of multiple myeloma cells.1,2,3,4 In doing so, daratumumab triggers the patient’s own immune system to attack the cancer cells, resulting in rapid tumour cell death through multiple immune-mediated and other mechanisms of action.5

The MAA includes data from the Phase 2 MMY2002 (SIRIUS) monotherapy study, presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper),6 and data from the Phase 1/2 GEN501 monotherapy study, recently published in The New England Journal of Medicine,7 and data from three additional supportive studies.

"Janssen is pleased with the CHMP’s acceptance of an accelerated regulatory review timeline for daratumumab, which reflects the high unmet need for new treatment options for patients with multiple myeloma, currently an incurable disease," said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. "We continue to work closely with European health authorities to make daratumumab available to these patients as soon as possible."

In July 2013 daratumumab was granted Orphan Drug Status by the EMA for the treatment of plasma cell myeloma.8 Furthermore, this step forward in Europe also follows the acceptance for Priority Review of the Biologics License Application for daratumumab with the U.S. FDA on September 4, 2015.

In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement which granted Janssen an exclusive worldwide license to develop, manufacture, and commercialise daratumumab.

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.9 MM is the second most common form of blood cancer, with around 39,000 new cases in Europe in 2012.10 MM most commonly affects people over the age of 65 and is more common in men than in women.11 Across Europe, five-year survival rates are 23 percent to 47 percent of people diagnosed.12 Almost 29 percent of patients with MM will die within one year of diagnosis.13 Although treatment may result in remission, unfortunately patients will most likely relapse as there is currently no cure. While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.11 Patients who relapse after treatment with standard therapies, including proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), have poor prognoses and few treatment options available.14

About Daratumumab

Daratumumab is an investigational human monoclonal antibody that binds with high affinity to the CD38 molecule, which is found on the surface of multiple myeloma cells. It is believed to induce rapid tumour cell death through multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosic and antibody-dependent cellular cytotoxicity, as well as via induction of apoptosis.5 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases in which CD38 is expressed, such as smouldering myeloma and non-Hodgkin lymphoma.