On November 25, 2015 Merck and Pfizer reported that the European Medicines Agency (EMA)’s Committee for Orphan Medicinal Products (COMP) has issued a positive opinion for Orphan Drug designation (ODD) for avelumab*, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody, pending an official decision by the European Commission (EC), expected in December (Press release, Merck KGaA, NOV 25, 2015, View Sourcemanetec-69.de/apps/merckreports/base.nsf/IDs/49FA0220D59AE9E6C1257F08002C7E01/$FILE/151125_Merck_Pfizer_Opinion_Orphan_Drug_Designation_Avelumab_Merkel_Cell_Carcinoma_EMACommittee_EN.pdf" target="_blank" title="View Sourcemanetec-69.de/apps/merckreports/base.nsf/IDs/49FA0220D59AE9E6C1257F08002C7E01/$FILE/151125_Merck_Pfizer_Opinion_Orphan_Drug_Designation_Avelumab_Merkel_Cell_Carcinoma_EMACommittee_EN.pdf" rel="nofollow">View Source [SID:1234508350]). Schedule your 30 min Free 1stOncology Demo! The COMP positive opinion is for the cancer immunotherapy avelumab, for the treatment of Merkel cell carcinoma (MCC), a rare and aggressive type of skin cancer.1,2 Each year, there are approximately 2,500 new cases of MCC diagnosed in the European Union (EU).3 There is currently no therapy approved specifically for the treatment of metastatic MCC.4
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"While significant therapeutic advances have been made against other types of skin cancer, similar progress has not been made against Merkel cell carcinoma. There is a great need for effective therapies in this disease," said Dr. Mace Rothenberg, Senior Vice President of Clinical Development and Medical Affairs and Chief Medical Officer for Pfizer Oncology. "Orphan Drug Designation is an important regulatory tool that can help facilitate development of a new treatment option for patients in Europe with this serious and rare condition."
The COMP’s positive opinion follows the US Food and Drug Administration’s ODD for avelumab for the treatment of MCC that was received in September, Fast Track designation for avelumab for the treatment of metastatic MCC that was received in October, and Breakthrough Therapy Designation for avelumab for the treatment of metastatic MCC that was received in November. In order for a drug to be granted ODD by the EMA, it must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating; the prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development; and where no satisfactory treatment is currently available.
"We are delighted the EMA’s Committee for Orphan Medicinal Products has considered that avelumab matches the Orphan Drug designation criteria for metastatic Merkel cell carcinoma in the EU," said Dr. Luciano Rossetti, Head of Global Research & Development at Merck’s biopharma business. "We look forward to working closely with the EMA to make this potential treatment available to patients as soon as possible, and we eagerly await the results of our Phase II trial in this rare skin cancer."
Merck and Pfizer are currently conducting a Phase II study (JAVELIN Merkel 200) to assess the safety and efficacy of avelumab in patients with metastatic MCC whose disease has progressed after at least one prior chemotherapy regimen. JAVELIN Merkel 200 is a multicenter, single-arm, open-label Phase II study with a primary objective of objective response rate.
The clinical development program for avelumab now includes more than 1,400 patients who have been treated across more than 15 tumor types, including breast cancer, gastric/gastro-esophageal junction cancers, head and neck cancer, MCC, mesothelioma, melanoma, non-small cell lung cancer, ovarian cancer, renal cell carcinoma and urothelial (e.g. bladder) cancer.
About the EMA Orphan Drug Designation
An ODD by the EMA allows a pharmaceutical company to benefit from incentives from the EU to develop a medicine for a rare disease. Applications for ODD are examined by the COMP, which adopts an opinion that is forwarded to the EC. The EC then decides whether to grant an orphan designation for the medicine in question within 30 days of receipt of the COMP opinion.
Pharmaceutical companies that obtain ODD benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
*Avelumab is the proposed International Nonproprietary Name for the anti-PD-L1 monoclonal antibody (MSB0010718C). Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.
References
1. Hughes MP et al. Merkel cell carcinoma: epidemiology, target, and therapy. Curr Dermatol Rep 2014;3:46-53.
2. Kaae J et al. Merkel cell carcinoma: incidence, mortality, and risk of other cancers. J Natl Cancer Inst 2010;102(11):793-801.
3. IMMOMEC (European Commission). Merkel cell carcinoma. Available at: View Source immomec.eu/project/objectives/background/merkel-cell-carcinoma/ Last accessed November 2015
4. Miller NJ et al. Emerging and mechanism-based therapies for recurrent or metastatic Merkel cell carcinoma. Curr Treat Options Oncol; 2013 14(2): 249-6
About Merkel Cell Carcinoma (MCC)
MCC is a rare and aggressive disease in which cancer cells form in the top layer of the skin, close to nerve endings. MCC, which is also known as neuroendocrine carcinoma of the skin or trabecular cancer, often starts in those areas of skin that are most often exposed to the sun, including the head and neck, arms, legs, and trunk. Risk factors for MCC include sun exposure and having a weak immune system (i.e., solid organ transplant recipients, people with HIV/AIDS and people with other cancers, such as chronic lymphocytic leukemia, are at higher risk). Caucasian males over age 50 are at increased risk. MCC tends to metastasize at an early stage, spreading initially to nearby lymph nodes, and then potentially to more distant areas in the body, including other lymph nodes or areas of skin, lungs, brain, bones or other organs. Current treatment options for MCC include surgery, radiation and chemotherapy. Treatment for metastatic or Stage IV MCC is generally palliative.
About Avelumab
Avelumab (also known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to potentially enable the activation of
T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.
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Exelixis Announces European Commission Approval of COTELLIC™ (Cobimetinib) for Use in Combination with Vemurafenib in Advanced BRAF V600 Mutation-Positive Melanoma
On November 25, 2015 Exelixis, Inc. (NASDAQ:EXEL) reported that the European Commission (EC) has approved COTELLIC (cobimetinib) for use in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (Press release, Exelixis, NOV 25, 2015, View Source [SID:1234508348]). Schedule your 30 min Free 1stOncology Demo! COTELLIC was discovered by Exelixis and is now the subject of a collaboration between Exelixis and Genentech, a member of the Roche Group. Roche sponsored COTELLIC’s EU Marketing Authorization Application, which received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use in September 2015.
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"The approval of COTELLIC by the European Commission for use in combination with vemurafenib is an important milestone in the development of new treatments that can help patients with advanced melanoma," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "We look forward to continuing to execute on our collaboration agreement for COTELLIC."
The approval in the EU is based primarily on results of the phase 3 coBRIM study, which showed that people with previously untreated BRAF V600 mutation-positive advanced melanoma who were being treated with the MEK inhibitor COTELLIC in combination with vemurafenib lived a median of one year (12.3 months) without their disease worsening or death (progression-free survival; PFS) compared to 7.2 months with vemurafenib alone (hazard ratio [HR]=0.58, 95 percent confidence interval [CI] 0.46-0.72).1
The objective response rate with the combination was 70 percent (16 percent complete response [CR], 54 percent partial response [PR]) compared to 50 percent (11 percent CR, 40 percent PR) in the vemurafenib arm.1 Possible serious side effects with COTELLIC include risk of skin cancers, increased risk of bleeding, heart problems that can lead to inadequate pumping of the blood by the heart, rash, eye problems, abnormal liver test or liver injury, increased levels of an enzyme in the blood, and photosensitivity. The most common side effects of COTELLIC include diarrhea, sunburn or sun sensitivity, nausea, fever and vomiting. COTELLIC can also cause changes in blood test results.
Additional data were presented in November 2015 at the Society for Melanoma Research congress demonstrating that the combination of COTELLIC plus vemurafenib met its secondary endpoint of improving OS compared to vemurafenib alone. Roche and Genentech have guided that these data will be submitted to the European Medicines Agency for consideration and inclusion in the label.
After discovering COTELLIC internally, Exelixis advanced the product to investigational new drug (IND) status. In late 2006, the company entered into its worldwide collaboration with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop COTELLIC. Under the collaboration agreement, Exelixis is eligible to receive low double-digit royalties on sales of COTELLIC outside the United States. In the United States, Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and will share in U.S. marketing and commercialization costs. In November 2013, Exelixis exercised its option to co-promote COTELLIC in the United States and will field 25 percent of the U.S. sales force.
COTELLIC in combination with vemurafenib is now approved in the EU and Switzerland for the treatment of people with BRAF V600 mutation-positive advanced melanoma. The combination is approved in the United States for the treatment of patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Further country approvals are anticipated in 2016.
About COTELLIC in Combination with Vemurafenib
COTELLIC and vemurafenib are prescription medicines used in combination to treat melanoma that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene. Found in approximately half of melanomas, mutated BRAF causes abnormal signaling inside cancer cells leading to tumor growth. Vemurafenib is designed to inhibit some mutated forms of BRAF and COTELLIC is designed to inhibit some forms of MEK. Both BRAF and MEK are proteins in a cell signaling pathway that help control cell growth and survival. When used in combination, COTELLIC and vemurafenib are thought to reduce cancer cell growth longer than with vemurafenib alone. A patient’s healthcare provider will perform a test to make sure COTELLIC and vemurafenib are right for the patient. It is not known if COTELLIC and vemurafenib are safe and effective in children under 18 years of age.
About the coBRIM Trial
coBRIM is an international, randomized, double-blind, placebo-controlled phase 3 study evaluating the safety and efficacy of 60 mg once daily of cobimetinib plus 960 mg twice daily of vemurafenib compared to 960 mg twice daily of vemurafenib plus placebo. In the study, 495 patients with BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma (detected by the cobas 4800 BRAF Mutation Test) and previously untreated for advanced disease were randomized to receive vemurafenib every day on a 28-day cycle plus either cobimetinib or placebo on days 1-21. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. Investigator-assessed PFS is the primary endpoint. Secondary endpoints include PFS by independent review committee, objective response rate, overall survival, duration of response and other safety, pharmacokinetic and quality of life measures.
About Melanoma and its BRAF V600 Mutation-Positive Form
Melanoma is the less common, but more serious category of skin cancer that starts in the skin’s pigment producing cells known as melanocytes. According to the American Cancer Society, approximately five percent of skin cancer diagnoses are melanoma, but melanoma accounts for a large majority of skin cancer deaths. In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years. It is projected that approximately half of all melanomas, and eight percent of solid tumors, contain a mutation of the BRAF protein. BRAF is a key component of the RAS-RAF-MEK-ERK pathway involved in normal cell growth and survival. However, mutations that keep the BRAF protein in an active state may cause excessive signaling in the pathway, leading to uncontrolled cell growth and survival.
FDA approves Portrazza to treat advanced squamous non-small cell lung cancer
On November 24, 2015 The U.S. Food and Drug Administration reported that it approved Portrazza (necitumumab) in combination with two forms of chemotherapy to treat patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) who have not previously received medication specifically for treating their advanced lung cancer (Press release, , NOV 24, 2015, View Source [SID:1234508346]).
Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015. The most common type of lung cancer, non-small cell lung cancer, is further divided into two main types named for the kinds of cells found in the cancer – squamous cell and non-squamous cell (which includes adenocarcinoma).
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"Lung cancer tumors can be varied, so treatment options need to be tailored to the specific type of lung cancer in the patient," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. "Today’s approval provides certain patients with squamous cell lung cancer a new option that may extend survival."
Portrazza is a monoclonal antibody that blocks activity of EGFR, a protein commonly found on squamous NSCLC tumors.
The safety and efficacy of Portrazza were evaluated in a multicenter, randomized, open-label clinical study of 1,093 participants with advanced squamous NSCLC who received the chemotherapies gemcitabine and cisplatin with or without Portrazza. Those taking Portrazza plus gemcitabine and cisplatin lived longer on average (11.5 months) compared to those only taking gemcitabine and cisplatin (9.9 months). Portrazza was not found to be an effective treatment in patients with non-squamous NSCLC.
The most common side effects of Portrazza are skin rash and magnesium deficiency (hypomagnesemia), which can cause muscular weakness, seizure, irregular heartbeats and can be fatal. Portrazza includes a boxed warning to alert health care providers of serious risks of treatment with Portrazza, including cardiac arrest and sudden death, as well as hypomagnesemia.
Portrazza is marketed by Eli Lilly and Company, based in Indianapolis, Indiana.
European Commission Approves Reconciliation of Indications for nivolumab Under the Opdivo® European Marketing Authorization Application
On November 24, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the European Commission (EC) has approved the reconciliation of indications for nivolumab under the Opdivo European Marketing Authorization Application (MAA) (Press release, Bristol-Myers Squibb, NOV 24, 2015, View Source [SID:1234508345]). In compliance with European Commission regulations, Bristol-Myers Squibb previously submitted two separate MAAs to the European Medicines Agency (EMA); one under the name Opdivo for the treatment of unresectable or metastatic melanoma in adults, and one under the name Nivolumab BMS for the treatment of locally advanced or metastatic squamous (SQ) non-small cell lung cancer (NSCLC) after prior chemotherapy. An application to reconcile these two indications was then submitted under the Opdivo brand name.
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Following approval for both of these indications by the EC earlier this year, the Company is voluntarily withdrawing the Marketing Authorization under the Nivolumab BMS brand name. This withdrawal has no impact for SQ NSCLC patients taking nivolumab since Opdivo is now approved for the treatment of SQ NSCLC, as well as for melanoma.
Mathias Hukkelhoven, Ph.D., senior vice president, head of Global Regulatory, Safety and Biometrics, Bristol-Myers Squibb, commented, "To make Opdivo available to healthcare professionals and patients in the timeliest way possible, Bristol-Myers Squibb worked with European health authorities on an innovative regulatory approach – one that was critically focused on speed to patients for both patient populations. We submitted two separate Marketing Authorization Applications for indications in advanced melanoma and squamous non-small cell lung cancer for review in parallel. As the European Commission has now granted approval for both Opdivo and Nivolumab BMS, we have reconciled these indications under the Opdivo brand name."
While different in name, Nivolumab BMS and Opdivo are the same Immuno-Oncology agent approved at the same dosing level and schedule. Nivolumab BMS is currently marketed in a few countries in the European Union. Squamous NSCLC patients presently treated with Nivolumab BMS will be automatically switched to Opdivo when Nivolumab BMS is no longer available in their country. Patients or healthcare professionals who have further questions about the withdrawal or reconciliation may contact Bristol-Myers Squibb Medical Information.
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 monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide. Opdivo is the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 40 countries including the United States, Japan, and in the European Union.
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.
Immune-Mediated Pneumonitis
Immune-mediated pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in Checkmate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 037, 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: Grade 3 (n=1) and Grade 2 (n=5). In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5.2% (21/406) of patients receiving OPDIVO and 18.4% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In Checkmate 069, pneumonitis, including interstitial lung disease, occurred in 10% (9/94) of patients receiving OPDIVO in combination with YERVOY and 2.2% (1/46) of patients receiving YERVOY. Immune-mediated pneumonitis occurred in 6% (6/94) of patients receiving OPDIVO in combination with YERVOY: Grade 5 (n=1), Grade 3 (n=2) and Grade 2 (n=3).
Immune-Mediated Colitis
Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In combination with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 037, 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; Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In Checkmate 069, diarrhea or colitis occurred in 57% (54/94) of patients receiving OPDIVO in combination with YERVOY and 46% (21/46) of patients receiving YERVOY. Immune-mediated colitis occurred in 33% (31/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=1), Grade 3 (n=16), Grade 2 (n=9), and Grade 1 (n=5).
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 037, 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; Grade 3 (n=2) and Grade 2 (n=1). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3%) in the OPDIVO-treated and everolimus-treated groups, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 069, immune-mediated hepatitis occurred in 15% (14/94) of patients receiving OPDIVO in combination with YERVOY: Grade 4 (n=3), Grade 3 (n=9), and Grade 2 (n=2).
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.
Immune-Mediated Dermatitis
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.
Immune-Mediated Endocrinopathies
Hypophysitis, adrenal insufficiency, thyroid disorders, and type I diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type I diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.
In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 069, hypophysitis occurred in 13% (12/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=2) and Grade 2 (n=10). In Checkmate 037 and 057 (n=555), adrenal insufficiency occurred in 1% of patients receiving OPDIVO. In Checkmate 025, adrenal insufficiency occurred in 2% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 069, adrenal insufficiency occurred in 9% (8/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 037, 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 Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated TSH occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate 025, thyroid disease occurred in 43/406 (10.6%) patients receiving OPDIVO, including one Grade 3 event, and in 12/397 (3.0%) patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8.1% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 069, hypothyroidism occurred in 19% (18/94) of patients receiving OPDIVO in combination with YERVOY. All were Grade 1 or 2 in severity except for one patient who experienced Grade 3 autoimmune thyroiditis. Grade 1 hyperthyroidism occurred in 2.1% (2/94) of patients receiving OPDIVO in combination with YERVOY. In Checkmate 025, hyperglycemic adverse events occurred in 37/406 (9%) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1).
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 037, 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 Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 025, renal injury occurred in 6.6% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6). In Checkmate 069, Grade 2 or higher immune-mediated nephritis or renal dysfunction occurred in 2.1% (2/94) of patients. One patient died without resolution of renal dysfunction.
Immune-Mediated Rash
Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 037 (n=268), the incidence of rash was 21%; the incidence of Grade 3 or 4 rash was 0.4%. In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In Checkmate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7.4% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In Checkmate 069, immune-mediated rash occurred in 37% (35/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=6), Grade 2 (n=10), and Grade 1 (n=19).
Immune-Mediated Encephalitis
Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. Across clinical trials of 8490 patients receiving OPDIVO as a single agent or in combination with YERVOY, <1% of patients were identified as having encephalitis. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO.
Other Immune-Mediated Adverse Reactions
Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. The following clinically significant immune-mediated adverse reactions occurred in <2% of single-agent OPDIVO-treated patients: uveitis, pancreatitis, abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, and systemic inflammatory response syndrome. Across clinical trials of OPDIVO administered as a single agent at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: facial nerve paralysis, motor dysfunction, vasculitis, and myasthenic syndrome. In Checkmate 069, the following additional immune-mediated adverse reactions occurred in 1% of patients treated with OPDIVO in combination with YERVOY: Guillain-Barré syndrome and hypopituitarism. Across clinical trials of OPDIVO in combination with YERVOY, the following additional clinically significant, immune-mediated adverse reactions were identified: uveitis, sarcoidosis, duodenitis, pancreatitis, and gastritis.
Infusion Reactions
Severe infusion reactions have been reported in <1% of patients in clinical trials of OPDIVO as a single agent. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In Checkmate 057, Grade 2 infusion reactions occurred in 1% (3/287) of patients receiving OPDIVO. In Checkmate 025, hypersensitivity/infusion-related reactions occurred in 6.2% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In Checkmate 069, Grade 2 infusion reactions occurred in 3% (3/94) of patients receiving OPDIVO in combination with YERVOY.
Embryofetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 069, serious adverse reactions occurred in 62% of patients receiving OPDIVO; the most frequent serious adverse events with OPDIVO in combination with YERVOY, as compared to YERVOY alone, were colitis (17% vs 9%), diarrhea (9% vs 7%), pyrexia (6% vs 7%), and pneumonitis (5% vs 0).
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 069, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO in combination with YERVOY vs YERVOY alone were rash (67% vs 57%), pruritus (37% vs 26%), headache (24% vs 20%), vomiting (23% vs 15%), and colitis (22% vs 11%).
In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).
Please see U.S. Full Prescribing Information for OPDIVO and YERVOY including Boxed WARNING for YERVOY regarding immune-mediated adverse reactions.
Presage Biosciences In-‐ Licenses Clinical Stage Drug Program
November 24, 2015 – Presage Biosciences, an oncology company pioneering a radical new drug development approach that incorporates human efficacy data much earlier in development and clinical trials, reported that it has in–‐licensed voruciclib, its first clinical stage drug program (Press release, Presage Biosciences, NOV 24, 2015, View Source [SID1234520400]).
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Voruciclib is an oral CDK inhibitor that has been in clinical development for cancer indications and will be developed in combination with other standard of care agents. "Using our CIVO platform, we have been able to rapidly identify and understand the biology of voruciclib combinations that hold potential for further clinical development," said Nathan Caffo, President of Presage. "CIVO clearly distinguished voruciclib from other CDK inhibitors in ways that were unexpected." Voruciclib was previously being developed by Piramal Enterprises Limited, one of India’s large diversified companies, with a presence in Healthcare, Healthcare Information Management and Financial Services. "Presage is taking advantage of our unique capabilities to discover and validate effective cancer drug combinations as we develop voruciclib in the clinic," said Richard Klinghoffer, PhD., Chief Scientific Officer of Presage. "Combating drug resistance in cancer requires that clinicians identify the right combinations of drugs for patients at the outset of treatment. We expect that the CIVO platform can play a key role in informing this new approach to cancer drug development." Presage has developed CIVO, a predictive in vivo assessment technology for drug development that enables the first side–‐by–‐side comparison of multiple drugs and combinations within a single living tumor while still in a patient’s body, without exposing the patient to the toxicity of systemic dosing. Presage is actively in–‐licensing promising compounds and using CIVO to develop a portfolio of proprietary oncology therapies. CIVO was shown to accurately predict systemic response to oncology drugs in multiple experiments in human xenografted mouse models. Additional results in canine patients and a first–‐in–‐human study in lymphoma patients are summarized in a study published in the May 2015 issue of Science Translational Medicine by researchers at Fred Hutchinson Cancer Research Center and Presage Biosciences.