Generic Name and Formulations:
Ipilimumab 5mg/mL; soln for IV infusion; preservative-free.
Company:
Bristol-Myers Squibb
Indications for YERVOY:
Treatment of unresectable or metastatic melanoma.
Adult Dose for YERVOY:
Give by IV infusion over 90 minutes. 3mg/kg every 3 weeks for a total of 4 doses. Withhold dose for moderate immune-mediated reactions or symptomatic endocrinopathy. Complete/partial resolution of adverse reaction and receiving <7.5mg prednisone or equivalent per day: may resume treatment. Permanently discontinue and initiate systemic high-dose corticosteroids for severe adverse reactions.
Children's Dose for YERVOY:
Not established.
Pharmacological Class:
Cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody.
Warnings/Precautions:
Permanently discontinue if: persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5mg prednisone or equivalent per day; failure to complete full treatment course within 16 weeks from first dose; severe or life-threatening reactions, including: 1) colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency and incontinence, need for IV hydration for >24 hours, GI hemorrhage/perforation; 2) AST or ALT >5X ULN or total bilirubin >3X ULN; 3) Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; 4) severe motor or sensory neuropathy, Guillain-Barre syndrome, or myasthenia gravis; 5) severe immune-mediated reactions involving any organ system; 6) immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy. Monitor for enterocolitis, dermatitis, neuropathy, endocrinopathy; perform LFTs and thyroid tests at baseline and before each dose. Pregnancy (Cat. C). Nursing mothers: not recommended.
Adverse Reactions:
Fatigue, diarrhea, pruritus, rash, colitis; immune-mediated adverse reactions (may be severe and fatal).
How Supplied:
Single-use vial (50mg, 200mg)—1
Yervoy Approved for Metastatic Melanoma
YERVOY (ipilimumab) 50mg/10mL, 200mg/40mL injection by Bristol-Myers Squibb Bristol-Myers Squibb announced that Yervoy(ipilimumab injection) has been approved for the treatment of late stage (metastatic) melanoma. This approval was based on data from a study conducted in 676 patients with melanoma who had stopped responding to other FDA-approved or commonly used treatments for melanoma, and had disease that had spread or could not be surgically removed. Patients received Yervoy plus an experimental tumor vaccine called gp100, Yervoy alone, or the vaccine alone. Patients who received the combination of Yervoy plus the vaccine or Yervoy alone lived an average of about 10 months, while those who received only the experimental vaccine lived an average of 6.5 months.
Yervoy is a monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen (CTLA-4). CTLA-4 may play a role in slowing down or turning off the body's immune system, affecting its ability to fight off cancerous cells. Yervoy may work by allowing the body's immune system to recognize, target, and attack cells in melanoma tumors.
SAFETY ALERT: Risk eva luation and Mitigation Strategy (REMS) for Yervoy
Bristol-Myers Squibb informed healthcare professionals about the Risk eva luation and Mitigation Strategy (REMS), developed in collaboration with the FDA, that is required to ensure that the benefits of Yervoy (ipilimumab) outweigh the risks of 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.
Healthcare providers are advised to read the Boxed Warning and accompanying full Prescribing Information for a complete description of these risks and their management and are advised to discuss the risks that may be associated with therapy with patients and their caregivers. Clinicians are advised to:
•Permanently discontinue Yervoy and initiate systemic high-dose corticosteroid therapy for identified severe immune-mediated reactions
•Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and eva luate clinical chemistries, including liver function tests and thyroid function tests, at baseline and before each dose
Yervoy is indicated for the treatment of late-stage (metastatic) melanoma.
Phase 3 Trial Update of Ipilimumab + Dacarbazine for Metastatic Melanoma
(ChemotherapyAdvisor) – Ipilimumab (Yervoy) offers 4- and 5-year survival benefits for patients with metastatic melanoma, according to long-term follow-up analyses of a Phase 3 and several Phase 2 clinical trials reported by Bristol-Myers Squibb at the European Society for Medical Oncology (ESMO) 2012 Congress in Vienna, Austria.
“Results from these investigational studies showed a prolonged survival benefit with Yervoy at 4 and 5 years for some patients,” reported Celeste Lebbe, MD, Professor of Dermatology, Hôpital Saint-Louis in Paris, France. “These results add to the growing body of long-term survival data seen in some patients treated with Yervoy and further our understanding of the potential of this immunotherapy in the treatment of metastatic melanoma."
In the double-blind, randomized Phase 3 trial, 502 treatment-naïve patients with Stage III unresectable or Stage IV metastatic melanoma were randomized to receive ipilimumab (10mg/kg) plus dacarbazine (DTIC; Bayer) 850mg/m2 or DTIC alone. Follow-up analysis identified a 4-year survival rate among ipilimumab-arm patients of 19% (95% CI: 14.2%–24.2%) vs. 9.6% (95% CI: 6.1–13.5) among patients receiving DTIC alone, the authors reported.
Follow-up data from three Phase 2 trials, representing 487 patients, found 5-year survival rates of 38% to 49% among treatment-naïve patients who were administered ipilimumab, and 12% to 28% among non-treatment-naïve patients, the authors reported.
Ipilimumab “can result in severe and fatal immune-related adverse reactions due to T-cell activation and proliferation,” the authors cautioned.
“The combination of DTIC with Yervoy is not an FDA approved-regimen,” the authors noted. Nor were the analyses designed to compare the safety and efficacy of the FDA-approved monotherapy dose of 3mg/kg for unresectable or metastatic melanoma versus the investigational dose of 10mg/kg, they added.
Metastatic melanoma is an aggressive cancer with a historical 5-year survival rate of <10% in patients with metastatic disease, Dr. Lebbe noted.
Ipilimumab is a recombinant human monoclonal antibody and the first FDA-approved cancer immunotherapy that blocks the cytotoxic T- lymphocyte antigen-4 (CTLA-4), a negative regulator of T-cell activation.
Combo Antibody Therapy Effective for Melanoma
ASCO: Combo Antibody Therapy Effective for Melanoma (HealthDay News) – Concurrent use of two immune checkpoint antibodies -- ipilimumab and nivolumab -- may be effective for the treatment of advanced melanoma, according to a proof-of-principal study presented in advance of the annual meeting of the American Society of Clinical Oncology, held from May 31–June 4 in Chicago.
Jedd D. Wolchok, MD, PhD, from the Memorial Sloan-Kettering Cancer Center in New York City, and colleagues enrolled patients who had received no more than three prior treatments. Patients received intravenous nivolumab and ipilimumab concurrently for four doses, followed by nivolumab alone. Additionally, in two other study arms, patients who had undergone prior ipilimumab treatment received only nivolumab.
The researchers found that, based on the 37 patients treated with concurrent therapy, the objective response rate was 38%. In the three concurrent treatment arms that completed the trial, tumor shrinkage rates were 21, 47, and 50%, with the highest rates seen in patients treated with the highest dose of both drugs. The responses to therapy were rapid, with three out of four responding patients doing so within the first three months, which is faster than with single-agent ipilimumab. 30% of patients experienced significant tumor shrinkage of >80%. Adverse events for concurrent therapy were similar in nature (although some with higher frequency) than those typically seen for the monotherapies and were generally manageable using immunosuppressants.
"The complete and near-complete response rates we're seeing are unprecedented for an immunotherapy in melanoma," Wolchok said in a statement.
Several authors disclosed financial ties to Bristol-Myers Squibb, which funded the study and manufactures ipilimumab and nivolumab.
Abstract
More Information
Ipilimumab Active in Advanced Melanoma With Brain Mets
Ipilimumab Active in Advanced Melanoma With Brain Mets (HealthDay News) – For some patients with advanced melanoma and brain metastases, ipilimumab is active, according to the results of a phase 2 study published online March 27 in The Lancet Oncology.
Kim Margolin, MD, from the University of Washington in Seattle, and colleagues enrolled 72 patients with melanoma and brain metastases into two parallel cohorts to investigate the safety and activity of ipilimumab. Cohort A included 51 patients who were neurologically asymptomatic and were not receiving corticosteroid treatment at the time of study entry, and cohort B included 21 symptomatic patients treated with a stable dose of corticosteroids. Patients received four doses of ipilimumab, one dose every three weeks.
After 12 weeks, the researchers found that nine patients in cohort A and one in cohort B exhibited disease control (18% vs. 5%). When the brain alone was assessed, disease control was achieved by 12 patients in cohort A and two in cohort B (24% vs. 10%). Disease control was seen outside the brain in 14 patients in cohort A and one in cohort B (27% vs. 5%). In cohort A, the most common grade 3 adverse events included diarrhea and fatigue, while in cohort B, they included dehydration, hyperglycemia, and increased serum concentrations of aspartate aminotransferase. Grade 4 confusion was seen in one patient in each cohort.
"Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population," the authors write.
Several authors disclosed financial ties to Bristol-Myers Squibb, which funded the trial and manufactures ipilimumab.
New Treatments for Advanced Melanoma
New Treatments for Advanced Melanoma In 2012, it is estimated that over 76,000 men and women in the United States will be diagnosed with melanoma, and close to 9,200 will die of the disease.1 Over 800,000 men and women have a history of melanoma, with a lifetime risk of 1 in 51 for both sexes.2 Melanoma, a major form of morbidity and mortality in the U.S., accounts for approximately 5% of skin cancers, but is the cause of the vast majority of skin cancer deaths.1 It is the fifth most common type of cancer among men and seventh among women.3 Melanoma is the second most common type of invasive cancer in young adults, second only to breast cancer.4 This trend is of particular concern, since the incidence of cutaneous melanoma is rapidly rising among young adults, especially women.5 With melanoma cases on the rise, there is a definite need for new treatment options.
Current research is focusing on regulatory pathways that stimulate the immune response against cancer cells. This can be done by blocking inhibitory immune checkpoint receptors such as cytotoxic T-lymphocyte-associated-protein 4 (CTLA-4) that down-regulates T-cell activation pathways. Anti-CTLA-4 is one of the first immunostimulatory monoclonal antibodies that has been used in malignant melanoma.6 Ipilimumab (Yervoy, Bristol-Myers Squibb), a fully human monoclonal antibody (IgG1) indicated for the treatment of unresectable or metastatic melanoma, blocks CTLA-4 and promotes antitumor immunity.7,8,9 Ipilimumab monotherapy in Phase 2 clinical trials has demonstrated antitumor activity in patients with metastatic melanoma.10,11,12 It has also demonstrated antitumor activity when combined with other anticancer agents, including vaccines such as the anticancer vaccine HLA-A*0201-restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100).13,14
Hodi and colleagues eva luated the efficacy of ipilimumab with or without gp100 compared to gp100 alone in 676 HLA-A*0201-positive patients with unresectable stage 3 or 4 melanoma whose cancer had progressed while receiving therapy for metastatic disease.15 Patients were randomized in a 3:1:1 ratio to receive either ipilimumab 3mg/kg gp100 (N=403), ipilimumab 3mg/kg alone (N=137), or gp100 alone (N=136). Each regimen was administered every 3 weeks. The primary endpoint was overall survival. The median overall survival time was 10.0 months in patients receiving ipilimumab plus gp100 compared to 6.4 months in those receiving gp100 alone (P<0.001; HR 0.68). Median survival time was 10.5 months for patients receiving ipilimumab alone compared with 6.4 months for gp100 alone (P=0.003: HR 0.66). No differences in overall survival were observed between the 2 ipilimumab groups. Grade 3 or 4 immune-related adverse events occurred in 10% to 15% of patients receiving ipilimumab, and in 3% of those receiving gp100 alone. Even though adverse events were severe, long-lasting, or both, they were reversible with appropriate therapy. Hodi and colleagues concluded that ipilimumab with or without gp100 improved overall survival in patients with metastatic melanoma.
Despite ipilimumab's therapeutic success, its overall response rate is 10% to 15% in patients with advanced melanoma.15,16 When disease progression occurs, localized radiotherapy is administered to relieve tumor pressure. In some instances, the addition of radiotherapy results in an abscopal effect. The abscopal effect refers to a rare phenomenon of tumor regression at a sight distant from the primary site of radiotherapy. Localized radiotherapy has been shown to induce the abscopal effect in some types of cancer, including melanoma.17 The biologic characteristics underlying this effect are not clearly understood but may be mediated by immunologic mechanisms.18 Ipilimumab has also been shown to enhance immunity to NY-ES-01 and patients with pre-existing NY-ESO-1 antibodies seem to benefit even more. NY-ESO-1 is an antigen expressed in 30% to 40% of patients with advanced melanoma. It is not present in normal adult tissue except in testicular germ cells and the placenta.19
Postow and colleagues reported on the success of the addition of radiotherapy to a woman undergoing treatment for metastatic melanoma with ipilimumab and its effect on NY-ES-01.17 Radiotherapy was administered in order to reduce tumor pressure on her spine. Four months later, her spinal tumor, as well as tumors distant to the primary site of radiotherapy, began to shrink as is seen with the abscopal phenomenon. One metastatic lesion was removed prior to ipilimumab treatment and the NY-ESO-1 expression was confirmed. Temporal associations were also noted and included tumor shrinkage with antibody responses to NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibody responses to other antigens after radiotherapy. This patient's unexpected systematic response to radiotherapy in combination with ipilimumab provides new insights and may open the door for new therapeutic options for treating advanced melanoma.
Though these results appear promising, the vast majority of patients with metastatic melanoma do not respond to the anti-CTLA-4 antibody and still need effective treatment options. In 2002, researchers at the Sanger Institute discovered that mutations in the gene encoding the serine/threonine protein kinase B-RAF (BRAF) occurred in more than 60% of melanomas initially tested.20 Melanomas that carry the BRAF V600E mutation activate the mitogen-activated protein kinase (MAPK) pathway at a continuous rate, thereby promoting cell proliferation and preventing apoptosis.21 Vemurafenib (Zelboraf, Genentech, Inc.), a new agent approved in 2011 in the battle against melanoma, was developed as a potent kinase inhibitor with specificity for the BRAF V600E mutation within cancer cells.
Sosman and colleagues eva luated the overall response rate, duration of response, and overall survival of vemurafenib in previously treated patients with BRAF V600 mutant-metastatic melanoma.22 In this multicenter, Phase 2 trial, 132 patients received vemurafenib 960mg orally twice daily until the development of unacceptable adverse effects or disease progression. Patients with disease progression could continue with vemurafenib if it was thought that the patient would benefit clinically. Median follow-up was 12.9 months with a range of 0.6 to 20.1 months. The confirmed overall response rate was 53%, with 6% experiencing a complete response, and 47% experiencing a partial response. The median duration of response was 6.7 months and median progression-free survival was 6.8 months. Primary disease progression was only observed in 14% of treated patients. Response was not necessarily observed right away. Some patients did not start to experience a response until 6 months after treatment started. The median overall survival was 15.9 months. Vemurafenib appeared to be well tolerated. The more commonly reported adverse effects included grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. This clinical trial was able to demonstrate that vemurafenib can induce clinical responses in previously treated patients with BRAF V600 mutant-metastatic melanoma over an extended period of time (16 months).
The search for safe and effective advanced melanoma cancer treatment therapies has been a long and difficult struggle. The introduction of ipilimumab and vemurafenib may be the beginning of the identification of melanoma treatment options that improve survival outcomes based upon patient immune response.
