In March 2011, ipilimumab (YERVOY™; Bristol-Myers Squibb) gained US FDA approval for the treatment of adult patients with stage III to IV melanoma unresponsive to previous therapy. That's certainly good news for patients, who have few options once the melanoma spreads to other areas of the body (stage IV disease, metastatic melanoma).
Mechanism of action of ipilimumab
Regulatory pathways that limit the immune response to cancer are becoming well characterised. Ipilimumab is a fully human monoclonal antibody that activates the body's immune system to fight melanoma by inhibiting the cytotoxic T lymphocyte (T-cells)-associated antigen 4 (CTLA-4) molecule.
CTLA-4 is a molecule on T-cells, a type of white blood cell, that plays a critical role in regulating natural immune responses. The presence of CTLA-4 suppresses the immune system's response to disease, so blocking its activity stimulates the immune system to fight the melanoma.
Key clinical-trial evidence for ipilimumab
Three previous early-phase (phase II) clinical trials have shown that treatment with ipilimumab results in a one-year survival rate of 47% to 51% for people with stage III or IV melanoma, which is almost double the number not on this treatment.
Ipilimumab has also being tested in advanced (phase III) trials by itself and in combination with vaccines, other immunotherapies (such as interleukin-2) and chemotherapies (such as dacarbazine). Overall response rates ranged from 13% with ipilimumab plus vaccine in patients with stage IV disease to 17% and 22%, with ipilimumab plus dacarbazine or interleukin-2, respectively, in patients with metastatic disease. Responses have been long-lasting, with more than one-third of ipilimumab-treated patients with advanced melanoma experiencing a long-term survival benefit, a rare success story in the treatment of this disease.
Recently published results of a randomized, controlled phase III trial have shown a first-ever significant overall survival benefit with ipilimumab compared with a cancer vaccine comprising HLA-A*0201–restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100) in patients with metastatic melanoma, previously treated unsuccessfully with aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered intravenously with or without gp100 (2mg peptide by deep SC) every 3 weeks for up to four treatments.
- The median overall survival was 10.0 months among 403 patients receiving ipilimumab plus gp100, compared with 6.4 months among 136 patients receiving gp100 alone (statistically significant, P<0.001).
- The median overall survival with ipilimumab alone (in 137 patients) was 10.1 months (P=0.003).
- No difference in overall survival was detected between the ipilimumab groups (P=0.76).
- Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. The most common immune-related adverse event was diarrhoea, which occurred at any grade in 27 to 31% of the patients in the ipilimumab groups.
Based on these results, the US FDA granted marketing approval for ipilimumab as second-line treatment for metastatic melanoma in adult patients. The FDA noted in its approval announcement that the common adverse effects that can result from autoimmune reactions associated with ipilimumab use include fatigue, diarrhoea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe and some fatal autoimmune reactions were seen in 12.9% of patients treated with ipilimumab. Because of the unusual and severe adverse effects associated with ipilimumab, the therapy was approved with a Risk Evaluation and Mitigation Strategy to inform healthcare professionals about these serious risks. A medication guide has also been provided to patients to inform them about the therapy's potential adverse effects.
Adverse events from ipilimumab
Ipilimumab can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. These are:
- Immune-mediated enterocolitis
- Immune-mediated hepatitis
- Immune-mediated dermatitis
- Immune-mediated neuropathies
- Immune-mediated endocrinopathies
- Other immune-mediated adverse reactions, including ocular manifestations
In the event of any of these adverse events, ipilimumab should be discontinued and treatment initiated with systemic corticosteroids, i.e. prednis(ol)one or equivalent. Upon improvement, corticosterods should be tapered gradually.
Vitiligo has been reported as an adverse effect of ipilimumab. Vitiligo has been thought to be a good prognostic factor in metastatic melanoma.
Dosage and administration of ipilimumab
The recommended dose of ipilimumab is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.
For any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy, the scheduled dose of ipilimumab should be withheld. For patients with complete or partial resolution of adverse reactions (Grade 0–1), and who are receiving less than 7.5 mg prednisone or equivalent per day, ipilimumab should be resumed at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from first dose, whichever occurs earlier.
Ipilimumab should be discontinued permanently for any of the following reasons:
- Persistent moderate adverse reaction(s) 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 such as colitis with abdominal pain, fever, ileus, or peritoneal signs, increase in stool frequency (7 or more over baseline), stool incontinence, need for intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation.
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal or total bilirubin >3 times the upper limit of normal.
- 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 (eg, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis).
- Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy.
Contraindications to ipilimumab
None have been reported.
Drug interactions with ipilimumab
No formal drug-drug interaction studies have been conducted with ipilimumab.
Use of ipilimumab in specific populations
- There are no adequate and well-controlled studies of ipilimumab in pregnant women. Ipilimumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (Pregnancy Category C).
- It is not known whether ipilimumab is secreted in human milk. Because of the potential adverse effects to the infant, a decision should be made whether to discontinue nursing or to discontinue ipilimumab, taking into account the importance of ipilimumab to the mother.
- Safety and effectiveness of ipilimumab have not been established in pediatric patients.
- In clinical trials, no overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).
- No formal studies of ipilimumab in patients with renal impairment have been conducted.
- No formal studies of ipilimumab in patients with hepatic impairment have been conducted.
- The genotoxic potential of ipilimumab has not been evaluated.
- Fertility studies have not been performed with ipilimumab.
- The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies.
- It is unknown whether ipilimumab should be used before or after BRAF inhibitor therapy in patients suitable for both treatments.
Overdosge with ipilimumab
No data are currently available on overdosage with ipilimumab.