Ipilimumab instructions
Common name: ipilimumab
Trade name: Yervoy
All names: ipilimumab, Yervoy, ipilimumab, ipilimumab, ipilimumab, ipilimumab
Indications:
1. Treatment of adults and pediatric patients 12 years or older with unresectable or metastatic melanoma.
2. Adjuvant treatment for cutaneous melanoma (patients whose pathological involvement of lymph nodes exceeds 1mm and has been surgically removed, including total lymphadenectomy).
3. Combined with nivolumab to treat patients with previously untreated low- to intermediate-risk advanced renal cell carcinoma.
4. In combination with nivolumab for the treatment of adults and pediatric patients aged 12 years or older with microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed after treatment with fluoropyrimidine, oxaliplatin, irinotecan and other drugs.
Usage and dosage:
Unresectable or metastatic melanoma:
3 mg/kg intravenously over 90 minutes, once every 3 weeks, a total of 4 times. If toxicity occurs, infusion may be delayed, but all infusions should be completed within 16 weeks of the first infusion.
Adjuvant melanoma treatment:
10 mg/kg intravenously over 90 minutes, once every 3 weeks, a total of 4 times. Subsequently, 10 mg/kg every 12 weeks for 3 years or until disease recurrence or unacceptable toxicity is demonstrated. For serious adverse reactions, the drug should be permanently discontinued.
Renal cell carcinoma:
The dose of nivolumab is 3 mg/kg, intravenous infusion over 30 minutes, followed by ipilimumab, 1 mg/kg, intravenous infusion over 30 minutes. Both must be infused on the same day, once every 3 weeks. After 4 combined infusions, the regimen was changed to nivolumab monotherapy, with the regimen being 240 mg once every 2 weeks or 480 mg once every 4 weeks.
Microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer:
The dose of ipilimumab is 1 mg/kg, intravenous infusion over 30 minutes, followed by nivolumab, 3 mg/kg, intravenous infusion over 30 minutes. Both must be infused on the same day, once every 3 weeks, for 4 times or until intolerable toxicity or disease progression occurs.
Adverse reactions:
> 10%:
Immune-mediated manifestations of dermatitis (up to 70%)
Fatigue (41%)
Diarrhea (32%)
Pruritus (31%)
Skin rash (29%)
1-10%:
Colitis (8%)
Immune-mediated enterocolitis (7%)
Immune-mediated hepatitis (2%) Endocrinopathy (1.8%) ) include adrenocortical insufficiency, hypogonadism, and hypothyroidism
<1%:
Neuroimmune-mediated manifestations (e.g., Guillain–Barré, peripheral motor neuropathy)
Ocular immune-mediated manifestations (e.g., uveitis, iritis)
Renal immune-mediated manifestations (nephritis)
Pulmonary immune-mediated manifestations (pneumonia)
Other immune-mediated Caused adverse reactions (<1%) include nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia
Meningitis
Pericarditis
Myocarditis
Vascular disease
Temporal arteritis
Vasculitis
Polymyalgia rheumatica
Conjunctivitis
Blepharitis
Episcleritis
Scleritis
Leukocytocytosis Vasculitis
Erythema multiforme
Psoriasis
Pancreatitis
Arthritis
Autoimmune thyroiditis
Postmarketing reports:
Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
Immune system disorders: Graft versus host disease
Contraindications:
None.
Note:
Immune-mediated enterocolitis: Monitor patients for signs and symptoms of enterocolitis (eg, diarrhea, abdominal pain, mucus or blood in stools, presence of fever) and intestinal perforation (eg, peritoneal signs, intestinal obstruction). In symptomatic patients, exclude infectious causes and consider endoscopic evaluation for persistent or severe symptoms. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with glucocorticoid-refractory immune-mediated colitis. In cases of glucocorticoid-refractory colitis, consider repeating infectious testing to rule out other causes. Adding an alternative immunosuppressant or alternative corticosteroid therapy to corticosteroid therapy should be considered in corticosteroid-refractory immune-mediated colitis if other causes have been excluded.
Immune-Mediated Hepatitis: Monitor liver function tests (liver aminotransferase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose. For patients with hepatotoxicity, exclude infectious or malignant causes and increase the frequency of liver function testing and monitoring until resolution.
Immune-Mediated Dermatitis/Adverse Cutaneous Reactions: Monitor patients for signs and symptoms of dermatitis, such as rash and pruritus. Symptoms or signs of dermatitis should be considered immune-mediated unless another cause is identified.
Immune-Mediated Neuropathy: Monitor for symptoms of motor or sensory neuropathy, such as unilateral or bilateral weakness, sensory changes, or paresthesia. Permanently discontinue ipilimumab in patients with severe neuropathy that interferes with daily activities such as Guillain-Barré-like syndrome. Get appropriate medical intervention for severe neuropathy. For severe neuropathy, consider initiating systemic corticosteroid therapy at 1-2 mg/kg/day prednisone or equivalent. Discontinue ipilimumab in patients with moderate neuropathy that does not interfere with daily activities.
Immune-Mediated Endocrine Disorders: Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper or hypothyroidism. Patients may experience fatigue, headache, altered mental status, abdominal pain, abnormal bowel habits, and hypotension, or may be similar to nonspecific symptoms of other causes, such as brain metastases or underlying disease. Symptoms or signs of endocrine disease should be considered immune-mediated unless another cause is found.
Immune-Mediated Pneumonitis: Monitor patients for imaging signs and symptoms of pneumonia. For moderate (Grade 2) or more severe (Grade 3-4) pneumonitis, give corticosteroids at a dose of 1-2 mg/kg/day prednisone equivalent and then taper the corticosteroid dose. Discontinue medication in patients with moderate to severe symptoms and signs. Ipilimumab therapy was permanently discontinued due to life-threatening (grade 4) pneumonitis.
Immune-Mediated Nephritis and Renal Insufficiency: Monitor patients' serum creatinine levels before and periodically during treatment. Give corticosteroids in prednisone equivalents at 1-2 mg/kg/day, then taper corticosteroids. Give 0.5 to 1 mg/kg/day corticosteroids to patients with moderate (Grade 2) or severe (Grade 3) elevations in serum creatinine, and if disease worsens or does not improve, increase corticosteroids to 1 to 2 mg/kg/day. Discontinue the drug in patients with moderate to severe symptoms and signs. Permanently discontinue ipilimumab due to life-threatening (Grade 4) increases in serum creatinine.
Immune-Mediated Encephalitis: Evaluation of patients with neurological symptoms may include, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue ipilimumab in patients with new onset of moderate to severe neurological symptoms or signs and evaluate to rule out infectious or other causes of moderate to severe neurological deterioration. If other causes have been ruled out, give 1 to 2 mg/kg/day of prednisone-equivalent corticosteroids to patients with immune-mediated encephalitis and then taper the dose gradually. Permanently discontinued due to immune-mediated encephalitis.
Infusion-related reactions: Serious infusion-related reactions can occur with nivolumab and ipilimumab. Discontinue ipilimumab in patients who have severe or life-threatening infusion-related reactions. Interrupt or slow down the infusion rate in patients with mild or moderate infusion-related reactions.
Fetal toxicity: Based on its mechanism of action and animal experimental data, ipilimumab can cause fetal harm when administered to pregnant women. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from organogenesis to parturition resulted in higher rates of miscarriage, stillbirth, and prematurity (with corresponding lower birth weight). The effect of ipilimumab may be greater in the second and third trimesters of pregnancy. Inform pregnant women of potential risks to the fetus. Advise women to use an effective method of contraception during treatment with ipilimumab-containing regimens and for 3 months after the last dose of ipilimumab.
Storage:
Store at 2℃-8℃, do not freeze. Protect vial from light.
Mechanism of action:
Ipilimumab is a CTLA-4 inhibitor. CTLA-4 (cytotoxic T lymphocyte-associated protein 4) is a leukocyte differentiation antigen and a transmembrane receptor on T cells (thymus-dependent lymphocytes) that functions as an immune checkpoint and downregulates immune responses. CTLA-4 acts as a switch by binding to receptors on the surface of antigen cells and terminating the immune response. By inhibiting CTLA-4 molecules, CTLA-4 inhibitors can cause T cells to proliferate in large numbers and attack tumor cells. Ipilimumab blocks the binding of CTLA-4 to B7 molecular ligands, thereby ensuring the activation and proliferation of T cells, and ultimately achieves anti-tumor effects.
Safety and Efficacy:
The Phase III CheckMate-067 trial confirmed that patients with advanced melanoma receiving first-line treatment with nivolumab combined with ipilimumab can obtain a durable and sustained survival benefit. The median follow-up time was 46.9 months in the nivolumab plus ipilimumab group, 36.0 months in the nivolumab plus ipilimumab group, and 18.6 months in the ipilimumab group. Colorectal cancer. The Phase II CheckMate 142 study confirmed that nivolumab combined with ipilimumab was used to treat patients with recurrent or metastatic colorectal cancer, and the test confirmed that the patients were dMMR and/or MSI-H type. Regardless of the patient's BRAF, KRAS mutation status, PD-L1 expression status, or whether they had Lynch syndrome, all patients were observed to be effective. The overall effective rate among 119 patients was 54.6%.
The Phase II CheckMate-214 trial confirmed that compared with the standard treatment drug sunitinib, nivolumab combined with ipilimumab in the first-line treatment of renal cancer can significantly improve the overall survival rate of patients and reduce the mortality rate by 37%. The overall survival rates for the two treatments were 41.6% and 26.5%, respectively. Mild adverse reactions that may occur during treatment include: rash, diarrhea, hepatitis, thyroiditis, and adrenal insufficiency. Medication may be withheld until return to baseline and patients given less than 7.5 mg of prednisone or equivalent daily.
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