Ipilimumab Immunotherapy (YERVOY) for Metastatic Melanoma , Cutaneous Melanoma & Advanced Renal Cell Carcinoma: Indication, Side Effects and Mechanism of Action

Ipilimumab (Yervoy) is FDA Approved Immune Check Point Inhibitors For Certain Cancers

Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. 

Indication of Ipilimumab (YERVOY)

Ipilimumab (YERVOY) is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for: 

Metastatic Melanoma- treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older).  

Cutaneous Melonama- adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. 

Advanced Renal Cell Carcinoma: Treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma, in combination with nivolumab.

Ipilimumab Side effects, Warning & Precaution 

Immune-mediated adverse reactions: Permanently discontinue for severe reactions. Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and the patient is receiving less than 7.5 mg prednisone or equivalent per day. Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions. 

Immune-mediated hepatitis: Evaluate liver function tests before each dose of YERVOY. (5.2) Withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation. 

Immune-mediated endocrinopathies: Monitor clinical chemistries, ACTH level, and thyroid function tests prior to each dose. Evaluate at each visit for signs and symptoms of endocrinopathy. Institute hormone replacement therapy as needed. 

Immune-mediated pneumonitis: Withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis. 

Immune-mediated nephritis and renal dysfunction: Monitor for changes in renal function. Withhold for moderate or severe and permanently discontinue for life-threatening serum creatinine elevation. (5.7)

Immune-mediated encephalitis: Monitor for changes in neurologic function. Withhold for new-onset moderate to severe neurological signs or symptoms and permanently discontinue for immune-mediated encephalitis.  

Infusion reactions: Discontinue for severe and life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. 

Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. 

Adverse Reaction of Ipilimumab ( YERVOY): 

Most common adverse reactions (>5%) with YERVOY as a single agent are fatigue, diarrhea, pruritus, rash, and colitis. Additional common adverse reactions at the 10 mg/kg dose (5%) include nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia. 

The most common adverse reactions (>20%) with YERVOY in combination with nivolumab are fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. 

Formulation of YERVOY 

YERVOY is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution for intravenous infusion, which may contain a small amount of visible translucent-towhite, amorphous ipilimumab particulates. It is supplied in single-use vials of 50 mg/10 mL and 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7. 12 

Mechanism of Action of Ipilimumab (YERVOY)

 CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor-infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also 3 reduce T-regulatory cell function, which may contribute to a general increase in T cell responsiveness, including the anti-tumor immune response.


 The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. The PK of ipilimumab is linear in the dose range of 0.3 to 10 mg/kg. Following administration of YERVOY every 3 weeks, the systemic accumulation was 1.5-fold or less. 

Steady-state concentrations of ipilimumab were reached by the third dose; the mean Cmin at steady state was 19.4 mcg/mL at 3 mg/kg and 58.1 mcg/mL at 10 mg/kg every 3 weeks. The mean value (percent coefficient of variation) based on population 

PK analysis for the terminal half-life (t1/2) was 15.4 days (34%) and for clearance (CL) was 16.8 mL/h (38%). YERVOY with nivolumab: When YERVOY 1 mg/kg was administered in combination with nivolumab 3 mg/kg, the CL of ipilimumab and nivolumab were unchanged. 

When administered in combination, the CL of ipilimumab was unchanged in presence of anti-ipilimumab antibodies and the CL of nivolumab increased by 20% in the presence of antinivolumab antibodies.