Yervoy
Yervoy
Generic Name
Yervoy
Mechanism
- Blockade of CTLA‑4: Ipilimumab binds CTLA‑4 on activated T cells, preventing its interaction with costimulatory ligands CD80/CD86 on antigen‑presenting cells.
- Enhancement of T‑cell activation: By disengaging the inhibitory signal, T‑cell proliferation and cytokine production are amplified.
- Augmented antitumor immunity: The heightened T‑cell response increases tumor cytolysis and can lead to durable clinical remission in a subset of patients.
Pharmacokinetics
- Formulation & route: 3 mg/mL sterile, preservative‑free solution, administered IV.
- Distribution: Large extravascular volume, reflecting antibody size and glycoprotein binding.
- Metabolism & elimination: Proteolytic catabolism; negligible renal clearance.
- Half‑life: 10–15 days, variable with disease state; steady‑state achieved after ~4–5 doses.
- Dose‑response: Linear pharmacokinetics up to the approved dosing of 10 mg/kg during maintenance.
- Interactions: No clinically significant interactions with concomitant drugs.
Indications
- Unresectable or metastatic melanoma (alone or combined with nivolumab).
- Recurrent (rare) melanoma following prior therapy.
- Best‑line therapy with nivolumab for patients with untreated, unresectable stage III/IV melanoma.
- Approved in combination with nivolumab for certain off‑label indications with evidence of benefit (e.g., renal cell carcinoma in combination studies).
Contraindications
- Hypersensitivity: IgE‑mediated angioedema, anaphylaxis, or anaphylactoid reactions to ipilimumab.
- Active autoimmune disease: Systemic lupus erythematosus, inflammatory bowel disease, or severe organ‑specific autoimmunity.
- Uncontrolled infection: Active tuberculosis or other systemic infections.
- Pregnancy/Breastfeeding: No safety data; use of effective contraception advised.
- Severe hepatic impairment: Liver function tests >5× upper limit of normal (ULN).
- Concurrent use of other immune‑modulating agents: Unless clinically justified and monitored.
Dosing
| Condition | Dose | Schedule | Infusion Duration | Notes |
| Adjuvant/metastatic melanoma | 3 mg/kg | 1 mg/kg q3 wk × 4 doses, then 10 mg/kg q3 wk | 90 min | No requirement for food or additional premedication; pre‑infusion corticosteroid optional in severe cases. |
| Combination with nivolumab | 3 mg/kg | Same schedule as above | 90 min | Nivolumab 240 mg IV q2 wk is administered on alternate cycle. |
• Premedication: Acetaminophen, antihistamine, or cortico‑steroids may be given for infusion reaction prophylaxis, especially in patients with history of reactions.
• Administration site: Peripheral venous access; central lines not required.
• IV access: Infusion over 90 min; ensure IV line integrity; monitor for hypotension during infusion.
• Post‑infusion: Observe for ≥30 min for immediate hypersensitivity.
Adverse Effects
| Class | Common (≥10%) | Serious (≥1%) | Management |
| Infusion Reaction | Fever, chills, rash | Anaphylaxis, bronchospasm | Slow infusion, hold dose, administer epinephrine, steroids, antihistamine |
| Dermatologic | Rash, pruritus | Stevens–Johnson syndrome, toxic epidermal necrolysis | Topical steroids, oral prednisone (≤10 mg/d) |
| Gastrointestinal | Diarrhea, abdominal pain | Colitis, perforation | Corticosteroids 1–2 mg/kg IV × 3–5 days, consider infliximab |
| Endocrine | Fatigue | Hypophysitis, adrenal insufficiency | Hormone replacement, endocrine consultation |
| Hepatic | Elevated ALT/AST | Hepatitis | Steroid therapy, hold drug |
| Pulmonary | Cough, dyspnea | Pneumonitis | Corticosteroids, discontinue drug for grade ≥3 |
| Renal | Hematuria | Nephritis | Steroids, monitor creatinine |
| Neurologic | Peripheral neuropathy | Neurotoxicity | Neurology support, steroids |
Monitoring
- Baseline & every 3 weeks: CBC, CMP (including LFTs), LDH, ferritin, thyrotropin, cortisol, albumin.
- Stool: Evaluate for infection when diarrhea occurs.
- Endocrine evaluation: Serum ACTH, TSH, free T4, lithium‑screen for SIADH.
- Imaging: CT/PET at baseline, then every 12 weeks or clinically indicated.
- Infusion reaction monitoring: Vital signs pre‑ and during infusion.
- Patient education: Recognize early irAE symptoms (diarrhea, shortness of breath, abdominal pain).
Clinical Pearls
- Early Identification of Colitis: In patients with new-onset watery stools, always obtain a stool culture and CBC before initiating steroids. If infectious causes are ruled out, start high‑dose prednisone (1–2 mg/kg) immediately; consider infliximab if refractory.
- Endocrine Pitfalls: Hypophysitis presents with headache, visual changes, or adrenal crisis. A baseline and quarterly endocrine panel detects ACTH deficiency early, reducing morbidity.
- Infusion Desensitization: For patients with prior mild reaction, a step‑wise infusion rate increase with premedication can reduce repeat dosing interruptions.
- Steroids vs. Renewal: If an irAE is grade ≥3, hold and taper steroids over at least 4 weeks before re‑introducing ipilimumab; do not restart until the AE resolves to grade ≤1.
- Combination Therapy Schedules: When combined with nivolumab, maintain the 3 mg/kg every 3 weeks and stagger the dosing to reduce cumulative toxicity: ipilimumab on day 1, nivolumab on day 8 of a 21‑day cycle.
- Patient Selection: Consider ipilimumab only after careful assessment of baseline immune status; patients with autoimmune disease or organ dysfunction often tolerate the drug poorly.
- Adjuvant Use Benefit: Even in early metastatic melanoma, post‑surgery ipilimumab may reduce recurrence; discuss risk–benefit with patient.
These concise, evidence‑based points equip clinicians and trainees to safely prescribe and manage Yervoy, ensuring optimal efficacy while mitigating the significant immune‑related adverse effects associated with CTLA‑4 blockade.