What Is Ipilimumab (Yervoy)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA Approved: Yes (Initial approval: 28 March 2011)
• Brand Name: Yervoy
• Active Ingredient: Ipilimumab
• Route of Administration: IV (vial)
• Class: Anti-CTLA-4 monoclonal antibody (IgG1κ)
• Category: Immunotherapy, immune checkpoint inhibitor
• Manufacturer: Bristol-Myers Squibb
• Distribution in Turkey: Bristol-Myers Squibb
• Cancers for Which It Is Approved:
  • Unresectable or metastatic melanoma (alone or with nivolumab).
  • Cutaneous melanoma with regional lymph node involvement following complete resection.
  • Advanced renal cell cancer (combined with nivolumab).
  • MSI-H or dMMR metastatic colorectal cancer (after fluoropyrimidine, oxaliplatin, and irinotecan treatment).
  • Hepatocellular cancer (HCC) previously treated with sorafenib.
  • Metastatic NSCLC with PD-L1 >1% and no EGFR or ALK mutation (with nivolumab).
  • Malignant pleural mesothelioma (first-line treatment with nivolumab).
  • Advanced or metastatic esophageal squamous cell cancer (with nivolumab).

2020 Onward

• 02 October 2020: The Opdivo (nivolumab) + Yervoy (ipilimumab) combination was approved as the first and only immunotherapy for unresectable malignant pleural mesothelioma.
• 26 May 2020: The Opdivo + Yervoy combination with limited chemotherapy was approved as first-line treatment for metastatic or recurrent NSCLC.
• 15 May 2020: The Opdivo + Yervoy combination was approved as first-line treatment for metastatic NSCLC with tumor PD-L1 expression ≥1%.
• 11 March 2020: The FDA approved Opdivo + Yervoy for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib.

2015–2019

• 11 July 2018: Opdivo combined with low-dose Yervoy was approved for previously treated MSI-H/dMMR metastatic colorectal cancer.
• 16 April 2018: Opdivo + Yervoy was approved as first-line treatment for advanced renal cell carcinoma in intermediate- and poor-risk groups.
• 24 July 2017: The FDA expanded Yervoy's use to treat unresectable or metastatic melanoma in pediatric patients aged 12 years and older.
• 23 January 2016: The Opdivo + Yervoy regimen received expanded approval for metastatic melanoma regardless of BRAF status.
• 28 October 2015: Yervoy was approved to reduce the risk of melanoma recurrence after surgery.
• 01 October 2015: The FDA approved the Opdivo + Yervoy regimen for patients with BRAF V600 wild-type melanoma.

2011–2014

• 28 March 2011: The FDA approved Yervoy for advanced melanoma.

Turkey's Social Security Institution (SGK) reimburses it for certain indications:

• For unresectable relapsed or metastatic malignant melanoma in adults whose disease has progressed after at least one line of systemic treatment, medical oncologists may prescribe it on the basis of a medical board report valid for 3 months that includes a medical oncology specialist.
• Up to 4 doses are reimbursed (1 dose = treatment administered at 3 mg/kg once every 3 weeks).
• Dabrafenib, vemurafenib, and ipilimumab cannot be used in combination.

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Price (June 2026):
Pharmacy selling price of Yervoy 50 mg / 10 ml vial: 72078.19 TL
Pharmacy selling price of Yervoy 200 mg / 40 ml vial: 288006.26 TL. 

At 1 mg/kg, the cost per cycle for an average person weighing 70 kg is 144156.38 TL. 

At 3 mg/kg, the cost per cycle for an average person weighing 70 kg is 360084.45 TL. 

Resistance Mechanisms:

• Increased expression/activity of alternative immune checkpoint pathways (e.g., TIGIT, TIM3, LAG3).
• Increased infiltration of immunosuppressive cells into the tumor microenvironment (Tregs, MDSCs, and M2 macrophages).
• Release of cytokines, chemokines, and metabolites (e.g., CSF-1, TGF-β, and adenosine).

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Pharmacokinetic Properties:

• Absorption: Administered only intravenously (IV).
• Distribution: Not clearly characterized; steady state is reached at the third dose.
• Metabolism: Not clearly characterized; the terminal half-life is approximately 16–17 days.

Through its effects on the immune system, ipilimumab activates T cells and promotes their proliferation. This can cause immune-mediated side effects that may be serious or even fatal. These effects are covered by the medicine's strongest warning, the "boxed warning". This highlights their potential severity.

When Ipilimumab Must Be Permanently Discontinued:

• Persistent moderate side effects or inability to reduce the daily steroid (prednisone) dose below 7.5 mg.
• Inability to complete treatment within 16 weeks of the first dose.
• Severe intestinal inflammation (grade 3-4 colitis) and serious lung inflammation (grade 3-4 pneumonitis).
• Severely abnormal liver tests (SGOT/SGPT >5 times the upper limit or total bilirubin >3 times the upper limit).
• Severe kidney inflammation and failure (grade 4 nephritis) or severe heart inflammation (grade 2, 3, or 4 myocarditis).
• Stevens-Johnson syndrome, toxic epidermal necrolysis, or severe rashes with deep ulcers/blisters.
• Severe neurological disorders (Guillain-Barré syndrome or myasthenia gravis).
• Serious immune-mediated reactions affecting any organ or eye disease that does not respond to local treatment.

Temporarily Withholding Ipilimumab:

Treatment is withheld for moderate immune-mediated side effects and significant hormonal problems (endocrinopathies). It may resume every 3 weeks once symptoms improve and the prednisone dose has been reduced.

Managing Intestinal and Eye Problems:

• Intestines: For moderate inflammation, withhold treatment and start prednisone at 0.5 mg/kg. For severe inflammation, discontinue treatment permanently and administer prednisone at 1-2 mg/kg/day.
• Eyes: Use steroid eye drops if uveitis or iritis develops. If local treatment fails, discontinue the medicine and start systemic prednisone.

• Infusion reactions
• Immune-related enterocolitis (diarrhea, abdominal pain)
• Hepatotoxicity
• Dermatological reactions
• Endocrinopathies (hypophysitis, hypothyroidism)
• Neurotoxicity (Guillain-Barré-like)
• Cardiac toxicity (myocarditis)
• Renal toxicity (nephritis)

Other Recommendations: Thyroid function tests should be performed before treatment and before each dose. Its pregnancy category is C; it should not be used during pregnancy or breastfeeding.