Ipilimumab (Yervoy) and Nivolumab (Opdivo) Treatment Regimen

What Are Ipilimumab and Nivolumab?

Ipilimumab and nivolumab are two different immune checkpoint inhibitors used to strengthen the immune system and enhance the immune response against tumor cells.

• Ipilimumab is a CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) inhibitor.
• Nivolumab is a PD-1 (programmed death-1) receptor inhibitor.

These drugs are generally given in combination to create a synergistic immune response.

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Mechanism of Action

Ipilimumab (CTLA-4 Inhibitor)

• Acts during the early phase of T-cell activation.
• CTLA-4 is a receptor on the T-cell surface that inhibits costimulatory signals, halting the immune response.
• By inhibiting CTLA-4, ipilimumab allows T cells to activate and proliferate.
• This brings more antitumor T cells into circulation.

Nivolumab (PD-1 Inhibitor)

• Helps T cells maintain activity in peripheral tissues, particularly the tumor microenvironment.
• PD-1 is present on activated T cells and suppresses the cell when it interacts with its ligand PD-L1.
• By inhibiting PD-1, nivolumab protects T cells from apoptosis or inactivation in the tumor microenvironment.

The Combination's Synergistic Effect

• Ipilimumab increases T-cell proliferation in lymph nodes, while
• Nivolumab keeps these cells effective in peripheral tissues (the tumor site).
• This dual immune response may produce greater tumor regression than monotherapy.

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Indications

Malignant Melanoma

• Indication: used for stage III (unresectable) and stage IV (metastatic) melanoma.
• Clinical basis: CheckMate-067 showed that ipilimumab + nivolumab was superior to nivolumab or ipilimumab monotherapy in progression-free survival (PFS) and overall survival (OS).
• Treatment goal: reduce tumor burden, prolong survival, and achieve a long-term immune response.

Renal Cell Carcinoma (Kidney Cancer)

• Indication: used first line in newly diagnosed metastatic renal cell carcinoma (RCC), particularly patients with intermediate or poor IMDC risk scores.
• Clinical basis: CheckMate-214 showed that ipi+nivo provided a survival advantage and a higher objective response rate.

Non-Small Cell Lung Cancer

• Indications: as a chemotherapy-free combination in stage IV patients with tumor PD-L1 expression ≥1%.
• CheckMate-9LA regimen: ipilimumab + nivolumab combined with short-course chemotherapy (2 platinum-based cycles).
• Clinical basis: CheckMate-227 and CheckMate-9LA showed a survival advantage for this combination, particularly in patients with high PD-L1 expression.
• Treatment goal: avoid chemotherapy or enhance the early immune response.

Malignant Pleural Mesothelioma

• Indication: first-line treatment in newly diagnosed, unresectable malignant pleural mesothelioma.
• Clinical basis: CheckMate-743 showed longer overall survival with this combination than with platinum-based chemotherapy.
• Note: greater benefit was seen particularly in epithelial histology.

Colorectal Cancer (MSI-H / dMMR)

• Indication: first-line treatment for metastatic colorectal cancer with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR).
• Clinical basis: CheckMate-142 found a high objective response rate (ORR) and durable duration of response (DOR) with ipi+nivo.
• Treatment goal: enhance the immune response and achieve disease control as an alternative to chemotherapy.

Hepatocellular Carcinoma (HCC)

• Indication: second or later lines in progressive HCC after previous systemic treatment (e.g., sorafenib).
• Clinical basis: received accelerated FDA approval through CheckMate-040.
• Note: the combination is particularly preferred in patients with good liver function, especially Child-Pugh A.

Endometrial Cancer (MSI-H / dMMR)

• Indication: advanced or recurrent endometrial cancer with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H).
• Clinical basis: although less widespread than pembrolizumab + lenvatinib, ipilimumab + nivolumab is also included as an alternative in studies.
• Status: an NCCN-recommended indication that, due to limited data, remains mostly within clinical trials.

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Dosing Intervals

Malignant Melanoma

Induction phase (4 cycles):

• Nivolumab: 1 mg/kg IV, every 3 weeks
• Ipilimumab: 3 mg/kg IV, every 3 weeks

Maintenance phase:

• Nivolumab: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks (up to 12 months)

 Preferred Patient Profile:

• Young patients with good performance status (ECOG 0–1)
• Extensive visceral metastases requiring a rapid response
• Melanomas with high tumor burden
• Brain metastases (under certain conditions)

Renal Cell Carcinoma (mRCC)

Induction (4 cycles):

• Nivolumab: 3 mg/kg IV, every 3 weeks
• Ipilimumab: 1 mg/kg IV, every 3 weeks

Maintenance:

• Nivolumab: 240 mg IV every 2 weeks or 480 mg IV every 4 weeks

Preferred Patient Profile:

• IMDC score: Intermediate or Poor risk (≥1 risk factor)
• Long life expectancy, good performance status (ECOG 0–1)
• No previous cytokine treatment (interferon, etc.)
• Visceral metastases with a rapid response expected

NSCLC (Metastatic Lung Cancer)

a) CheckMate-227 protocol (for patients with PD-L1 ≥ 1%):

• Nivolumab: 3 mg/kg IV, every 2 weeks
• Ipilimumab: 1 mg/kg IV, every 6 weeks

b) CheckMate-9LA protocol (chemotherapy + immunotherapy):

• 2 cycles of platinum-based chemotherapy +
• Nivolumab: 360 mg IV, every 3 weeks
• Ipilimumab: 1 mg/kg IV, every 6 weeks

Preferred Patient Profile:

• PD-L1 expression ≥1% (if unsuitable for chemotherapy)
• NSCLC patients without genetic mutations (such as EGFR, ALK)
• Particularly an aggressive clinical course requiring a rapid response (CheckMate-9LA option)
• Good performance status suitable for immunotherapy (ECOG 0–1)

Malignant Pleural Mesothelioma

• Nivolumab: 3 mg/kg IV, every 2 weeks
• Ipilimumab: 1 mg/kg IV, every 6 weeks
• Treatment duration: 2 years or until disease progression

Preferred Patient Profile:

• Epithelial histology (better response)
• Young or middle-aged, good performance status
• Unwilling or unable to tolerate chemotherapy
• Noncirrhotic patients with adequate lung function

Colorectal Cancer (MSI-H/dMMR)

Induction (4 cycles):

• Nivolumab: 3 mg/kg IV, every 2 weeks
• Ipilimumab: 1 mg/kg IV, every 6 weeks

Maintenance:

• Nivolumab alone, every 2 or 4 weeks, until progression

Preferred Patient Profile:

• Metastatic cases with MSI-H or dMMR tumor biology
• No previous chemotherapy or unsuitable for chemotherapy
• High immune response potential without rapid progression
• Good performance status, no inflammatory bowel disease

Hepatocellular Carcinoma (HCC)

Dosing Schedule: (CheckMate-040 protocol)

• Ipilimumab: 3 mg/kg IV, every 3 weeks (4 doses total)
• Nivolumab: 1 mg/kg IV, every 3 weeks (throughout induction)

Maintenance:

• Nivolumab 240 mg IV every 2 weeks

Preferred Patient Profile:

• Patients with Child-Pugh A liver function
• Progression after sorafenib or lenvatinib
• ECOG 0–1, active hepatitis B/C suppressed
• No or limited portal vein thrombosis

Endometrial Cancer (MSI-H/dMMR)

Dosing Schedule (in clinical trials):

• Nivolumab: 240 mg IV every 2 weeks
• Ipilimumab: 1 mg/kg IV every 6 weeks

(Treatment continues until disease progression or toxicity)

Preferred Patient Profile:

• MSI-H or dMMR molecular profile
• Progression after chemotherapy
• No response to hormone therapy
• Good performance status, no history of autoimmune disease

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Patients in Whom the Combination Should Not Be Preferred

• Active autoimmune disease (e.g., lupus, rheumatoid arthritis, inflammatory bowel disease)
• Organ transplant recipients (risk of rejection)
• ECOG ≥ 2 (poor performance status)
• History of a serious immune-related adverse effect

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SGK Reimbursement 

In Türkiye, SGK (Social Security Institution) reimburses it for 4 indications.

Malignant Melanoma (First Line) 

• Unresectable locally advanced or metastatic
• ECOG 0-1 
• A maximum of 4 ipilimumab doses is covered. 
• Repeat immunotherapy after progression is not reimbursed. 

Renal Cell Carcinoma (Kidney Cancer) – First Line

• Metastatic renal cell carcinoma 
• IMDC intermediate/poor risk, Karnofsky 70 or above 
• Ipilimumab, maximum 4 doses (1 mg/kg, 1 cycle every 3 weeks)
• Repeat immunotherapy after progression is not reimbursed. 

Nonepithelioid Pleural Mesothelioma – First Line

• Unresectable locally advanced/metastatic 
• Use is reimbursed for up to 24 months in patients without disease progression or unacceptable toxicity.
• Repeat immunotherapy after progression is not reimbursed.

Non-Small Cell Lung Cancer (PD-L1 < 50%) – First Line

• In metastatic disease 
• Combination with 2 cycles of platinum-based chemotherapy
• If PD-L1 testing cannot be performed, reimbursement is provided with documentation.
• A maximum of 24 months 
• In nonsquamous metastatic non-small cell lung cancer, the report must state the absence of EGFR, ALK, and ROS mutations.
• EGFR, ALK, and ROS testing is not required in the squamous cell subtype. 
• Cannot be reused after adjuvant treatment.

Price: As of July 2025: Opdivo 100 mg vial: 38,053.16 TL, Opdivo 40 mg vial: 15,221.26 TL, Yervoy 200 mg vial: 310,837.43 TL, Yervoy 50 mg vial: 77,792.05 TL. 

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Points Requiring Attention

Immune-Related Adverse Effects

During this treatment, the immune system may attack normal tissues as well as the tumor. Immune-mediated toxicities affecting organ systems must therefore be recognized and managed early:

Criteria for Treatment Delay or Discontinuation

• For Grade ≥2 immune-related adverse effects, treatment is generally withheld and corticosteroids started.
• Grade 3–4 toxicity: immunotherapy may be permanently discontinued.
• For example, continuing treatment with grade 3 colitis can cause serious complications.

History of Autoimmune Disease

• In people with active or uncontrolled autoimmune disease (such as lupus, MS, rheumatoid arthritis), this treatment can cause severe flares.
• Before deciding, the patient should be assessed with relevant specialties such as rheumatology or neurology.

Organ Transplant Recipients

• It carries a high rejection risk in solid organ transplant recipients (liver, kidney, etc.).
• PD-1/PD-L1 inhibitors in particular may cause graft loss. Use is generally contraindicated in this group.

Cardiac and Pulmonary Risks

• Pre-existing pneumonia, COPD, cardiomyopathy, and similar conditions increase pulmonary toxicity risk.
• Immune-mediated myocarditis is rare but may be fatal. Early diagnosis is lifesaving.

Laboratory Monitoring

Regular laboratory monitoring is essential throughout treatment:

• AST/ALT, bilirubin — before every cycle
• TSH, fT4, cortisol — 1 time a month or if symptoms occur
• Creatinine — before every cycle
• Complete blood count — before every cycle

Steroid Use and Nonresponse

• Second-line immunosuppressive agents (e.g., infliximab, mycophenolate mofetil) may be used for steroid-refractory toxicity.
• Delaying these drugs can cause serious complications (e.g., bowel perforation, respiratory failure).

Patient Education and Information

• Clearly explain to patients that they are receiving "a treatment that activates the immune system, not chemotherapy."
• Do not dismiss symptoms such as fever, diarrhea, rash, weakness, blurred vision, or headache; seek medical attention immediately.

Pregnancy and Fertility

• Both agents are teratogenic in pregnancy. Effective contraception is recommended during treatment and for at least 5 months afterward.
• Use during breastfeeding is contraindicated.

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Immune-Related Adverse Effects

By strengthening the body's immune system, ipilimumab + nivolumab may generate an immune response targeting healthy tissues as well as tumor cells. Immune-mediated toxicity can therefore affect many organ systems.

The most common immune-related adverse effects requiring clinical attention are:

• Skin toxicities are among the earliest and most common adverse effects. Rash, itching, dryness, vitiligo, and eczema-like lesions are common. Symptomatic treatment (antihistamines, topical steroids) may suffice in mild cases, while widespread rash or severe itching may require systemic steroids.
• Gastrointestinal toxicities are particularly common with ipilimumab. Diarrhea, abdominal pain, and bloody stools may develop, indicating immune-mediated colitis; above grade 2, systemic steroids are required. Untreated cases may lead to serious complications such as bowel perforation.
• Hepatic toxicities appear as immune-mediated hepatitis. Usually asymptomatic, they are detected as raised AST, ALT, and/or bilirubin on routine liver function tests. With severe elevations, immunotherapy is stopped and steroids started. Mycophenolate mofetil may be used in resistant cases.
• Endocrine adverse effects appear as autoimmune endocrinopathies such as hypophysitis (pituitary inflammation), thyroiditis, and adrenalitis. Hypophysitis may cause headache, weakness, hypotension, and nausea. Thyroiditis generally progresses from hyperthyroidism to hypothyroidism. Adrenal insufficiency requires hydrocortisone replacement. These effects are usually permanent and may require lifelong hormone replacement.
• Pulmonary toxicity generally takes the form of immune-mediated pneumonitis, with dyspnea, dry cough, and reduced oxygen saturation. Particular caution is needed in patients with pre-existing lung disease. Lung CT may show widespread infiltrates. In Grade 2 or higher cases, treatment should be stopped immediately and high-dose steroids started.
• Neurological toxicities are rare but may have serious consequences. They may present as peripheral neuropathy, myasthenia gravis-like muscle weakness, encephalitis, or aseptic meningitis. They require early diagnosis and intensive immunosuppression.
• Renal toxicity is uncommon and usually recognized through elevated creatinine. Immune-mediated interstitial nephritis should be considered. Corticosteroids are given in moderate or severe cases.
• Ocular toxicities such as uveitis, iritis, and blurred vision have rarely been reported as immune reactions. Ophthalmological assessment and topical or systemic steroids may be needed.

Thus, ipilimumab + nivolumab may cause immune-mediated toxicity in many systems. Although initially presenting with mild symptoms, these effects can progress to serious or fatal complications if not recognized and treated promptly. Multidisciplinary monitoring, patient education, and early intervention are therefore vital.

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Adverse Effects

Below are adverse effects and their reported percentages during ipilimumab + nivolumab combination immunotherapy in clinical trials and real-world data. Frequencies are based on pooled data from tumor types such as melanoma, RCC, and NSCLC:

• Fatigue: 37%
• Diarrhea: 32%
• Itching (pruritus): 30%
• Rash: 29%
• Nausea: 24%
• Loss of appetite (anorexia): 22%
• Hypothyroidism: 18%
• Elevated liver enzymes (AST/ALT): 16%
• Hypophysitis: 12%
• Hyperthyroidism: 11%
• Colitis: 10%
• Vomiting: 10%
• Nephritis (elevated creatinine): 9%
• Headache: 9%
• Pneumonitis: 8%
• Joint pain (arthralgia): 8%
• Myalgia (muscle pain): 7%
• Urticaria: 6%
• Fever (pyrexia): 6%
• Infections (particularly upper respiratory): 5%
• Encephalitis and neurological disorders: 2%
• Adrenal insufficiency: 2%
• Myocarditis: <1%
• Stevens-Johnson syndrome / toxic epidermal necrolysis: <1%

These rates may vary with dose, dosing interval, and the patient's individual immune response. Because most adverse effects are immune-mediated, they can often be reversed through early diagnosis and appropriate immunosuppression.