Yervoy (Ipilimumab)
ipilimumab — fully human IgG1 anti-CTLA-4 monoclonal antibody
Indications
Ipilimumab was the first immune checkpoint inhibitor approved by the FDA (March 2011), establishing the paradigm of checkpoint blockade in oncology. As a CTLA-4 inhibitor, it acts at the T-cell priming stage rather than at the tumour microenvironment level targeted by PD-1/PD-L1 agents. Ipilimumab is used as monotherapy only in melanoma; all other indications require combination with nivolumab. The dose of ipilimumab varies significantly by indication (3 mg/kg or 1 mg/kg), with correspondingly different toxicity profiles.
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Unresectable / metastatic melanoma | Adults + paediatric ≥12 years | Monotherapy OR + nivolumab | FDA Approved |
| Adjuvant melanoma | Adults (node+ >1 mm, post-complete resection + lymphadenectomy) | Monotherapy | FDA Approved |
| Advanced RCC (intermediate/poor risk, 1L) | Adults | + nivolumab | FDA Approved |
| MSI-H / dMMR metastatic CRC | Adults + paediatric ≥12 years | + nivolumab | FDA Approved |
| HCC — first-line | Adults (unresectable or metastatic) | + nivolumab | FDA Approved |
| HCC — post-sorafenib | Adults (unresectable or metastatic, previously treated with sorafenib) | + nivolumab | FDA Approved |
| Metastatic NSCLC (PD-L1 ≥1%, 1L) | Adults (no EGFR/ALK) | + nivolumab | FDA Approved |
| Metastatic / recurrent NSCLC (1L) | Adults (no EGFR/ALK) | + nivolumab + 2 cycles platinum-doublet chemo | FDA Approved |
| Malignant pleural mesothelioma (1L) | Adults (unresectable) | + nivolumab | FDA Approved |
| ESCC (1L, PD-L1 ≥1) | Adults (unresectable advanced or metastatic) | + nivolumab | FDA Approved |
Ipilimumab dosing is critically indication-dependent: melanoma and HCC use the higher 3 mg/kg dose (with nivolumab at 1 mg/kg), while RCC, CRC, NSCLC, mesothelioma, and ESCC use the lower 1 mg/kg dose (with nivolumab at 3 mg/kg or 360 mg flat dose). This dosing asymmetry directly influences the toxicity profile, with the 3 mg/kg ipilimumab regimen carrying substantially higher rates of immune-mediated colitis, hepatitis, and rash.
Adjuvant melanoma at 10 mg/kg: The original adjuvant melanoma approval (2015, EORTC 18071) used 10 mg/kg. The E1609 trial subsequently demonstrated that 3 mg/kg was equally effective and less toxic than 10 mg/kg. The current PI (May 2025) lists 3 mg/kg as the recommended adjuvant dose. Some institutions may still reference the historical 10 mg/kg dose. Evidence quality: high for 3 mg/kg.
Dosing
Ipilimumab is always dosed by weight (mg/kg). The dose is either 3 mg/kg or 1 mg/kg depending on the indication and combination partner. No dose reductions are recommended. All infusions are given over 30 minutes. When combined with nivolumab, nivolumab is infused first, followed by ipilimumab on the same day.
Monotherapy Indications
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Unresectable / metastatic melanoma (monotherapy) | 3 mg/kg Q3W | N/A (fixed course) | 4 doses total | Maximum of 4 doses. No maintenance phase. Original CTLA-4 monotherapy regimen. |
| Adjuvant melanoma (post-resection, node+ >1 mm) | 3 mg/kg Q3W (4 doses) | 3 mg/kg Q12W (up to 4 additional doses) | 8 doses total | Induction: 4 doses Q3W. Maintenance: up to 4 doses Q12W. PI revised May 2025 from historical 10 mg/kg to 3 mg/kg based on E1609 data |
Combination Regimens (Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Unresectable / metastatic melanoma (+ nivolumab) | Ipi 3 mg/kg + nivo 1 mg/kg Q3W | Nivolumab mono (per nivo PI) | 4 combo doses | After 4 combo doses, continue nivolumab as monotherapy until progression. Higher toxicity regimen. Paediatric ≥12 yr: same dosing |
| HCC first-line or post-sorafenib (+ nivolumab) | Ipi 3 mg/kg + nivo 1 mg/kg Q3W | Nivolumab mono (per nivo PI) | 4 combo doses | Same high-dose ipi regimen as melanoma. After up to 4 combo doses, continue nivolumab mono. |
Combination Regimens (Ipilimumab 1 mg/kg + Nivolumab)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Advanced RCC (intermediate/poor risk, 1L) | Ipi 1 mg/kg + nivo 3 mg/kg Q3W | Nivolumab mono (per nivo PI) | 4 combo doses | Intermediate or poor risk per IMDC criteria only. After 4 combo doses, continue nivo mono. |
| MSI-H / dMMR metastatic CRC (+ nivolumab) | Ipi 1 mg/kg + nivo 240 mg Q3W (≥40 kg) or nivo 3 mg/kg (<40 kg) | Nivolumab mono (up to 2 years) | 4 combo doses | Paediatric ≥12 yr eligible. After combo, nivo mono until progression, toxicity, or 2 years. |
| Metastatic NSCLC (PD-L1 ≥1%, + nivolumab) | Ipi 1 mg/kg Q6W + nivo 360 mg Q3W | Same (ipi Q6W ongoing) | Up to 2 years | No EGFR/ALK. PD-L1 ≥1% by FDA-approved test. Ipi continues Q6W (not limited to 4 doses). |
| Metastatic / recurrent NSCLC (+ nivo + chemo) | Ipi 1 mg/kg Q6W + nivo 360 mg Q3W + 2 cycles platinum-doublet | Ipi Q6W + nivo Q3W (ongoing) | Up to 2 years | No EGFR/ALK. Any PD-L1 status. Only 2 cycles of chemo. Ipi continues Q6W ongoing. |
| Malignant pleural mesothelioma (1L, + nivolumab) | Ipi 1 mg/kg Q6W + nivo 360 mg Q3W | Same | Up to 2 years | Unresectable. Continue until progression, toxicity, or 2 years. |
| ESCC (1L, PD-L1 ≥1, + nivolumab) | Ipi 1 mg/kg Q6W + nivo 3 mg/kg Q2W or 360 mg Q3W | Same | Up to 2 years | Unresectable advanced or metastatic. PD-L1 ≥1 (scoring method not specified in PI). FDA-approved companion diagnostic not yet available for ESCC PD-L1 testing. |
Ipilimumab’s dosing falls into two distinct paradigms with dramatically different toxicity profiles. The 3 mg/kg ipi + 1 mg/kg nivo regimen (melanoma, HCC) is a high-CTLA-4-dose schedule that produces higher rates of colitis (25%), hepatitis (15%), and overall Grade 3–4 irAEs (~59%). The 1 mg/kg ipi + 3 mg/kg nivo (or flat dose nivo) regimen (RCC, CRC, NSCLC, mesothelioma, ESCC) has markedly lower GI and hepatic toxicity. Furthermore, the NSCLC/mesothelioma/ESCC regimens use ipilimumab Q6W (not Q3W) and continue ipilimumab beyond 4 doses, in contrast to the limited 4-dose Q3W schedule used in melanoma, RCC, CRC, and HCC.
Pharmacology
Mechanism of Action
Ipilimumab is a fully human IgG1 monoclonal antibody that blocks CTLA-4, a negative regulator of T-cell activation. CTLA-4 competes with the co-stimulatory receptor CD28 for binding to B7 ligands (CD80/CD86) on antigen-presenting cells. By blocking this competitive inhibition, ipilimumab enhances T-cell activation, proliferation, and anti-tumour immune responses at the priming stage of the immune response, which occurs in lymph nodes rather than at the tumour site.
This mechanism distinguishes CTLA-4 inhibitors from PD-1/PD-L1 agents, which act at the effector phase within the tumour microenvironment. CTLA-4 blockade also reduces T-regulatory cell function, contributing to broader immune activation. The combination of ipilimumab with nivolumab provides complementary checkpoint blockade across both the priming and effector phases, producing higher response rates but also significantly higher toxicity than either agent alone.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | IV route: 100% bioavailability. Linear PK in 0.3–10 mg/kg range. Accumulation ≤1.5-fold with Q3W dosing. | Weight-based dosing appropriate. No flat-dose option approved (unlike nivolumab). |
| Distribution | Primarily extracellular fluid. Biphasic elimination: distribution t½α ~27.4 hours. | CL increases with body weight and baseline LDH, but no dose adjustment needed with mg/kg dosing. |
| Metabolism | Catabolised by non-specific proteolytic pathways. Not metabolised by CYP450 enzymes. | No hepatic CYP drug interactions. No formal PK interaction studies conducted. |
| Elimination | Terminal t½ = 15.4 days (CV 34%). CL = 16.8 mL/h (CV 38%). Time-invariant (unlike PD-1/PD-L1 agents). Steady state by 3rd dose (Q3W). | Shorter half-life than nivolumab (25 days) or atezolizumab (27 days). Clearance does not change over time, reflecting CTLA-4’s T-cell priming target rather than tumour-associated targets. ADA: 1.1% (mono) with no clinically significant impact. |
Side Effects
Ipilimumab carries the highest immune-mediated adverse reaction (irAE) burden among approved checkpoint inhibitors. Toxicity is critically dose-dependent: the 3 mg/kg regimen (melanoma, HCC) produces substantially more colitis, hepatitis, and dermatitis than the 1 mg/kg regimen (RCC, CRC, NSCLC). All rates below are from the FDA PI (revised May 2025).
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Fatigue | 20–40% | Universal across all regimens. Exclude endocrine causes (hypophysitis, adrenal insufficiency, hypothyroidism). |
| Diarrhoea / colitis | 12% (mono 3 mg/kg); 9% (1 mg/kg + nivo); 25% (3 mg/kg + nivo) | Defining CTLA-4 toxicity. Grade 3–5 in 7% (mono), 4.4% (1 mg/kg combo), 14% (3 mg/kg combo). Fatal colitis reported. |
| Rash / pruritus | 15–28% | 15% immune-mediated rash (mono); 16% (1 mg/kg + nivo); 28% (3 mg/kg + nivo). Includes bullous and exfoliative dermatitis. |
| Nausea | 20–35% | Higher with chemotherapy-containing regimens (NSCLC + chemo). |
| Hypothyroidism | 18–20% | 18% with 1 mg/kg + nivo (RCC/CRC); 20% with 3 mg/kg + nivo (melanoma/HCC). Requires long-term levothyroxine. |
| Decreased appetite | 20–25% | Higher with nivolumab combinations. Exclude adrenal insufficiency. |
| Musculoskeletal pain | 20–30% | With nivolumab combinations. Includes arthralgia, myalgia, back pain. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Immune-mediated hepatitis | 4.1% (mono); 7% (1 mg/kg + nivo); 15% (3 mg/kg + nivo) | Dramatically dose-dependent. Grade 3–4 in 1.6% (mono), 6.1% (1 mg/kg combo), 13.4% (3 mg/kg combo). Grade 4 (life-threatening) in 2.4% of 3 mg/kg combo patients. |
| Hyperthyroidism | 12% (1 mg/kg + nivo); 9% (3 mg/kg + nivo) | Monotherapy endocrinopathies 4% total (specific hyperthyroidism rate not reported separately). Often transient, preceding hypothyroidism. Thyroiditis in 2.7% with combo. |
| Immune-mediated pneumonitis | Not reported (mono); 3.9% (1 mg/kg + nivo); 7% (3 mg/kg + nivo); 9% (NSCLC) | Pneumonitis is primarily a nivolumab-related toxicity, but rates increase with ipi combination. Fatal pneumonitis 0.7% in NSCLC combination. |
| Hypophysitis | 1.8% (mono); 4.4% (1 mg/kg + nivo); 9% (3 mg/kg + nivo) | CTLA-4-characteristic toxicity. Can cause adrenal insufficiency, hypogonadism, hypothyroidism. Often requires lifelong hormone replacement. |
| Adrenal insufficiency | 7% (1 mg/kg + nivo); 8% (3 mg/kg + nivo) | May be secondary to hypophysitis. ~94% require lifelong hormone replacement. |
| Immune-mediated nephritis | 4.1% (1 mg/kg + nivo) | Grade 3–4 in 1.7%. Monitor creatinine before each dose. |
| Infusion-related reactions | 0.6% (mono); 5% (1 mg/kg + nivo); 8% (3 mg/kg + nivo HCC); 12% (mesothelioma) | Rates vary by regimen. Higher with mesothelioma combination. |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Immune-mediated colitis (Grade 3–5) | 7% (mono); 14% (3 mg/kg combo) | 5–10 weeks after first dose | Withhold for Grade 2; permanently discontinue for Grade 3–4. High-dose corticosteroids. Infliximab for steroid-refractory (23% of combo patients). CMV testing for refractory cases. |
| Immune-mediated hepatitis (Grade 3–4) | 1.6% (mono); 13.4% (3 mg/kg combo) | 3–9 weeks | Withhold for AST/ALT >3–5× ULN; permanently discontinue >5× ULN. Mycophenolate for steroid-refractory. |
| Hypophysitis | 9% (3 mg/kg combo) | 6–12 weeks | Withhold or discontinue based on severity. High-dose corticosteroids. Hormone replacement usually lifelong (86% in 3 mg/kg combo). |
| Immune-mediated pneumonitis (fatal) | 0.7% fatal (NSCLC combo) | Variable | Withhold for Grade 2; permanently discontinue for Grade 3–4. High-dose corticosteroids. |
| Myocarditis | Rare (<1%); potentially fatal | First 1–3 cycles | Permanently discontinue for Grade 2–4. Immediate high-dose corticosteroids. Cardiology consultation. |
| Severe dermatologic reactions (SJS, TEN, DRESS) | Rare (<1%) | Days to weeks | Withhold for suspected; permanently discontinue if confirmed. |
| Neurological toxicity (GBS, myasthenia, encephalitis) | Autoimmune neuropathy 2%; other <1% | Variable | Withhold for Grade 2; permanently discontinue for Grade 3–4. |
Colitis is the signature ipilimumab toxicity, occurring in up to 25% of patients receiving the 3 mg/kg combination regimen (Grade 3–4 in 14%). Onset is typically 5–10 weeks after the first dose but can occur after any dose. Approximately 23% of patients with colitis in the combination setting require infliximab in addition to high-dose corticosteroids. CMV reactivation should be excluded in steroid-refractory cases. Unlike PD-1/PD-L1 inhibitors, where colitis occurs in 1–3%, CTLA-4-driven colitis is more frequent, more severe, and more likely to require biological immunosuppression.
Drug Interactions
No formal pharmacokinetic drug interaction studies have been conducted with ipilimumab. As a monoclonal antibody cleared by protein catabolism, metabolic drug interactions through CYP enzymes are not expected. Ipilimumab clearance is unchanged in the presence of anti-ipilimumab antibodies.
Monitoring
- Liver Function (AST, ALT, bilirubin)Baseline and before each dose
RoutineHepatitis occurs in 4–15% depending on dose. Monitor more frequently during the combination phase (first 12 weeks). Higher thresholds for patients with hepatic tumour involvement. - Renal Function (creatinine)Baseline and before each dose
RoutineNephritis in up to 4.1% with combination therapy. Withhold for Grade 2–3; permanently discontinue for Grade 4. - Thyroid Function (TSH, free T4)Baseline and before each dose
RoutineHypothyroidism 18–20%, hyperthyroidism 9–12% with combinations. Most hypothyroidism requires lifelong replacement. - ACTH / CortisolBaseline and before each dose
RoutineHypophysitis is a characteristic CTLA-4 toxicity (up to 9%). Adrenal insufficiency 7–8%. ACTH monitoring at baseline and before each dose per PI. - GI AssessmentBefore each dose; urgently if diarrhoea develops
Trigger-basedColitis in 12–25%. Any diarrhoea ≥4 stools/day over baseline warrants urgent evaluation. Consider stool studies for C. difficile and CMV. - Ophthalmologic AssessmentIf visual symptoms develop
Trigger-basedUveitis, iritis, episcleritis reported. Permanently discontinue for Grade 2–4 not improving within 2 weeks of topical therapy. Consider Vogt-Koyanagi-Harada-like syndrome if combined with other irAEs. - Blood GlucosePeriodically
Trigger-basedType 1 diabetes in 2.7% with combo. May present as DKA.
Contraindications & Cautions
Absolute Contraindications
The FDA PI lists no absolute contraindications for ipilimumab.
Relative Contraindications (Specialist Input Recommended)
- Active, severe autoimmune disease (particularly IBD): risk of life-threatening flare. Trial exclusion criterion.
- Prior organ transplantation: high risk of allograft rejection and fatal GVHD.
- Prior life-threatening irAE from any CTLA-4 or PD-1/PD-L1 inhibitor.
- Pregnancy or planned pregnancy: can cause fetal harm. Contraception required during treatment and for 3 months after last dose.
- Baseline transaminases ≥5× ULN or bilirubin >3× ULN: PI advises caution; hepatitis risk is dose-dependent and can be fatal.
Use with Caution
- Controlled autoimmune conditions: elevated flare risk; close monitoring required.
- Concurrent vemurafenib: hepatotoxicity observed in 60% of patients in dose-finding trial. Do not use concurrently.
Ipilimumab can cause severe and fatal immune-mediated colitis, hepatitis, dermatologic reactions, endocrinopathies, pneumonitis, nephritis, and neurological toxicities. In the 3 mg/kg monotherapy setting for melanoma, Grade 3–5 immune-mediated reactions occurred in 15% of patients. In the 3 mg/kg + nivolumab combination for melanoma, Grade 3–4 irAEs occurred in approximately 59% of patients. Fatal GVHD and other serious complications can occur in patients who receive allogeneic HSCT before or after ipilimumab treatment.
Patient Counselling
Purpose of Therapy
Ipilimumab is an immunotherapy that boosts the immune system’s ability to fight cancer by removing a natural brake on immune cells called CTLA-4. It is often given together with nivolumab (another immunotherapy) to provide two complementary ways of activating the immune system against the tumour.
How to Take
Ipilimumab is given by intravenous infusion over 30 minutes. When combined with nivolumab, nivolumab is given first, followed by ipilimumab on the same day. Treatment schedules vary by cancer type, but typically involve receiving ipilimumab for a limited number of doses (usually 4), after which nivolumab may continue alone.
Sources
- Bristol-Myers Squibb. YERVOY (ipilimumab) injection, for intravenous use. Full Prescribing Information. Revised 05/2025. BMS.comPrimary source for all dosing, indications, adverse reactions, and warnings in this monograph.
- Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–723. doi:10.1056/NEJMoa1003466MDX010-20: landmark trial establishing ipilimumab 3 mg/kg as the first checkpoint inhibitor to improve OS in metastatic melanoma.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535–1546. doi:10.1056/NEJMoa1910836CheckMate-067 5-year update: ipi 3 mg/kg + nivo 1 mg/kg achieved 52% 5-year OS in advanced melanoma.
- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–1290. doi:10.1056/NEJMoa1712126CheckMate-214: basis for ipi 1 mg/kg + nivo 3 mg/kg in intermediate/poor risk RCC.
- Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773–779. doi:10.1200/JCO.2017.76.9901CheckMate-142: basis for ipi + nivo in MSI-H/dMMR mCRC.
- Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 2020;6(11):e204564. doi:10.1001/jamaoncol.2020.4564CheckMate-040: basis for ipi 3 mg/kg + nivo 1 mg/kg in previously treated HCC.
- Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020–2031. doi:10.1056/NEJMoa1910231CheckMate-227: basis for ipi 1 mg/kg Q6W + nivo in PD-L1≥1% NSCLC.
- Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743). Lancet. 2021;397(10272):375–386. doi:10.1016/S0140-6736(20)32714-8CheckMate-743: basis for ipi 1 mg/kg Q6W + nivo in malignant pleural mesothelioma.
- Tarhini AA, Lee SJ, Hodi FS, et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J Clin Oncol. 2020;38(6):567–575. doi:10.1200/JCO.19.01381E1609: demonstrated adjuvant ipi 3 mg/kg superior OS vs HDI with less toxicity than ipi 10 mg/kg, supporting the May 2025 PI dose revision.
- NCCN Clinical Practice Guidelines in Oncology. Melanoma: Cutaneous. Version 3.2026. NCCN.orgIncorporates ipi + nivo as preferred first-line therapy for advanced melanoma; notes adjuvant ipi role diminished by PD-1 inhibitors.
- Brahmer JR, Abu-Sbeih H, Ascierto PA, et al. SITC clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6):e002435. doi:10.1136/jitc-2021-002435Comprehensive irAE management guidelines with specific CTLA-4 toxicity sections for colitis, hepatitis, and hypophysitis.
- Feng Y, Roy A, Masson E, et al. Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma. Br J Clin Pharmacol. 2014;78(1):106–117. doi:10.1111/bcp.12323Definitive population PK model establishing two-compartment PK, linear and time-invariant clearance, and covariate effects (body weight, LDH) on ipilimumab exposure.