Side Effects of Yervoy (ipilimumab)

Yervoy (ipilimumab) is a monoclonal antibody used to treat a kind of skin cancer called melanoma. 

Yervoy may be used in adults and children 12 years of age and older when melanoma has spread or cannot be removed by surgery; to help prevent melanoma from coming back after it, and lymph nodes that contain cancer, have been removed by surgery; and in people with kidney cancer (renal cell carcinoma). 

Yervoy may be used in combination with nivolumab in certain people when their cancer has spread: in adults and children 12 years of age and older, with a type of colon or rectal cancer (colorectal cancer). 

Yervoy in combination with nivolumab may be used when your colon or rectal cancer: has spread to other parts of the body (metastatic); is microsatellite stability-high (MSI-H) or mismatch repair deficient (dMMR); and you have tried treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working. 

It is not known if Yervoy is safe and effective in children younger than 12 years of age.

Common side effects of Yervoy include

• feeling tired,
• diarrhea,
• nausea,
• itching,
• rash,
• vomiting,
• headache,
• weight loss,
• fever,
• decreased appetite, and
• difficulty falling or staying asleep.

Common side effects of Yervoy when used in combination with nivolumab include the above and

• pain in muscles/bones/joints,
• abdominal pain,
• cough, and
• shortness of breath.

Serious side effects of Yervoy include

• colitis,
• liver problems that can lead to liver failure,
• skin problems that can lead to severe skin reaction,
• nerve problems that can lead to paralysis,
• hormone gland problems (especially the pituitary, adrenal, and thyroid glands),
• pneumonitis,
• kidney problems,
• encephalitis,
• eye problems, and
• severe infusion reactions. 

No formal pharmacokinetic drug interaction studies have been conducted with Yervoy. 

Yervoy can cause fetal harm. Females who are able to become pregnant should use effective birth control during treatment with Yervoy and for 3 months after the last dose of Yervoy. 

Do not breastfeed during treatment with Yervoy and for 3 months after the last dose of Yervoy.

Yervoy can cause serious side effects in many parts of your body which can lead to death. These problems may happen anytime during treatment with Yervoy or after you have completed treatment. Some of these problems may happen more often when Yervoy is used in combination with nivolumab.

Call your healthcare provider right away if you develop any of these signs or symptoms or they get worse. Do not try to treat symptoms yourself.

Intestinal problems (colitis) that can cause tears or holes (perforation) in the intestines

Signs and symptoms of colitis may include:

• diarrhea (loose stools) or more bowel movements than usual
• mucus or blood in your stools
• dark, tarry, sticky stools
• stomach pain (abdominal pain) or tenderness
• you may or may not have fever

Liver problems (hepatitis) that can lead to liver failure

Signs and symptoms of hepatitis may include:

• yellowing of your skin or the whites of your eyes
• dark urine (tea colored)
• nausea or vomiting
• pain on the right side of your stomach
• bleeding or bruise more easily than normal
• decreased energy

Skin problems that can lead to severe skin reaction

Signs and symptoms of severe skin reactions may include:

• skin rash with or without itching
• sores in your mouth
• your skin blisters or peels

Nerve problems that can lead to paralysis

Symptoms of nerve problems may include:

• unusual weakness of legs, arms, or face
• numbness or tingling in hands or feet

Hormone gland problems (especially the pituitary, adrenal, and thyroid glands)

Signs and symptoms that your glands are not working properly may include:

• persistent or unusual headaches
• unusual sluggishness
• feeling cold all the time
• weight gain
• changes in mood or behavior such as decreased sex drive, irritability, or forgetfulness
• dizziness or fainting Lung problems (pneumonitis).

Symptoms of pneumonitis may include:

• new or worsening cough
• chest pain
• shortness of breath Kidney problems, including nephritis and kidney failure.

Signs of kidney problems may include:

• decrease in the amount of urine
• blood in your urine
• swelling in your ankles
• loss of appetite Inflammation of the brain (encephalitis).

Signs and symptoms of encephalitis may include:

• headache
• fever
• tiredness or weakness
• confusion
• memory problems
• sleepiness
• seeing or hearing things that are not really there (hallucinations)
• seizures
• stiff neck

Eye problems

Symptoms may include:

• blurry vision, double vision, or other vision problems
• eye pain or redness

Severe infusion reactions

Tell your doctor or nurse right away if you get these symptoms during an infusion of Yervoy:

• chills or shaking
• itching or rash
• flushing
• difficulty breathing
• dizziness
• fever
• feeling like passing out

Common side effects

The most common side effects of Yervoy when used alone include:

• feeling tired
• diarrhea
• nausea
• itching
• rash
• vomiting
• headache
• weight loss
• fever
• decreased appetite
• difficulty falling or staying asleep

The most common side effects of Yervoy when used in combination with nivolumab include:

• feeling tired
• rash
• diarrhea
• nausea
• fever
• pain in muscles, bones, and joints
• itching
• abdominal pain
• vomiting
• cough
• decreased appetite
• shortness of breath

These are not all of the possible side effects of Yervoy. Call your doctor for medical advice about side effects.

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Immune-mediated enterocolitis/colitis
• Immune-mediated hepatitis
• Immune-mediated dermatitis/skin adverse reactions
• Immune-mediated neuropathies
• Immune-mediated endocrinopathies
• Immune-mediated pneumonitis
• Immune-mediated nephritis and renal dysfunction
• Immune-mediated encephalitis
• Infusion reactions
• Other immune-mediated adverse reactions
• Embryo-fetal toxicity

In patients receiving Yervoy 3 mg/kg for unresectable or metastatic melanoma in MDX010-20, 15% of patients receiving monotherapy and 12% of patients treated in combination with gp100 peptide vaccine experienced Grade 3 to 5 immune-mediated reactions. In patients receiving Yervoy 10 mg/kg for adjuvant treatment of melanoma in CA184-029, 41% experienced Grade 3 to 5 immune-mediated reactions.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to Yervoy 3 mg/kg as a single agent in MDX010-20, a randomized trial in patients with unresectable or metastatic melanoma; to Yervoy 10 mg/kg as a single agent in CA184-029, a randomized trial in patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma; to Yervoy 1 mg/kg, administered in combination with nivolumab, in three trials:

• Checkmate214, a randomized trial in previously untreated patients with advanced renal cell carcinoma,
• Checkmate-142, an open-label, multicenter, non-randomized multiple parallel cohort trial in patients with previously treated, MSI-H or dMMR metastatic colorectal cancer, and
• Checkmate-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations; and to Yervoy 3 mg/kg, administered in combination with nivolumab, in Checkmate-040, a multicenter, multiple cohort, open-label trial conducted in patients with hepatocellular carcinoma who progressed on or were intolerant to sorafenib; and to Yervoy 1 mg/kg, administered in combination with nivolumab and platinum-doublet chemotherapy in Checkmate-9LA, an open-label, multicenter, randomized trial in adult patients with previously untreated metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations.

Clinically significant adverse reactions were evaluated in a total of 982 patients treated in MDX010-20 and CA184-029 and in 21 dose-ranging trials (n=2478) administering Yervoy at doses of 0.1 to 20 mg/kg.

Unresectable Or Metastatic Melanoma

The safety of Yervoy was evaluated in MDX010-20, a randomized, double-blind clinical trial in which 643 previously treated patients with unresectable or metastatic melanoma received Yervoy 3 mg/kg for 4 doses given by intravenous infusion as a single agent (n=131), Yervoy with an investigational gp100 peptide vaccine (gp100) (n=380), or gp100 peptide vaccine as a single agent (n=132). Patients in the trial received a median of 4 doses (range: 1 to 4 doses).

MDX010-20 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation.

The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% white, and baseline ECOG performance status 0 (56%).

Yervoy was discontinued for adverse reactions in 10% of patients.

Table 2 presents selected adverse reactions from MDX010-20, which occurred in at least 5% of patients in the Yervoy-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3 to 5 events.

Table 2: Selected Adverse Reactions in MDX010-20

Table 3 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from MDX010-20.

Table 3: Severe to Fatal Immune-Mediated Adverse Reactions in MDX010-20

Adjuvant Treatment Of Melanoma

The safety of Yervoy was evaluated in CA184-029, a randomized (1:1), double-blind, placebo-controlled trial in which 945 patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma received Yervoy 10 mg/kg (n=471) or placebo (n=474) administered as an intravenous infusion for 4 doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at Week 24 up to a maximum of 3 years.

In this trial, 36% of patients received Yervoy for longer than 6 months and 26% of patients received Yervoy for longer than 1 year. Yervoy-treated patients in the trial received a median of 4 doses (range: 1 to 16).

CA184-029 excluded patients with prior systemic therapy for melanoma, autoimmune disease, a condition requiring systemic immunosuppression, or a positive test for hepatitis B, hepatitis C, or HIV.

The trial population characteristics were:

• median age 51 years (range: 18 to 84 years),
• 62% male,
• 99% white, and
• baseline ECOG performance status 0 (94%).

Yervoy was discontinued for adverse reactions in 52% of patients.

Table 4 presents selected adverse reactions from CA184-029 which occurred in at least 5% of Yervoy-treated patients and with at least 5% increased incidence over the placebo group for all-grade events.

Table 4: Selected Adverse Reactions in CA184-029

Table 5 presents selected laboratory abnormalities from CA184-029 which occurred in at least 10% of Yervoy-treated patients at a higher incidence compared to placebo.

Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Yervoy-Treated Patients (CA184-029)^a

Table 6 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from CA184-029.

Table 6: Severe to Fatal Immune-Mediated Adverse Reactions in CA184-029

Other Clinical Experience

Across clinical studies that utilized Yervoy doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted):

• urticaria (2%),
• large intestinal ulcer,
• esophagitis,
• acute respiratory distress syndrome,
• renal failure, and
• infusion reaction.

Previously Untreated Renal Cell Carcinoma

The safety of nivolumab 3 mg/kg, administered with Yervoy 1 mg/kg was evaluated in Checkmate-214, a randomized open-label trial in which 1082 patients with previously untreated advanced RCC received nivolumab 3 mg/kg in combination with Yervoy 1 mg/kg every 3 weeks for 4 doses followed by nivolumab monotherapy at the 3 mg/kg dose (n=547) every 2 weeks or sunitinib administered orally 50 mg daily for 4 weeks followed by 2 weeks off, every cycle (n=535).

The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in nivolumab plus Yervoy-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the nivolumab plus Yervoy arm were exposed to treatment for greater than 6 months, and 38% of patients were exposed to treatment for greater than 1 year.

• Study therapy was discontinued for adverse reactions in 31% of nivolumab plus Yervoy patients and in 21% of sunitinib patients.
• Fifty-four percent (54%) of patients receiving nivolumab plus Yervoy and 43% of patients receiving sunitinib had a drug delay for an adverse reaction.
• In the sunitinib group, 53% of patients required a dose reduction; dose reductions were not permitted in the nivolumab plus Yervoy treatment group.
• Serious adverse reactions occurred in 59% of patients receiving nivolumab plus Yervoy and in 43% of patients receiving sunitinib.
• The most frequent serious adverse reactions reported in at least 2% of patients treated with nivolumab plus Yervoy were
  • diarrhea,
  • pyrexia,
  • pneumonia,
  • pneumonitis,
  • hypophysitis,
  • acute kidney injury,
  • dyspnea,
  • adrenal insufficiency, and
  • colitis;
• in patients treated with sunitinib, they were
  • pneumonia,
  • pleural effusion, and
  • dyspnea.

The most common adverse reactions (reported in at least 20% of nivolumab plus Yervoy-treated patients) were

• fatigue,
• rash,
• diarrhea,
• musculoskeletal pain,
• pruritus,
• nausea,
• cough,
• pyrexia,
• arthralgia,
• vomiting,
• dyspnea, and
• decreased appetite.

Table 7 summarizes adverse reactions that occurred in greater than 15% of nivolumab plus Yervoy-treated patients.

Table 7: Grade 1-4 Adverse Reactions in >15% of Patients Receiving Nivolumab plus Yervoy (Checkmate-214)

The most common laboratory abnormalities which have worsened compared to baseline in≥30% of nivolumab plus Yervoy-treated patients include

• increased lipase,
• anemia,
• increased creatinine,
• increased ALT,
• increased AST,
• hyponatremia,
• increased amylase, and
• lymphopenia.

Table 8 summarizes the laboratory abnormalities that occurred in greater than 15% of nivolumab plus Yervoy-treated patients.

Table 8: Grade 1-4 Laboratory Values Worsening from Baseline Occurring in >15% of Patients on Nivolumab plus Yervoy (Checkmate-214)

In addition, among patients with TSH less than or equal to the ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH greater than the ULN in the nivolumab plus Yervoy group compared to the sunitinib group (31% and 61%, respectively).

Previously Treated MSI-H Or dMMR Metastatic Colorectal Cancer

The safety of Yervoy was evaluated in Checkmate-142, an open-label, multicenter, non-randomized, multiple parallel-cohort study. In Checkmate-142, 119 patients with previously treated MSI-H or dMMR mCRC received Yervoy, in combination with nivolumab, in a single-arm cohort.

All patients had received prior fluorouracil-based chemotherapy for metastatic disease;

• 69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; and
• 29% had received an anti-EGFR antibody.

Patients received Yervoy 1 mg/kg and nivolumab 3 mg/kg on Day 1 of each 21-day cycle for 4 doses, then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity.

The median duration of exposure for Yervoy was 2.1 months. Serious adverse reactions occurred in 47% of Yervoy-treated patients.

The most frequent serious adverse reactions reported in at least 2% of patients were

• colitis/diarrhea,
• hepatic events,
• abdominal pain,
• acute kidney injury, pyrexia, and
• dehydration.

The most common adverse reactions (reported in at least 20% of Yervoy-treated patients) were

• fatigue,
• diarrhea,
• pyrexia,
• musculoskeletal pain,
• abdominal pain,
• pruritus,
• nausea,
• rash,
• decreased appetite, and
• vomiting.

Table 9 summarizes adverse reactions that occurred in greater than 10% of patients receiving Yervoy. Table 10 summarizes laboratory tests that worsened from baseline in greater than 10% of patients receiving Yervoy.

Table 9: Adverse Reactions Occurring in ≥10% of Patients (Checkmate-142)

Other clinically important adverse reactions reported in less than 10% of patients receiving Yervoy in Checkmate-142 were

• encephalitis (0.8%),
• necrotizing myositis (0.8%), and
• uveitis (0.8%).

Table 10: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients (Checkmate-142)

Hepatocellular Carcinoma

• The safety of Yervoy 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in a subgroup of 49 patients with HCC and Child-Pugh Class A cirrhosis who progressed on or were intolerant to sorafenib enrolled in Cohort 4 of Checkmate-040.
• Yervoy and nivolumab were administered every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity.
• During the Yervoy and nivolumab combination period, 33 of 49 (67%) patients received all four planned doses of Yervoy and nivolumab.
• During the entire treatment period, the median duration of exposure to Yervoy was 2.1 months (range: 0 to 4.5 months) and to nivolumab was 5.1 months (range: 0 to 35+ months).
• Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year.
• Serious adverse reactions occurred in 59% of patients.
• Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction.

Serious adverse reactions reported in ≥4% of patients were

• pyrexia,
• diarrhea,
• anemia,
• increased AST,
• adrenal insufficiency,
• ascites,
• esophageal varices hemorrhage,
• hyponatremia,
•  increased blood bilirubin, and
• pneumonitis.

Table 11 summarizes the adverse reactions and Table 12 summarizes the laboratory abnormalities of Yervoy in combination with nivolumab in Checkmate-040.

Table 11: Adverse Reactions Occurring in ≥10% of Patients Receiving Yervoy in Combination with Nivolumab in Cohort 4 of Checkmate-040

Clinically important adverse reactions reported in <10% of patients receiving Yervoy with nivolumab were

• hyperglycemia (8%),
• colitis (4%), and
• increased blood creatine phosphokinase (2%).

Table 12: Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients Receiving Yervoy in Combination with Nivolumab in Cohort 4 of Checkmate-040

• In patients who received Yervoy with nivolumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively.
• HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline.
•  HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline.

First-Line Treatment Of Metastatic NSCLC: In Combination With Nivolumab

• The safety of Yervoy in combination with nivolumab was evaluated in Checkmate-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.
• The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression.
• Patients received Yervoy 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks and nivolumab 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles.
• The median duration of therapy in Yervoy and nivolumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received Yervoy and nivolumab for >6 months and 23% of patients received Yervoy and nivolumab for >1 year.
• The population characteristics were:
  • median age 64 years (range: 26 to 87);
  • 48% were ≥65 years of age,
  • 76% White, and
  • 67% male.
• Baseline ECOG performance status was
  • 0 (35%) or 1 (65%),
  • 85% were former/current smokers,
  • 11% had brain metastases,
  • 28% had squamous histology and
  • 72% had non-squamous histology.

Serious adverse reactions occurred in 58% of patients. Yervoy and nivolumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.

The most frequent (≥2%) serious adverse reactions were

• pneumonia,
• diarrhea/colitis,
• pneumonitis,
• hepatitis,
• pulmonary embolism,
• adrenal insufficiency, and
• hypophysitis.

Fatal adverse reactions occurred in 1.7% of patients; these included events of

• pneumonitis (4 patients),
• myocarditis,
• acute kidney injury,
• shock,
• hyperglycemia,
• multi-system organ failure, and
• renal failure.

The most common (≥20%) adverse reactions were

• fatigue,
• rash,
• decreased appetite,
• musculoskeletal pain,
• diarrhea/colitis,
• dyspnea,
• cough,
• hepatitis,
• nausea, and
• pruritus.

Tables 13 and 14 summarize selected adverse reactions and laboratory abnormalities, respectively, in Checkmate-227.

Table 13: Adverse Reactions in ≥10% of Patients Receiving Yervoy and Nivolumab ­Checkmate-227

Other clinically important adverse reactions in Checkmate-227 were:

• Skin and Subcutaneous Tissue: urticaria, alopecia, erythema multiforme, vitiligo
• Gastrointestinal: stomatitis, pancreatitis, gastritis
• Musculoskeletal and Connective Tissue: arthritis, polymyalgia rheumatica, rhabdomyolysis
• Nervous System: peripheral neuropathy, autoimmune encephalitis
• Blood and Lymphatic System: eosinophilia
• Eye Disorders: blurred vision, uveitis
• Cardiac: atrial fibrillation, myocarditis

Table 14: Laboratory Values Worsening from Baseline^a Occurring in ≥20% of Patients on Yervoy and Nivolumab - Checkmate-227

First-line Treatment Of Metastatic Or Recurrent NSCLC: In Combination With Ipilimumab And Platinum-Doublet Chemotherapy

• The safety of Yervoy in combination with nivolumab and platinum-doublet chemotherapy was evaluated in Checkmate-9LA.
• Patients received either Yervoy 1 mg/kg administered every 6 weeks in combination with nivolumab 360 mg administered every 3 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles.
• The median duration of therapy in Yervoy in combination with nivolumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received Yervoy and nivolumab for >6 months and 13% of patients received Yervoy and nivolumab for >1 year.
• Serious adverse reactions occurred in 57% of patients who were treated with Yervoy in combination with nivolumab and platinum-doublet chemotherapy.
• The most frequent (>2%) serious adverse reactions were
  • pneumonia,
  • diarrhea,
  • febrile neutropenia,
  • anemia,
  • acute kidney injury,
  • musculoskeletal pain,
  • dyspnea,
  • pneumonitis, and
  • respiratory failure.
• Fatal adverse reactions occurred in 7 (2%) patients, and included
  • hepatic toxicity,
  • acute renal failure,
  • sepsis,
  • pneumonitis,
  • diarrhea with hypokalemia, and
  • massive hemoptysis in the setting of thrombocytopenia.

Study therapy with Yervoy in combination with nivolumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction.

The most common (>20%) adverse reactions were

• fatigue,
• musculoskeletal pain,
• nausea,
• diarrhea,
• rash,
• decreased appetite,
• constipation, and
• pruritus.

Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in Checkmate-9LA.

Table 15: Adverse Reactions in >10% of Patients Receiving Yervoy and Nivolumab and Platinum-Doublet Chemotherapy - Checkmate-9LA

Table 16: Laboratory Values Worsening from Baseline^a Occurring in >20% of Patients on Yervoy and Nivolumab and Platinum-Doublet Chemotherapy - Checkmate-9LA

Immunogenicity

• As with all therapeutic proteins, there is a potential for immunogenicity.
• The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
• Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including
  • assay methodology,
  • sample handling,
  • timing of sample collection,
  • concomitant medications, and
  • underlying disease.
• For these reasons, comparison of the incidence of antibodies to ipilimumab in the studies described below with the incidences of antibodies in other studies or to other products may be misleading.
• Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab (TE-ADAs) in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of 144 patients receiving ipilimumab and 7 (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for TE-ADAs using an ECL assay with improved drug tolerance. No patients tested positive for neutralizing antibodies. No infusion-related reactions occurred in patients who tested positive for TE-ADAs.
• Of 499 patients evaluable for anti-ipilimumab antibodies in Checkmate-214 and Checkmate-142, 27 (5.4%) were positive for anti-ipilimumab antibodies; there were no patients with neutralizing antibodies against ipilimumab.
• There was no evidence of increased incidence of infusion reactions to Yervoy in patients with anti-ipilimumab antibodies.
• Of 503 patients evaluable for anti-nivolumab antibodies in Checkmate-214 and Checkmate-142 trials, 126 (25%) were positive for anti-nivolumab antibodies and 3 (0.6%) were positive for neutralizing antibodies against nivolumab.
• Of 483 patients evaluable for anti-ipilimumab antibodies in Checkmate-227 Part 1, 8.5% were positive for treatment-emergent anti-ipilimumab antibodies.
• No patients had neutralizing antibodies against ipilimumab. In Part 1 of the same study, of 491 patients evaluable for antinivolumab antibodies, 36.7% were positive for anti-nivolumab antibodies and 1.4% had neutralizing antibodies against nivolumab.
• Of 305 patients evaluable for anti-ipilimumab antibodies in Checkmate-9LA, 8% were positive for anti-ipilimumab antibodies and 1.6% were positive for anti-ipilimumab neutralizing antibodies.
• There was no evidence of increased incidence of infusion reactions to Yervoy in patients with anti-ipilimumab antibodies.
• Of 308 patients evaluable for anti-nivolumab antibodies in Checkmate-9LA, 34% were positive for anti-nivolumab antibodies and 2.6% had neutralizing antibodies against nivolumab.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Yervoy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Immune system disorders: graft-versus-host disease
• Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

• No formal pharmacokinetic drug interaction studies have been conducted with Yervoy.