Does Yervoy (ipilimumab) cause side effects?

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

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

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.

What are the important side effects of Yervoy (ipilimumab)?

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:

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:

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:

Symptoms of pneumonitis may include:

Signs of kidney problems may include:

Signs and symptoms of encephalitis may include:

Eye problems

Symptoms may include:

Severe infusion reactions

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

Common side effects

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

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.

Yervoy (ipilimumab) side effects list for healthcare professionals

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

System Organ Class/ Preferred TermPercentage (%) of Patientsa
Yervoy 3 mg/kg
n=131
Yervoy 3 mg/kg + gp100
n=380
gp100
n=132
Any GradeGrade 3 to 5Any GradeGrade 3 to 5Any GradeGrade 3 to 5
General Disorders and Administration-Site Conditions
Fatigue417345313
Gastrointestinal Disorders
Diarrhea325374201
Colitis855320
Skin and Subcutaneous Tissue Disorders
Pruritus31021<1110
Rash29225280
a Incidences presented in this table are based on reports of adverse events regardless of causality.

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

Percentage (%) of Patients
Yervoy 3 mg/kg
n=131
Yervoy 3 mg/kg+gp100
n=380
Any Immune-Mediated Adverse Reaction1512
Enterocolitisa,b77
Hepatotoxicitya12
Dermatitisa23
Neuropathya1<1
Endocrinopathy41
Hypopituitarism41
Adrenal insufficiency01
Other
Pneumonitis0<1
Meningitis0<1
Nephritis10
Eosinophiliac10
Pericarditisa,c0<1
a Including fatal outcome.
b Including intestinal perforation.
c Underlying etiology not established.

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

System Organ Class/ Preferred TermPercentage (%) of Patientsa
Yervoy 10 mg/kg n=471Placebo n=474
Any GradeGrade 3 to 5Any GradeGrade 3 to 5
Skin and Subcutaneous Tissue Disorders
Rash502.1200
Pruritus452.3150
Gastrointestinal Disorders
Diarrhea4910302.1
Nausea250.2180
Colitisb1681.50.4
Vomiting130.460.2
Investigations
Weight Decreased320.290.4
General Disorders and Administration-Site Conditions
Fatigue462.3381.5
Pyrexia181.14.90.2
Nervous System Disorders
Headache330.8180.2
Metabolism and Nutrition Disorders
Decreased Appetite140.23.40.2
Psychiatric Disorders
Insomnia1004.40
a Incidences presented in this table are based on reports of adverse events regardless of causality.
b Includes 1 death.

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

TestPercentage of Patients with Worsening Laboratory Test from Baselinea
YervoyPlacebo
All GradesGrade 3 to 4All GradesGrade 3 to 4
Chemistry
Increased ALT4610160
Increased AST389140.2
Increased lipaseb269174.5
Increased amylaseb172.070.6
Increased alkaline phosphatase170.660.2
Increased bilirubin111.590
Increased creatinine100.260
Hematology
Decreased hemoglobin250.2140
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Excluding lipase and amylase, Yervoy group (range: 466 to 470 patients) and placebo group (range: 472 to 474 patients).
b For lipase and amylase, Yervoy group (range: 447 to 448 patients) and placebo group (range: 462 to 464 patients).

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

Percentage (%) of Patients
Yervoy 10 mg/kg
n=471
Any Immune-Mediated Adverse Reaction41
Enterocolitisa,b16
Hepatitis11
Dermatitis4.0
Neuropathya1.7
Endocrinopathy8
Hypopituitarism7
Primary hypothyroidism0.2
Hyperthyroidism0.6
Other
Myocarditisa0.2
Meningitis0.4
Pericarditisc0.2
Pneumonitis0.2
Uveitis0.2
a Including fatal outcome.
b Including intestinal perforation.
c Underlying etiology not established.

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):

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
  • in patients treated with sunitinib, they were

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

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)

Nivolumab plus Yervoy
(n=547)
Sunitinib
(n=535)
Percentage (%) of Patients
Grades 1-4Grades 3-4Grades 1-4Grades 3-4
Adverse Reaction99659976
General Disorders and Administration Site Conditions
Fatiguea5886913
Pyrexia250.7170.6
Edemab160.5170.6
Respiratory, Thoracic, and Mediastinal Disorders
Cough/productive cough280.2250.4
Dyspnea/exertional dyspnea202.4212.1
Gastrointestinal Disorders
Diarrhea384.6586
Nausea302.0431.5
Vomiting200.9282.1
Abdominal pain191.6241.9
Constipation170.4180
Skin and Subcutaneous Tissue Disorders
Rashc393.7251.1
Pruritus/generalized pruritus330.5110
Endocrine Disorders
Hypothyroidism180.4270.2
Nervous System Disorders
Headache190.9230.9
Metabolism and Nutrition Disorders
Decreased appetite211.8290.9
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paind374.0402.6
Arthralgia231.3160
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema, peripheral swelling.
c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.

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

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)

Laboratory AbnormalityPercentage of Patients with Worsening Laboratory Test from Baselinea
Nivolumab plus YervoySunitinib
Grades 1-4Grades 3-4Grades 1-4Grades 3-4
Hematology
Anemia433.0649
Lymphopenia3656314
Chemistry
Increased lipase48205120
Increased creatinine422.1461.7
Increased ALT417442.7
Increased AST404.8602.1
Increased amylase3912337
Hyponatremia3910367
Increased alkaline phosphatase292.0321.0
Hyperkalemia292.4282.9
Hypocalcemia210.4350.6
Hypomagnesemia160.4261.6
plus Yervoy group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).

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)

Adverse ReactionYervoy plus Nivolumab MSI-H/dMMR Cohort
(n=119)
Percentage (%) of Patients
All GradesGrades 3-4
General Disorders and Administration Site Conditions
Fatiguea496
Pyrexia360
Edemab70
Gastrointestinal Disorders
Diarrhea453.4
Abdominal painc305
Nausea260.8
Vomiting201.7
Constipation150
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paind363.4
Arthralgia140.8
Skin and Subcutaneous Tissue Disorders
Pruritus281.7
Rashe254.2
Dry Skin110
Infections and Infestations
Upper respiratory tract infectionf 90
Metabolism and Nutrition Disorders
Decreased appetite201.7
Respiratory, Thoracic, and Mediastinal Disorders
Cough190.8
Dyspnea131.7
Nervous System Disorders
Headache171.7
Dizziness110
Endocrine Disorders
Hyperglycemia61
Hypothyroidism140.8
Hyperthyroidism120
Investigations
Weight decreased100
Psychiatric Disorders
Insomnia130.8
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema and peripheral swelling.
c Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
d Includes back pain, pain in extremity, myalgia, neck pain, and bone pain.
e Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized.
f Includes nasopharyngitis and rhinitis.

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

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

Laboratory AbnormalityPercentage of Patients with Worsening Laboratory Test from Baselinea
Yervoy plus Nivolumab MSI-H/dMMR Cohort
(n=119)
All GradesGrades 3-4
Hematology
Anemia429
Thrombocytopenia260.9
Lymphopenia256
Neutropenia180
Chemistry
Increased AST4012
Increased lipase3912
Increased amylase363.4
Increased ALT3312
Increased alkaline phosphatase285
Hyponatremia265
Increased creatinine253.6
Hyperkalemia230.9
Increased bilirubin215
Hypomagnesemia180
Hypocalcemia160
Hypokalemia151.8
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Number of evaluable patients ranges from 87 to 114 for nivolumab with Yervoy and from 62 to 71 for nivolumab.

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

Adverse ReactionYervoy and Nivolumab
(n=49)
All Grades (%)Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rash538
Pruritus534
Musculoskeletal and Connective Tissue
Musculoskeletal pain412
Arthralgia100
Gastrointestinal
Diarrhea394
Abdominal pain226
Nausea200
Ascites146
Constipation140
Dry mouth120
Dyspepsia122
Vomiting122
Stomatitis100
Respiratory, Thoracic and Mediastinal
Cough370
Dyspnea140
Pneumonitis102
Metabolism and Nutrition
Decreased appetite352
General
Fatigue272
Pyrexia270
Malaise182
Edema162
Influenza-like illness140
Chills100
Nervous System
Headache220
Dizziness200
Endocrine
Hypothyroidism200
Adrenal insufficiency184
Investigations
Weight decreased200
Psychiatric
Insomnia180
Blood and Lymphatic System
Anemia104
Infections
Influenza102
Vascular
Hypotension100

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

Laboratory AbnormalityYervoy and Nivolumab
(n=47)
All Grades (%)Grades 3-4 (%)
Hematology
Lymphopenia5313
Anemia434.3
Neutropenia439
Leukopenia402.1
Thrombocytopenia344.3
Chemistry
Increased AST6640
Increased ALT6621
Increased bilirubin5511
Increased lipase5126
Hyponatremia4932
Hypocalcemia470
Increased alkaline phosphatase404.3
Increased amylase3815
Hypokalemia262.1
Hyperkalemia234.3
Increased creatinine210
Hypomagnesemia110

  • 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

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

Adverse ReactionYervoy and Nivolumab (n=576)Platinum-doublet Chemotherapy (n=570)
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
General
Fatiguea446424.4
Pyrexia180.5110.4
Edemab140.2120.5
Skin and Subcutaneous Tissue
Rashc344.7100.4
Pruritusd210.53.30
Metabolism and Nutrition
Decreased appetite312.3261.4
Musculoskeletal and Connective Tissue
Musculoskeletal paine271.9160.7
Arthralgia130.92.50.2
Gastrointestinal
Diarrhea/colitisf 263.6160.9
Nausea211.0422.5
Constipation180.3270.5
Vomiting131.0182.3
Abdominal paing100.290.7
Respiratory, Thoracic, and Mediastinal
Dyspneah264.3162.1
Coughi230.2130
Hepatobiliary
Hepatitisj219101.2
Endocrine
Hypothyroidismk160.51.20
Hyperthyroidisml1000.50
Infections and Infestations
Pneumoniam13784.0
Nervous System
Headache110.560
a Includes fatigue and asthenia.
b Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, and periorbital edema.
c Includes autoimmune dermatitis, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, granulomatous dermatitis, rash generalized, drug eruption, dyshidrotic eczema, eczema, exfoliative rash, nodular rash, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption.
d Includes pruritus and pruritus generalized.
e Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, and pain in extremity.
f Includes colitis, colitis microscopic, colitis ulcerative, diarrhea, enteritis infectious, enterocolitis, enterocolitis infectious, and enterocolitis viral.
g Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness.
h Includes dyspnea and dyspnea exertional.
i Includes cough and productive cough.
j Includes alanine aminotransferase increased, aspartate aminotransferase increased, autoimmune hepatitis, blood bilirubin increased, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatitis, hepatitis E, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test abnormal, liver function test increased, transaminases increased.
k Includes autoimmune thyroiditis, blood thyroid stimulating hormone increased, hypothyroidism, primary hypothyroidism, thyroiditis, and tri-iodothyronine free decreased.
l Contains blood thyroid stimulating hormone decreased, hyperthyroidism, and tri-iodothyronine free increased.
m Includes lower respiratory tract infection, lower respiratory tract infection bacterial, lung infection, pneumonia, pneumonia adenoviral, pneumonia aspiration, pneumonia bacterial, pneumonia klebsiella, pneumonia influenzal, pneumonia viral, atypical pneumonia, organizing pneumonia.

Other clinically important adverse reactions in Checkmate-227 were:

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

Laboratory AbnormalityYervoy and NivolumabPlatinum-doublet Chemotherapy
Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)
Hematology
Anemia463.67814
Lymphopenia4656015
Chemistry
Hyponatremia4112264.9
Increased AST395260.4
Increased ALT367270.7
Increased lipase3514143.4
Increased alkaline phosphatase343.8200.2
Increased amylase289181.9
Hypocalcemia281.7171.3
Hyperkalemia273.4220.4
Increased creatinine220.9170.2
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Yervoy and nivolumab group (range: 494 to 556 patients) and chemotherapy group (range: 469 to 542 patients).

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

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

Adverse ReactionYervoy and Nivolumab and Platinum-Doublet Chemotherapy
(n=358)
Platinum-Doublet Chemotherapy
(n=349)
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
General
Fatiguea495404.9
Pyrexia140.6100.6
Musculoskeletal and Connective Tissue
Musculoskeletal painb394.5272.0
Gastrointestinal
Nausea321.7410.9
Diarrheac316181.7
Constipation210.6230.6
Vomiting182.0171.4
Abdominal paind120.6110.9
Skin and Subcutaneous Tissue
Rashe304.7100.3
Pruritusf210.82.90
Alopecia110.8100.6
Metabolism and Nutrition
Decreased appetite282.0221.7
Respiratory, Thoracic and Mediastinal
Coughg190.6150.9
Dyspneah184.7143.2
Endocrine
Hypothyroidismi190.33.40
Nervous System
Headache110.670
Dizzinessj110.660

Toxicity was graded per NCI CTCAE v4.
a Includes fatigue and asthenia
b Includes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, synovitis
c Includes colitis, ulcerative colitis, diarrhea, and enterocolitis
d Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain
e Includes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blenorrhagica, palmar-plantar erythrodysaesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, urticaria
f Includes pruritus and generalized pruritus
g Includes cough, productive cough, and upper-airway cough syndrome
h Includes dyspnea, dyspnea at rest, and exertional dyspnea
i Includes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine
j Includes dizziness, vertigo and positional vertigo

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

Laboratory AbnormalityYervoy and Nivolumab and Platinum-Doublet ChemotherapyPlatinum-Doublet Chemotherapy
Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)
Hematology
Anemia7097416
Lymphopenia4164011
Neutropenia40154215
Leukopenia3610409
Thrombocytopenia234.3245
Chemistry
Hyperglycemia457422.6
Hyponatremia3710277
Increased ALT344.3241.2
Increased lipase3112102.2
Increased alkaline phosphatase311.2260.3
Increased amylase307191.3
Increased AST303.5220.3
Hypomagnesemia291.2330.6
Hypocalcemia261.4221.8
Increased creatinine261.2230.6
Hyperkalemia221.7212.1
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Yervoy and nivolumab and platinum-doublet chemotherapy group (range: 197 to 347 patients) and platinum-doublet chemotherapy group (range: 191 to 335 patients).

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)

What drugs interact with Yervoy (ipilimumab)?

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

Summary

Yervoy (ipilimumab) is a monoclonal antibody used to treat a kind of skin cancer called melanoma. It is also used to treat colorectal cancer and kidney cancer. 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. 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.

Treatment & Diagnosis

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Medically Reviewed on 10/9/2020
References
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