Yervoy Side Effects Center

Last updated on RxList: 12/5/2022
Yervoy Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

What Is Yervoy?

Yervoy (ipilimumab) is a monoclonal antibody used to treat late-stage, metastatic melanoma, a deadly skin cancer. Yervoy is thought to work by allowing the body's immune system to recognize, target, and attack cells in these tumors. Patients with metastatic melanoma are shown to live longer when treated with Yervoy.

What Are Side Effects of Yervoy?

Yervoy may cause serious side effects including:

  • hives,
  • difficulty breathing,
  • swelling of your face, lips, tongue, or throat,
  • fever,
  • sore throat,
  • burning eyes,
  • skin pain, red or purple skin rash with blistering and peeling,
  • lightheadedness,
  • dizziness,
  • shortness of breath,
  • tingling,
  • feeling chills,
  • severe or ongoing diarrhea,
  • severe stomach pain,
  • bloody or tarry stools,
  • swollen glands,
  • body aches,
  • new or worsening skin rash,
  • itching,
  • blistering,
  • chest pain,
  • irregular heartbeats,
  • severe muscle weakness,
  • ongoing pain in your muscles or joints,
  • little or no urination,
  • swelling in your feet or ankles,
  • blood in your urine,
  • right sided upper stomach pain,
  • tiredness,
  • bruising,
  • bleeding,
  • dark urine,
  • yellowing of your skin or eyes (jaundice),
  • frequent or unusual headaches,
  • lack of energy,
  • fainting,
  • mood changes,
  • increased thirst,
  • increased urination,
  • feeling cold,
  • weight gain,
  • weight loss,
  • confusion,
  • headache,
  • memory problems,
  • hallucinations,
  • neck stiffness,
  • drowsiness, and
  • seizure

Get medical help right away, if you have any of the symptoms listed above.

Common side effects of Yervoy include:

  • mild diarrhea,
  • mild skin rash or itching,
  • tiredness,
  • nausea, or
  • vomiting.

Tell your doctor if you have serious side effects of Yervoy including:

  • severe stomach pain, bloating, constipation, or vomiting; loss of bowel control;
  • trouble with daily activities;
  • feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin;
  • urinating less than usual or not at all;
  • severe upper stomach pain spreading to your back, nausea and vomiting, fast heart rate;
  • fever, cough, trouble breathing; or
  • chest pain, feeling short of breath (even with mild exertion), swelling, rapid weight gain.

Seek medical care or call 911 at once if you have the following serious side effects:

  • Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
  • Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheadedness, or passing out;
  • Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

Dosage for Yervoy

The recommended dose of Yervoy is 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years.

What Drugs, Substances, or Supplements Interact with Yervoy?

Yervoy may interact with other drugs. Tell your doctor all medications and supplements you use.

Yervoy During Pregnancy and Breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant while using Yervoy; it is unknown if it will harm a fetus. It is unknown if Yervoy passes into breast milk or if it could harm a nursing baby. Breastfeeding while receiving Yervoy is not recommended.

Additional Information

Our Yervoy (ipilimumab) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

QUESTION

Self-examination is important in the detection of skin cancer. See Answer
Yervoy Consumer Information

Get emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).

Some side effects may occur during the injection. Tell your caregiver if you feel dizzy, light-headed, short of breath, itchy, tingly, chilled, or feverish.

Serious and sometimes fatal reactions may occur during treatment with ipilimumab or months after stopping. Call your doctor right away if you have symptoms such as:

  • severe or ongoing diarrhea, severe stomach pain, bloody or tarry stools;
  • fever, swollen glands, body aches;
  • new or worsening skin rash, itching, or blistering;
  • chest pain, irregular heartbeats;
  • severe muscle weakness, ongoing pain in your muscles or joints;
  • numbness or tingling in your hands or feet;
  • vision problems, eye pain or redness;
  • lung problems--new or worsening cough, chest pain, feeling short of breath;
  • kidney problems--little or no urination, swelling in your feet or ankles, blood in your urine;
  • liver problems--right-sided upper stomach pain, tiredness, bruising or bleeding, dark urine, yellowing of your skin or eyes;
  • signs of a hormonal disorder--frequent or unusual headaches, lack of energy, dizziness, fainting, mood or behavior changes, increased thirst or urination, feeling cold, weight gain, or weight loss; or
  • symptoms of brain swelling--confusion, headache, memory problems, hallucinations, neck stiffness, drowsiness, seizure (convulsions).

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

  • fever, cough, shortness of breath;
  • nausea, vomiting, stomach pain, loss of appetite;
  • diarrhea, constipation;
  • weight loss;
  • hormonal problems;
  • rash or itching;
  • headache, dizziness, tiredness;
  • sleep problems (insomnia); or
  • pain in your muscles, joints, or bones.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

SLIDESHOW

Sun-Damaged Skin: Pictures of Sun Spots, Wrinkles, Sunburns See Slideshow
Yervoy Professional Information

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Severe and fatal immune-mediated adverse reactions [see WARNINGS AND PRECAUTIONS].
  • Infusion-related reactions [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described in the Warnings and Precautions section reflect exposure to YERVOY 3 mg/kg as a single agent (or in combination with an investigational gp100 peptide vaccine) in 511 patients in Study MDX010-20; YERVOY 10 mg/kg as a single agent in 471 patients in Study CA184-029; YERVOY 1 mg/kg administered with nivolumab 3 mg/kg in 1,362 patients in CHECKMATE-214, CHECKMATE-142, CHECKMATE-227, and CHECKMATE-743; YERVOY 3 mg/kg administered with nivolumab 1 mg/kg in 456 patients enrolled in CHECKMATE-067, CHECKMATE-040, and another randomized trial; and to YERVOY 1 mg/kg, administered in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA.

Unresectable Or Metastatic Melanoma

The safety of YERVOY was evaluated in 643 previously treated patients with unresectable or metastatic melanoma in Study MDX010-20 [see Clinical Studies]. Study MDX010-20 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Patients received YERVOY 3 mg/kg by intravenous infusion for 4 doses as a single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (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).

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 4 presents adverse reactions from Study MDX010-20.

Table 4: Selected Adverse Reactions (≥ 5%) in Patients Receiving YERVOY with a Difference Between Arms of >5% for All Grades and >1% for Grades 3 to 5 Compared to gp100 Peptide Vaccine in Study MDX010-20

Adverse Reactions YERVOY 3 mg/kg
n=131
YERVOY 3 mg/kg and gp100
n=380
gp100
n=132
All Grades (%) Grade 3 to 5 (%) All Grades (%) Grade 3 to 5 (%) All Grades (%) Grade 3 to 5 (%)
General and Administration-Site Conditions
Fatigue 41 7 34 5 31 3
Gastrointestinal
Diarrhea 32 5 37 4 20 1
Colitis 8 5 5 3 2 0
Dermatologic
Pruritus 31 0 21 <1 11 0
Rash 29 2 25 2 8 0

Unresectable Or Metastatic Melanoma: In Combination With Nivolumab

The safety of YERVOY, administered with nivolumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies]. The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV.

Patients were randomized to receive:

  • YERVOY 3 mg/kg by intravenous infusion over 90 minutes with nivolumab 1 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (YERVOY and nivolumab arm; n=313), or
  • Nivolumab 3 mg/kg by intravenous infusion every 2 weeks (nivolumab arm; n=313), or
  • YERVOY 3 mg/kg by intravenous infusion over 90 minutes every 3 weeks for up to 4 doses (YERVOY arm; n=311).

The median duration of exposure to nivolumab was 2.8 months (range: 1 day to 36.4 months) for the YERVOY and nivolumab arm. In the YERVOY and nivolumab arm, 39% were exposed to nivolumab for ≥6 months and 30% exposed for >1 year.

Serious adverse reactions (74%), adverse reactions leading to permanent discontinuation (47%) or to dosing delays (58%), and Grade 3 or 4 adverse reactions (72%) occurred in patients treated with YERVOY and nivolumab.

The most frequent (≥10%) serious adverse reactions in the YERVOY and nivolumab arm were diarrhea (13%), colitis (10%), and pyrexia (10%). The most frequent adverse reactions leading to discontinuation of both drugs in the YERVOY and nivolumab arm were colitis (10%), diarrhea (8%), increased ALT (4.8%), increased AST (4.5%), and pneumonitis (1.9%).

The most common (≥20%) adverse reactions in the YERVOY and nivolumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases.

Tables 5 and 6 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.

Table 5: Adverse Reactions Occurring in ≥10% of Patients on the YERVOY and Nivolumab Arm or the Nivolumab Arm and at a Higher Incidence than in the YERVOY Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067

Adverse Reaction YERVOY and Nivolumab
(n=313)
Nivolumab
(n=313)
YERVOY
(n=311)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
General
Fatiguea 62 7 59 1.6 51 4.2
Pyrexia 40 1.6 16 0 18 0.6
Gastrointestinal
Diarrhea 54 11 36 5 47 7
Nausea 44 3.8 30 0.6 31 1.9
Vomiting 31 3.8 20 1.0 17 1.6
Skin and Subcutaneous Tissue
Rashb 53 6 40 1.9 42 3.5
Vitiligo 9 0 10 0.3 5 0
Musculoskeletal and Connective Tissue
Musculoskeletal painc 32 2.6 42 3.8 36 1.9
Arthralgia 21 0.3 21 1.0 16 0.3
Metabolism and Nutrition
Decreased appetite 29 1.9 22 0 24 1.3
Respiratory, Thoracic and Mediastinal
Cough/productive cough 27 0.3 28 0.6 22 0
Dyspnea/exertional dyspnea 24 2.9 18 1.3 17 0.6
Infections
Upper respiratory tract infectiond 23 0 22 0.3 17 0
Endocrine
Hypothyroidism 19 0.6 11 0 5 0
Hyperthyroidism 11 1.3 6 0 1 0
Investigations
Decreased weight 12 0 7 0 7 0.3
Vascular
Hypertensione 7 2.2 11 5 9 2.3
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia and fatigue.
b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.
c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
e Includes hypertension and blood pressure increased.

Clinically important adverse reactions in <10% of patients who received YERVOY with nivolumab:

Gastrointestinal Disorders: stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders: vitiligo

Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren's syndrome, spondyloarthropathy, myositis (including polymyositis)

Nervous System Disorders: neuritis, peroneal nerve palsy

Table 6: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥20% of Patients Treated with YERVOY with Nivolumab or Single-Agent Nivolumab and at a Higher Incidence than in the YERVOY Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067

Laboratory Abnormality YERVOY and Nivolumab Nivolumab YERVOY
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Chemistry
Increased ALT 55 16 25 3.0 29 2.7
Hyperglycemia 53 5 46 7 26 0
Increased AST 52 13 29 3.7 29 1.7
Hyponatremia 45 10 22 3.3 26 7
Increased lipase 43 22 32 12 24 7
Increased alkaline phosphatase 41 6 27 2.0 23 2.0
Hypocalcemia 31 1.1 15 0.7 20 0.7
Increased amylase 27 10 19 2.7 15 1.6
Increased creatinine 26 2.7 19 0.7 17 1.3
Hematology
Anemia 52 2.7 41 2.6 41 6
Lymphopenia 39 5 41 4.9 29 4.0
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 (range: 75 to 297); nivolumab (range: 81 to 306); YERVOY (range: 61 to 301)

Adjuvant Treatment Of Melanoma

The safety of YERVOY was evaluated in 945 patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma in Study CA184- 029 [see Clinical Studies]. Study 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. Patients 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).

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 7 presents selected adverse reactions from Study CA184-029.

Table 7: Adverse Reactions (≥ 5%) in Patients Receiving YERVOY with a Difference Between Arms >5% Compared to Placebo in Study CA184-029

Adverse Reaction YERVOY 10 mg/kg
n=471
Placebo
n=474
All Grades (%) Grade 3 to 5 (%) All Grades (%) Grade 3 to 5 (%)
Dermatologic
Rash 50 2.1 20 0
Pruritus 45 2.3 15 0
Gastrointestinal
Diarrhea 49 10 30 2.1
Nausea 25 0.2 18 0
Colitis 16 8 1.5 0.4
Vomiting 13 0.4 6 0.2
General and Administration-Site Conditions
Fatigue 46 2.3 38 1.5
Weight Decreased 32 0.2 9 0.4
Pyrexia 18 1.1 4.9 0.2
Nervous System
Headache 33 0.8 18 0.2
Metabolism and Nutrition
Decreased Appetite 14 0.2 3.4 0.2
Psychiatric
Insomnia 10 0 4.4 0

Table 8 presents selected laboratory abnormalities from Study CA184-029.

Table 8: Laboratory Abnormalities (>5%) Worsening from Baseline in Patients Receiving YERVOY with a Difference Between Arms of >5% Compared to Placebo in CA184-029a

Laboratory Abnormality YERVOY 10 mg/kga Placeboa
All Grades (%) Grade 3 to 4 (%) All Grades (%) Grade 3 to 4 (%)
Chemistry
Increased ALT 46 10 16 0
Increased AST 38 9 14 0.2
Increased lipase 26 9 17 4.5
Increased amylase 17 2.0 7 0.6
Increased alkaline phosphatase 17 0.6 6 0.2
Increased bilirubin 11 1.5 9 0
Increased creatinine 10 0.2 6 0
Hematology
Decreased hemoglobin 25 0.2 14 0
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). For lipase and amylase, YERVOY group (range: 447 to 448 patients) and placebo group (range: 462 to 464 patients).

Other Clinical Experience

Across clinical studies in which patients received YERVOY as a single agent at doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence <1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

Advanced Renal Cell Carcinoma: In Combination With Nivolumab

The safety of YERVOY in combination with nivolumab was evaluated in 1082 patients with previously untreated advanced RCC in CHECKMATE-214 [see Clinical Studies]. Patients received YERVOY 1 mg/kg with nivolumab 3 mg/kg intravenously every 3 weeks for 4 doses followed by nivolumab as a single agent at a dose of 3 mg/kg every 2 weeks (n=547) or sunitinib 50 mg orally daily for first 4 weeks of each 6-week cycle (n=535). The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in YERVOY and nivolumab arm. In this trial, 57% of patients in the YERVOY and nivolumab arm were exposed to treatment for greater than 6 months and 38% of patients were exposed to treatment for greater than 1 year.

Serious adverse reactions occurred in 59% of patients receiving YERVOY with nivolumab. The most frequent serious adverse reactions reported in ≥2% of patients treated with YERVOY and nivolumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis.

In patients who received YERVOY with nivolumab, study therapy was discontinued for adverse reactions in 31% and delayed for adverse reactions in 54%.

The most common adverse reactions (≥20%) in the YERVOY and nivolumab arm were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, vomiting, dyspnea, and decreased appetite. Table 9 summarizes adverse reactions in CHECKMATE-214.

Table 9: Adverse Reactions (>15%) in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214

Adverse Reaction YERVOY 1 mg/kg and Nivolumab
n=547
Sunitinib
n=535
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
General and Administration Site Conditions
Fatiguea 58 8 69 13
Pyrexia 25 0.7 17 0.6
Edemab 16 0.5 17 0.6
Skin and Subcutaneous Tissue
Rashc 39 3.7 25 1.1
Pruritus/generalized pruritus 33 0.5 11 0
Gastrointestinal
Diarrhea 38 4.6 58 6
Nausea 30 2.0 43 1.5
Vomiting 20 0.9 28 2.1
Abdominal pain 19 1.6 24 1.9
Constipation 17 0.4 18 0
Musculoskeletal and Connective Tissue
Musculoskeletal paind 37 4.0 40 2.6
Arthralgia 23 1.3 16 0
Respiratory, Thoracic, and Mediastinal
Cough/productive cough 28 0.2 25 0.4
Dyspnea/exertional dyspnea 20 2.4 21 2.1
Metabolism and Nutrition
Decreased appetite 21 1.8 29 0.9
Nervous System
Headache 19 0.9 23 0.9
Endocrine
Hypothyroidism 18 0.4 27 0.2
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.

Table 10 summarizes the laboratory abnormalities in CHECKMATE-214.

Table 10: Laboratory Abnormalities (>15%) Worsening from Baseline in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214

Laboratory Abnormality YERVOY 1 mg/kg and Nivolumaba Sunitiniba
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Chemistry
Increased lipase 48 20 51 20
Increased creatinine 42 2.1 46 1.7
Increased ALT 41 7 44 2.7
Increased AST 40 4.8 60 2.1
Increased amylase 39 12 33 7
Hyponatremia 39 10 36 7
Increased alkaline phosphatase 29 2.0 32 1.0
Hyperkalemia 29 2.4 28 2.9
Hypocalcemia 21 0.4 35 0.6
Hypomagnesemia 16 0.4 26 1.6
Hematology
Anemia 43 3.0 64 9
Lymphopenia 36 5 63 14
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: nivolumab and YERVOY group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).

In addition, among patients with TSH ≤ ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the YERVOY with nivolumab group compared to the sunitinib group (31% and 61%, respectively).

MSI-H Or dMMR Metastatic Colorectal Cancer: In Combination With Nivolumab

The safety of YERVOY with nivolumab was evaluated in 119 patients with previously treated MSI-H or dMMR mCRC in a single-arm cohort of CHECKMATE-142 [see Clinical Studies]. 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 patients receiving YERVOY and nivolumab. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration.

The most common adverse reactions (≥20%) in the YERVOY and nivolumab cohort were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting. Table 11 summarizes adverse reactions in CHECKMATE-142.

Table 11: Adverse Reactions Occurring in ≥10% of Patients (CHECKMATE-142)

Adverse Reaction YERVOY and Nivolumab MSI-H/dMMR Cohort
(n=119)
All Grades (%) Grades 3-4 (%)
General and Administration Site Conditions
Fatiguea 49 6
Pyrexia 36 0
Edemab 7 0
Gastrointestinal
Diarrhea 45 3.4
Abdominal painc 30 5
Nausea 26 0.8
Vomiting 20 1.7
Constipation 15 0
Musculoskeletal and Connective Tissue
Musculoskeletal paind 36 3.4
Arthralgia 14 0.8
Skin and Subcutaneous Tissue
Pruritus 28 1.7
Rashe 25 4.2
Dry Skin 11 0
Infections and Infestations
Upper respiratory tract infectionf 9 0
Metabolism and Nutrition
Decreased appetite 20 1.7
Respiratory, Thoracic, and Mediastinal
Cough 19 0.8
Dyspnea 13 1.7
Nervous System
Headache 17 1.7
Dizziness 11 0
Endocrine
Hyperglycemia 6 1
Hypothyroidism 14 0.8
Hyperthyroidism 12 0
Investigations
Weight decreased 10 0
Psychiatric
Insomnia 13 0.8
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 <10% of patients receiving YERVOY in CHECKMATE-142 were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).

Table 12 summarizes laboratory abnormalities in CHECKMATE-142.

Table 12: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients (CHECKMATE-142)

Laboratory Abnormality YERVOY and Nivolumab MSI-H/dMMR Cohort
(n=119)
All Grades (%) Grades 3-4 (%)
Hematology
Anemia 42 9
Thrombocytopenia 26 0.9
Lymphopenia 25 6
Neutropenia 18 0
Chemistry
Increased AST 40 12
Increased lipase 39 12
Increased amylase 36 3.4
Increased ALT 33 12
Increased alkaline phosphatase 28 5
Hyponatremia 26 5
Increased creatinine 25 3.6
Hyperkalemia 23 0.9
Increased bilirubin 21 5
Hypomagnesemia 18 0
Hypocalcemia 16 0
Hypokalemia 15 1.8
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: In Combination With Nivolumab

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 13 summarizes the adverse reactions and Table 14 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040.

Table 13: Adverse Reactions Occurring in ≥10% of Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040

Adverse Reaction YERVOY and Nivolumab
(n=49)
All Grades (%) Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rash 53 8
Pruritus 53 4
Musculoskeletal and Connective Tissue
Musculoskeletal pain 41 2
Arthralgia 10 0
Gastrointestinal
Diarrhea 39 4
Abdominal pain 22 6
Nausea 20 0
Ascites 14 6
Constipation 14 0
Dry mouth 12 0
Dyspepsia 12 2
Vomiting 12 2
Stomatitis 10 0
Respiratory, Thoracic and Mediastinal
Cough 37 0
Dyspnea 14 0
Pneumonitis 10 2
Metabolism and Nutrition
Decreased appetite 35 2
General
Fatigue 27 2
Pyrexia 27 0
Malaise 18 2
Edema 16 2
Influenza-like illness 14 0
Chills 10 0
Nervous System
Headache 22 0
Dizziness 20 0
Endocrine
Hypothyroidism 20 0
Adrenal insufficiency 18 4
Investigations
Weight decreased 20 0
Psychiatric
Insomnia 18 0
Blood and Lymphatic System
Anemia 10 4
Infections
Influenza 10 2
Vascular
Hypotension 10 0

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 14: Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040

Laboratory Abnormality YERVOY and Nivolumab
(n=47)
All Grades (%) Grades 3-4 (%)
Hematology
Lymphopenia 53 13
Anemia 43 4.3
Neutropenia 43 9
Leukopenia 40 2.1
Thrombocytopenia 34 4.3
Chemistry
Increased AST 66 40
Increased ALT 66 21
Increased bilirubin 55 11
Increased lipase 51 26
Hyponatremia 49 32
Hypocalcemia 47 0
Increased alkaline 40 4.3
phosphatase
Increased amylase 38 15
Hypokalemia 26 2.1
Hyperkalemia 23 4.3
Increased creatinine 21 0
Hypomagnesemia 11 0

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 [see Clinical Studies]. 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 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.

Table 15: Adverse Reactions in ≥10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-227

Adverse Reaction YERVOY and Nivolumab
(n=576)
Platinum-doublet Chemotherapy
(n=570)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
General
Fatiguea 44 6 42 4.4
Pyrexia 18 0.5 11 0.4
Edemab 14 0.2 12 0.5
Skin and Subcutaneous Tissue
Rashc 34 4.7 10 0.4
Pruritusd 21 0.5 3.3 0
Metabolism and Nutrition
Decreased appetite 31 2.3 26 1.4
Musculoskeletal and Connective Tissue
Musculoskeletal paine 27 1.9 16 0.7
Arthralgia 13 0.9 2.5 0.2
Gastrointestinal
Diarrhea/colitisf 26 3.6 16 0.9
Nausea 21 1.0 42 2.5
Constipation 18 0.3 27 0.5
Vomiting 13 1.0 18 2.3
Abdominal paing 10 0.2 9 0.7
Respiratory, Thoracic, and Mediastinal
Dyspneah 26 4.3 16 2.1
Coughi 23 0.2 13 0
Hepatobiliary
Hepatitisj 21 9 10 1.2
Endocrine
Hypothyroidismk 16 0.5 1.2 0
Hyperthyroidisml 10 0 0.5 0
Infections and Infestations
Pneumoniam 13 7 8 4.0
Nervous System
Headache 11 0.5 6 0
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:

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 16: Laboratory Values Worsening from Baselinea Occurring in ≥20% of Patients on YERVOY and Nivolumab - CHECKMATE-227

Laboratory Abnormality YERVOY and Nivolumab Platinum-doublet Chemotherapy
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Hematology
Anemia 46 3.6 78 14
Lymphopenia 46 5 60 15
Chemistry
Hyponatremia 41 12 26 4.9
Increased AST 39 5 26 0.4
Increased ALT 36 7 27 0.7
Increased lipase 35 14 14 3.4
Increased alkaline phosphatase 34 3.8 20 0.2
Increased amylase 28 9 18 1.9
Hypocalcemia 28 1.7 17 1.3
Hyperkalemia 27 3.4 22 0.4
Increased creatinine 22 0.9 17 0.2
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 Nivolumab And Platinum-Doublet Chemotherapy

The safety of YERVOY in combination with nivolumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies]. 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 platinumdoublet 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 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.

Table 17: Adverse Reactions in >10% of Patients Receiving YERVOY and Nivolumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA

Adverse Reaction YERVOY and Nivolumab and Platinum-Doublet Chemotherapy
(n=358)
Platinum-Doublet Chemotherapy
(n=349)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
General
Fatiguea 49 5 40 4.9
Pyrexia 14 0.6 10 0.6
Musculoskeletal and Connective Tissue
Musculoskeletal painb 39 4.5 27 2.0
Gastrointestinal
Nausea 32 1.7 41 0.9
Diarrheac 31 6 18 1.7
Constipation 21 0.6 23 0.6
Vomiting 18 2.0 17 1.4
Abdominal paind 12 0.6 11 0.9
Skin and Subcutaneous Tissue
Rashe 30 4.7 10 0.3
Pruritusf 21 0.8 2.9 0
Alopecia 11 0.8 10 0.6
Metabolism and Nutrition
Decreased appetite 28 2.0 22 1.7
Respiratory, Thoracic and Mediastinal
Coughg 19 0.6 15 0.9
Dyspneah 18 4.7 14 3.2
Endocrine
Hypothyroidismi 19 0.3 3.4 0
Nervous System
Headache 11 0.6 7 0
Dizzinessj 11 0.6 6 0
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 18: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on YERVOY and Nivolumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA

Laboratory Abnormality YERVOY and Nivolumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Hematology
Anemia 70 9 74 16
Lymphopenia 41 6 40 11
Neutropenia 40 15 42 15
Leukopenia 36 10 40 9
Thrombocytopenia 23 4.3 24 5
Chemistry
Hyperglycemia 45 7 42 2.6
Hyponatremia 37 10 27 7
Increased ALT 34 4.3 24 1.2
Increased lipase 31 12 10 2.2
Increased alkaline phosphatase 31 1.2 26 0.3
Increased amylase 30 7 19 1.3
Increased AST 30 3.5 22 0.3
Hypomagnesemia 29 1.2 33 0.6
Hypocalcemia 26 1.4 22 1.8
Increased creatinine 26 1.2 23 0.6
Hyperkalemia 22 1.7 21 2.1
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).

First-line Treatment Of Unresectable Malignant Pleural Mesothelioma: In Combination With Nivolumab

The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Clinical Studies]. Patients received either YERVOY 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks and nivolumab 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in YERVOY and nivolumab-treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received YERVOY and nivolumab for >6 months and 24% of patients received YERVOY and nivolumab for >1 year.

Serious adverse reactions occurred in 54% of patients who were treated with YERVOY in combination with nivolumab. The most frequent (≥2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.

Both YERVOY and nivolumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction. An additional 4.7% of patients permanently discontinued YERVOY alone due to adverse reactions.

The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.

Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.

Table 19: Adverse Reactions in ≥10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-743

Adverse Reaction YERVOY and Nivolumab
(n=300)
Chemotherapy
(n=284)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
General
Fatiguea 43 4.3 45 6
Pyrexiab 18 1.3 4.6 0.7
Edemac 17 0 8 0
Musculoskeletal and Connective Tissue
Musculoskeletal paind 38 3.3 17 1.1
Arthralgia 13 1.0 1.1 0
Skin and Subcutaneous Tissue
Rashe 34 2.7 11 0.4
Pruritusf 21 1.0 1.4 0
Gastrointestinal
Diarrheag 32 6 12 1.1
Nausea 24 0.7 43 2.5
Constipation 19 0.3 30 0.7
Abdominal painh 15 1 10 0.7
Vomiting 14 0 18 2.1
Respiratory, Thoracic, and Mediastinal
Dyspneai 27 2.3 16 3.2
Coughj 23 0.7 9 0
Metabolism and Nutrition
Decreased appetite 24 1.0 25 1.4
Endocrine
Hypothyroidismk 15 0 1.4 0
Infections and Infestations
Upper respiratory tract infectionl 12 0.3 7 0
Pneumoniam 10 4.0 4.2 2.1
a Includes fatigue and asthenia.
b Includes pyrexia and tumor-associated fever.
c Includes edema, generalized edema, peripheral edema, and peripheral swelling.
d Includes musculoskeletal pain, back pain, bone pain, flank pain, involuntary muscle contractions, muscle spasms, muscle twitching, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, polymyalgia rheumatica, and spinal pain.
e Includes rash, acne, acneiform dermatitis, allergic dermatitis, atopic dermatitis, autoimmune dermatitis, bullous dermatitis, contact dermatitis, dermatitis, drug eruption, dyshidrotic eczema, eczema, erythematous rash, exfoliative rash, generalized exfoliative dermatitis, generalized rash, granulomatous dermatitis, keratoderma blenorrhagica, macular rash, maculopapular rash, morbilliform rash, nodular rash, papular rash, psoriasiform dermatitis, pruritic rash, pustular rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, toxic skin eruption, and urticaria.
f Includes pruritus, allergic pruritus, and generalized pruritus.
g Includes diarrhea, colitis, enteritis, infectious enteritis, enterocolitis, infectious enterocolitis, microscopic colitis, ulcerative colitis, and viral enterocolitis.
h Includes abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain, lower abdominal pain, and upper abdominal pain.
i Includes dyspnea, dyspnea at rest, and exertional dyspnea.
j Includes cough, productive cough, and upper-airway cough syndrome.
k Includes hypothyroidism, autoimmune thyroiditis, decreased free tri-iodothyronine, increased blood thyroid stimulating hormone, primary hypothyroidism, thyroiditis, and autoimmune hypothyroidism.
l Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
m Includes pneumonia, lower respiratory tract infection, lung infection, aspiration pneumonia, and Pneumocystis jirovecii pneumonia.

Table 20: Laboratory Values Worsening from Baselinea Occurring in ≥20% of Patients on YERVOY and Nivolumab - CHECKMATE-743

Laboratory Abnormality YERVOY and Nivolumab Chemotherapy
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Chemistry
Hyperglycemia 53 3.7 34 1.1
Increased AST 38 7 17 0
Increased ALT 37 7 15 0.4
Increased lipase 34 13 9 0.8
Hyponatremia 32 8 21 2.9
Increased alkaline phosphatase 31 3.1 12 0
Hyperkalemia 30 4.1 16 0.7
Hypocalcemia 28 0 16 0
Increased amylase 26 5 13 0.9
Increased creatinine 20 0.3 20 0.4
Hematology
Lymphopenia 43 8 57 14
Anemia 43 2.4 75 15
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: 109 to 297 patients) and chemotherapy group (range: 90 to 276 patients).

First-Line Treatment Of Unresectable Advanced Or Metastatic ESCC: In Combination With Nivolumab

The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-648, a randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC [see Clinical Studies]. Patients received one of the following treatments:

  • YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks.
  • 5-FU (fluorouracil) 800 mg/m²/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m² intravenously on day 1 (of a 4-week cycle).

Among patients who received YERVOY and nivolumab, the median duration of exposure was 2.8 months (range: 0 to 24 months).

Serious adverse reactions occurred in 69% of patients receiving YERVOY in combination with nivolumab.

The most frequent serious adverse reactions reported in ≥2% of patients who received YERVOY with nivolumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%).

Fatal adverse reactions occurred in 5 (1.6%) patients who received YERVOY in combination with nivolumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome.

Yervoy and/or nivolumab were discontinued in 23% of patients and delayed in 46% of patients for an adverse reaction.

The most common adverse reactions reported in ≥20% of patients treated with YERVOY in combination with nivolumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.

Tables 21 and 22 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648.

Table 21: Adverse Reactions in ≥10% of Patients Receiving YERVOY and Nivolumab - CHECKMATE-648

Adverse Reaction YERVOY and Nivolumab
(n=322)
Cisplatin and 5-FU
(n=304)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rasha 31 3.1 7 0
Pruritis 17 0.9 3.6 0
General
Fatiguec 28 2.5 41 4.9
Pyrexiab 23 0.9 12 0.3
Gastrointestinal
Nausea 22 0.6 56 2.6
Diarrhea 22 1.9 20 2.0
Constipation 20 0.3 43 1.0
Vomiting 15 1.6 19 3.0
Dysphagia 12 5 12 4.9
Stomatitisd 11 0.6 35 3.0
Abdominal paine 10 0.9 11 0.7
Metabolism and Nutrition
Decreased appetite 17 4.0 50 6
Musculoskeletal and Connective Tissue
Musculoskeletal painf 14 0.6 8 0.3
Infections and Infestations
Pneumoniag 14 8 10 2.6
Endocrine
Hypothyroidism 14 0 0.3 0
Respiratory, Thoracic and Mediastinal
Coughh 13 0.3 13 0.3
Investigations
Weight decreased 12 1.9 11 1.0
Toxicity was graded per NCI CTCAE v4.
a Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, and rash pruritic.
b Includes tumor associated fever.
c Includes asthenia and malaise.
d Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
e Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
f Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain.
g Includes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal.
h Includes productive cough.

Table 22: Laboratory Values Worsening from Baselinea Occurring in ≥10% of Patients on YERVOY and Nivolumab- CHECKMATE-648

Laboratory Abnormality YERVOY and Nivolumab
(n=322)
Cisplatin and 5-FU
(n=304)
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Hematology
Anemia 52 7 66 14
Lymphopenia 50 13 44 8
Neutropenia 13 1.3 48 13
Thrombocytopenia 12 1.0 29 2.8
Chemistry
Hyponatremia 45 11 40 8
Hyperglycemia 43 4.3 36 0.8
Increased AST 39 6 11 1.4
Increased ALT 33 6 8 0.7
Hypocalcemia 32 0 23 0.7
Increased alkaline phosphatase 31 3.3 15 0
Hyperkalemia 23 1.6 24 0.7
Hypokalemia 19 5 17 6
Hypercalcemia 15 2.0 8 0
Hypoglycemia 15 1.2 7 0
Increased creatinine 15 0.7 31 0.7
Hypomagnesemia 15 0 25 1.8
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 59 to 307 patients) or Cisplatin and 5-FU group (range: 56 to 283 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 in the studies described below with the incidences of antibodies to 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 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 developed antiipilimumab antibodies and 7 (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for anti-ipilimumab antibodies 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 anti-ipilimumab antibodies.

Of the 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 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.

Of 271 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-743, 13.7% were positive for anti-ipilimumab antibodies and 0.4% were positive for anti-ipilimumab neutralizing antibodies. Of 269 patients evaluable for anti-nivolumab antibodies in CHECKMATE-743, 25.7% were positive for anti-nivolumab antibodies and 0.7% 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.

Blood and lymphatic system disorders: hemophagocytic lymphohistiocytosis (HLH)

Immune System: graft-versus-host disease, solid organ transplant rejection

Skin and Subcutaneous Tissue: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

DRUG INTERACTIONS

No Information provided

Read the entire FDA prescribing information for Yervoy (Ipilimumab Injection)

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