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Opdivo

Last reviewed on RxList: 6/5/2020
Opdivo Side Effects Center

What Is Opdivo?

Opdivo (nivolumab) is a human monoclonal antibody used to treat patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor; and to treat metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

What Are Side Effects of Opdivo?

Common side effects of Opdivo include:

Dosage for Opdivo

The recommended dose of Opdivo depends on the condition being treated and whether Opdivo is being administered as a single agent or in combination with another drug.

What Drugs, Substances, or Supplements Interact with Opdivo?

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

Opdivo During Pregnancy and Breastfeeding

Opdivo is not recommended for use during pregnancy; it may harm a fetus. Women should talk to their doctor about using birth control while receiving Opdivo, and for at least 5 months after the last dose. It is unknown if Opdivo passes into breast milk or how it could affect a nursing infant. Breastfeeding while using Opdivo is not recommended.

Additional Information

Our Opdivo (nivolumab) 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
Opdivo Professional Information

SIDE EFFECTS

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

  • Immune-Mediated Pneumonitis [see WARNINGS AND PRECAUTIONS]
  • Immune-Mediated Colitis [see WARNINGS AND PRECAUTIONS]
  • Immune-Mediated Hepatitis [see WARNINGS AND PRECAUTIONS]
  • Immune-Mediated Endocrinopathies [see WARNINGS AND PRECAUTIONS]
  • Immune-Mediated Nephritis and Renal Dysfunction [see WARNINGS AND PRECAUTIONS]
  • Immune-Mediated Skin Adverse Reactions [see WARNINGS AND PRECAUTIONS]
  • Immune-Mediated Encephalitis [see WARNINGS AND PRECAUTIONS]
  • Other Immune-Mediated Adverse Reactions [see WARNINGS AND PRECAUTIONS]
  • Infusion-Related Reactions [see WARNINGS AND PRECAUTIONS]
  • Complications of Allogeneic HSCT [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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO as a single agent in 1994 patients enrolled in CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 or a single-arm trial in NSCLC (n=117); OPDIVO 1 mg/kg with ipilimumab 3 mg/kg in patients enrolled in CHECKMATE-067 (n=313), CHECKMATE-040 (n=49), or another randomized trial (n=94); OPDIVO 3 mg/kg administered with ipilimumab 1 mg/kg (n=666) in patients enrolled in CHECKMATE-214 or CHECKMATE-142; OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks (n=576) in patients enrolled in CHECKMATE-227; and OPDIVO 360 mg with ipilimumab 1 mg/kg and 2 cycles of platinum-doublet chemotherapy in CHECKMATE-9LA (n=361).

Unresectable Or Metastatic Melanoma

Previously Treated Metastatic Melanoma

The safety of OPDIVO was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies]. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received OPDIVO for >6 months and 3% of patients received OPDIVO for >1 year.

The population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).

Serious adverse reactions occurred in 41% of patients receiving OPDIVO. OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash.

Tables 4 and 5 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.

Table 4: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -CHECKMATE-037

Adverse ReactionOPDIVO
(n=268)
Chemotherapy
(n=102)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Skin and Subcutaneous Tissue
  Rasha210.470
  Pruritus1903.90
Respiratory, Thoracic and Mediastinal
  Cough17060
Infections
  Upper respiratory tract infectionb1102.00
General
  Peripheral edema10050
Toxicity was graded per NCI CTCAE v4.
a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis.
b Includes rhinitis, pharyngitis, and nasopharyngitis.

Clinically important adverse reactions in <10% of patients who received OPDIVO were:

Cardiac Disorders: ventricular arrhythmia

Eye Disorders: iridocyclitis

General Disorders and Administration Site Conditions: infusion-related reactions

Investigations: increased amylase, increased lipase

Nervous System Disorders: dizziness, peripheral and sensory neuropathy,

Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis

Table 5: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -CHECKMATE-037

Laboratory AbnormalityOPDIVOChemotherapy
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
Increased AST282.4121.0
Hyponatremia255181.1
Increased alkaline phosphatase222.4131.1
Increased ALT161.650
Hyperkalemia152.060
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients).

Previously Untreated Metastatic Melanoma

CHECKMATE-066

The safety of OPDIVO was also evaluated in CHECKMATE-066, a randomized, double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies]. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in OPDIVO-treated patients. In this trial, 47% of patients received OPDIVO for >6 months and 12% of patients received OPDIVO for >1 year.

The trial population characteristics in the OPDIVO group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the OPDIVO group with ECOG performance status 0 (71% vs. 59%).

Serious adverse reactions occurred in 36% of patients receiving OPDIVO. Adverse reactions led to permanent discontinuation of OPDIVO in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of OPDIVO discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO.

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were increased gamma-glutamyltransferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.

Tables 6 and 7 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.

Table 6: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -CHECKMATE-066

Adverse ReactionOPDIVO
(n=206)
Dacarbazine
(n=205)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
General
  Fatigue491.9393.4
  Edemaa121.54.90
Musculoskeletal and Connective Tissue
  Musculoskeletal painb322.9252.4
Skin and Subcutaneous Tissue
  Rashc281.5120
  Pruritus230.5120
  Vitiligo1100.50
  Erythema1002.90
Infections
  Upper respiratory tract infectiond17060
Toxicity was graded per NCI CTCAE v4.
a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema.
b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain.
c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction.
d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.

Clinically important adverse reactions in <10% of patients who received OPDIVO were:

Nervous System Disorders: peripheral neuropathy

Table 7: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) CHECKMATE-066

Laboratory AbnormalityOPDIVODacarbazine
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
Increased ALT253.0190.5
Increased AST243.6190.5
Increased alkaline phosphatase212.6141.6
Increased bilirubin133.160
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients).

CHECKMATE-067

The safety of OPDIVO, administered with ipilimumab 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:

  • OPDIVO 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO and ipilimumab arm; n=313), or
  • OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO arm; n=313), or
  • Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab arm; n=311).
  • The median duration of exposure to OPDIVO was 2.8 months (range: 1 day to 36.4 months) for the OPDIVO and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the OPDIVO arm. In the OPDIVO and ipilimumab arm, 39% were exposed to OPDIVO for ≥6 months and 30% exposed for >1 year. In the OPDIVO arm, 53% were exposed for ≥6 months and 40% for >1 year.

The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy.

Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO and ipilimumab arm relative to the OPDIVO arm.

The most frequent (≥10%) serious adverse reactions in the OPDIVO and ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO and ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1.0%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).

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

Tables 8 and 9 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.

Table 8: Adverse Reactions Occurring in ≥10% of Patients on the OPDIVO and Ipilimumab Arm or the OPDIVO Arm and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -CHECKMATE-067

Adverse ReactionOPDIVO and Ipilimumab
(n=313)
OPDIVO
(n=313)
Ipilimumab
(n=311)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
General
  Fatiguea627591.6514.2
  Pyrexia401.6160180.6
Gastrointestinal
  Diarrhea5411365477
  Nausea443.8300.6311.9
  Vomiting313.8201.0171.6
Skin and Subcutaneous Tissue
  Rashb536401.9423.5
  Vitiligo90100.350
Musculoskeletal and Connective Tissue
  Musculoskeletal painc322.6423.8361.9
  Arthralgia210.3211.0160.3
Metabolism and Nutrition
  Decreased appetite291.9220241.3
Respiratory, Thoracic and Mediastinal
  Cough/productive cough270.3280.6220
  Dyspnea/exertional dyspnea242.9181.3170.6
Infections
  Upper respiratory tract infectiond230220.3170
Endocrine
  Hypothyroidism190.611050
  Hyperthyroidism111.36010
Investigations
  Decreased weight1207070.3
Vascular
  Hypertensione72.211592.3
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 OPDIVO with ipilimumab or OPDIVO as a single agent were:

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

Laboratory AbnormalityOPDIVO and IpilimumabOPDIVOIpilimumab
All Grades
(%)
Grade 3-4
(%)
All Grades
(%)
Grade 3-4
(%)
All Grades
(%)
Grade 3-4
(%)
Chemistry
  Increased ALT5516253.0292.7
  Hyperglycemia535.3467260
  Increased AST5213293.7291.7
  Hyponatremia4510223.3267
  Increased lipase43223212247
  Increased alkaline phosphatase416272.0232.0
  Hypocalcemia311.1150.7200.7
  Increased amylase2710192.7151.6
  Increased creatinine262.7190.7171.3
Hematology
  Anemia522.7412.6416
  Lymphopenia395414.9294.0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab (range: 75 to 297); OPDIVO (range: 81 to 306); ipilimumab (range: 61 to 301).

Adjuvant Treatment Of Melanoma

The safety of OPDIVO as a single agent was evaluated in CHECKMATE-238, a randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Clinical Studies]. The median duration of exposure was 11.5 months in OPDIVO-treated patients and was 2.7 months in ipilimumabtreated patients. In this ongoing trial, 74% of patients received OPDIVO for >6 months.

Serious adverse reactions occurred in 18% of OPDIVO-treated patients. Study therapy was discontinued for adverse reactions in 9% of OPDIVO-treated patients and 42% of ipilimumabtreated patients. Twenty-eight percent of OPDIVO-treated patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients.

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).

Tables 10 and 11 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238.

Table 10: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients CHECKMATE-238

Adverse ReactionOPDIVO
(n=452)
Ipilimumab 10 mg/kg
(n=453)
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
General
  Fatiguea570.9552.4
Gastrointestinal
  Diarrhea372.45511
  Nausea230.2280
  Abdominal painb210.2230.9
  Constipation10090
Skin and Subcutaneous Tissue
  Rashc351.1475.3
  Pruritus280371.1
Musculoskeletal and Connective Tissue
  Musculoskeletal paind320.4270.4
  Arthralgia190.4130.4
Nervous System
  Headache230.4312.0
  Dizzinesse11080
Infections
  Upper respiratory tract infectionf220150.2
Respiratory, Thoracic and Mediastinal
  Cough/productive cough190190
  Dyspnea/exertional dyspnea100.4100.2
Endocrine
  Hypothyroidismg120.27.50.4
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness.
c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity.
e Includes postural dizziness and vertigo.
f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis.
g Includes secondary hypothyroidism and autoimmune hypothyroidism.

Table 11: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of OPDIVO-Treated Patients -CHECKMATE-238

Laboratory AbnormalityOPDIVOIpilimumab 10 mg/kg
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
Hematology
  Lymphopenia270.4120.9
  Anemia260340.5
  Leukopenia1402.70.2
  Neutropenia13060.5
Chemistry
  Increased Lipase257239
  Increased ALT251.84012
  Increased AST241.3339
  Increased Amylase173.3133.1
  Hyponatremia161.1223.2
  Hyperkalemia120.290.5
  Increased Creatinine120130
  Hypocalcemia100.7160.5
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group (range: 392 to 443 patients).

Metastatic Non-Small Cell Lung Cancer

First-line Treatment of Metastatic NSCLC: In Combination with Ipilimumab

The safety of OPDIVO in combination with ipilimumab 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 OPDIVO 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks and ipilimumab 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO and ipilimumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received OPDIVO and ipilimumab for >6 months and 23% of patients received OPDIVO and ipilimumab 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. OPDIVO and ipilimumab 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 12 and 13 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.

Table 12: Adverse Reactions in ≥10% of Patients Receiving OPDIVO and Ipilimumab CHECKMATE-227

Adverse ReactionOPDIVO and Ipilimumab
(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/colitisf263.6160.9
  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:

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 13: Laboratory Values Worsening from Baselinea Occurring in ≥20% of Patients on OPDIVO and Ipilimumab -CHECKMATE-227

Laboratory AbnormalityOPDIVO and IpilimumabPlatinum-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: OPDIVO and ipilimumab 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 OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies]. Patients received either OPDIVO 360 mg administered every 3 weeks in combination with ipilimumab 1 mg/kg administered every 6 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 OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received OPDIVO and ipilimumab for >6 months and 13% of patients received OPDIVO and ipilimumab for >1 year.

Serious adverse reactions occurred in 57% of patients who were treated with OPDIVO in combination with ipilimumab 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 OPDIVO in combination with ipilimumab 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 14 and 15 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.

Table 14: Adverse Reactions in >10% of Patients Receiving OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy -CHECKMATE-9LA

Adverse ReactionOPDIVO and Ipilimumab 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 15: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy CHECKMATE-9LA

Laboratory AbnormalityOPDIVO and Ipilimumab 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: OPDIVO and ipilimumab and platinum-doublet chemotherapy group (range: 197 to 347 patients) and platinum-doublet chemotherapy group (range: 191 to 335 patients).

Second-line Treatment of Metastatic NSCLC

The safety of OPDIVO was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies]. These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks or docetaxel 75 mg/m2 intravenously every 3 weeks. The median duration of therapy in OPDIVO-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 36% of patients received OPDIVO for at least 6 months and 18% of patients received OPDIVO for at least 1 year and in CHECKMATE-057, 30% of patients received OPDIVO for >6 months and 20% of patients received OPDIVO for >1 year.

Across both trials, the median age of OPDIVO-treated patients was 61 years (range: 37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were White. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%).

In CHECKMATE-057, in the OPDIVO arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients receiving OPDIVO. OPDIVO was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions (≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

Tables 16 and 17 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.

Table 16: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -CHECKMATE-017 and CHECKMATE-057

Adverse ReactionOPDIVO
(n=418)
Docetaxel
(n=397)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Respiratory, Thoracic and Mediastinal
  Cough310.7240
Metabolism and Nutrition
  Decreased appetite281.4231.5
Skin and Subcutaneous Tissue
  Pruritus100.22.00
Toxicity was graded per NCI CTCAE v4.

Other clinically important adverse reactions observed in OPDIVO-treated patients and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).

Table 17: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of OPDIVO-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -CHECKMATE-017 and CHECKMATE-057

Laboratory AbnormalityOPDIVODocetaxel
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
Chemistry
  Hyponatremia357344.9
  Increased AST271.9130.8
  Increased alkaline phosphatase260.7180.8
  Increased ALT221.7170.5
  Increased creatinine180120.5
  Increased TSHb14N/A6N/A
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients), except for TSH: OPDIVO group n=314 and docetaxel group n=297.
b Not graded per NCI CTCAE v4.

Small Cell Lung Cancer

The safety of OPDIVO was evaluated in CHECKMATE-032, a multicenter, multi-cohort, open-label, ongoing trial that enrolled 245 patients with SCLC with disease progression after platinum-based chemotherapy [see Clinical Studies]. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks. The median duration of therapy in OPDIVO-treated patients was 1 month (range: 0 to 44.2+ months): 17% of patients received OPDIVO for >6 months and 9% of patients received OPDIVO for >1 year.

The population characteristics were: median age 63 years (range: 29 to 83), 92% White, and 60% male. Baseline ECOG performance status was 0 (30%) or 1 (70%), 94% were former/current smokers, 56% received one prior line of therapy, and 44% received two or more prior lines of therapy.

Serious adverse reactions occurred in 45% of patients. OPDIVO was discontinued for adverse reactions in 10% of patients and 25% of patients had at least one dose withheld for an adverse reaction.

The most frequent (≥2%) serious adverse reactions were pneumonia, dyspnea, pneumonitis, pleural effusion, and dehydration. The most common (≥20%) adverse reactions were fatigue, decreased appetite, musculoskeletal pain, dyspnea, nausea, diarrhea, constipation, and cough.

The toxicity profile observed in patients with metastatic SCLC was generally similar to that observed in patients with other solid tumors who received OPDIVO as a single agent.

Advanced Renal Cell Carcinoma

Previously Treated Renal Cell Carcinoma

The safety of OPDIVO was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies]. The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in OPDIVO-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients.

Rate of death on treatment or within 30 days of the last dose was 4.7% on the OPDIVO arm. Serious adverse reactions occurred in 47% of patients receiving OPDIVO. Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients. Forty-four percent (44%) of patients receiving OPDIVO had a dose interruption for an adverse reaction.

The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH >ULN in the OPDIVO group compared to the everolimus group (26% and 14%, respectively).

Tables 18 and 19 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025.

Table 18: Adverse Reactions in >15% of Patients Receiving OPDIVO -CHECKMATE025

Adverse ReactionOPDIVO
(n=406)
Everolimus
(n=397)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Adverse Reaction98569662
General
  Fatiguea566577
  Pyrexia170.7200.8
Respiratory, Thoracic and Mediastinal
  Cough/productive cough340380.5
  Dyspnea/exertional dyspnea273.0312.0
  Upper respiratory infectionb180110
Gastrointestinal
  Nausea280.5291
  Diarrheac252.2321.8
  Constipation230.5180.5
  Vomiting160.5160.5
Skin and Subcutaneous Tissue
  Rashd281.5361.0
  Pruritus/generalized pruritus190140
Metabolism and Nutrition
  Decreased appetite231.2301.5
Musculoskeletal and Connective Tissue
  Arthralgia201.0140.5
  Back pain213.4162.8
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia, decreased activity, fatigue, and malaise.
b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI).
c Includes colitis, enterocolitis, and gastroenteritis.
d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema.

Other clinically important adverse reactions in CHECKMATE-025 were:

General Disorders and Administration Site Conditions: peripheral edema/edema

Gastrointestinal Disorders: abdominal pain/discomfort

Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain

Nervous System Disorders: headache/migraine, peripheral neuropathy

Investigations: weight decreased

Skin Disorders: palmar-plantar erythrodysesthesia

Table 19: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on OPDIVO -CHECKMATE-025

Laboratory AbnormalityOPDIVOEverolimus
Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)
Hematology
  Lymphopenia4265311
  Anemia3986916
Chemistry
  Increased creatinine422.0451.6
  Increased AST332.8391.6
  Increased alkaline phosphatase322.3320.8
  Hyponatremia327266
  Hyperkalemia304.0202.1
  Hypocalcemia230.9261.3
  Increased ALT223.2310.8
  Hypercalcemia193.260.3
Lipids
  Increased triglycerides321.56711
  Increased cholesterol210.3551.4
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients).

Previously Untreated Renal Cell Carcinoma

The safety of OPDIVO with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC received OPDIVO 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535) [see Clinical Studies]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in OPDIVO and ipilimumab-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 OPDIVO and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year.

Serious adverse reactions occurred in 59% of patients receiving OPDIVO and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of OPDIVO and ipilimumab patients. Fifty-four percent (54%) of patients receiving OPDIVO and ipilimumab had a dose interruption for an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of OPDIVO and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia.

Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of OPDIVO and ipilimumab-treated patients in CHECKMATE-214.

Table 20: Adverse Reactions in >15% of Patients Receiving OPDIVO and Ipilimumab CHECKMATE-214

Adverse ReactionOPDIVO and Ipilimumab
(n=547)
Sunitinib
(n=535)
Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)
Adverse Reaction99659976
General
  Fatiguea5886913
  Pyrexia250.7170.6
  Edemab160.5170.6
Skin and Subcutaneous Tissue
  Rashc393.7251.1
  Pruritus/generalized pruritus330.5110
Gastrointestinal
  Diarrhea384.6586
  Nausea302.0431.5
  Vomiting200.9282.1
  Abdominal pain191.6241.9
  Constipation170.4180
Musculoskeletal and Connective Tissue
  Musculoskeletal paind374.0402.6
  Arthralgia231.3160
Respiratory, Thoracic and Mediastinal
  Cough/productive cough280.2250.4
  Dyspnea/exertional dyspnea202.4212.1
Metabolism and Nutrition
  Decreased appetite211.8290.9
Nervous System
  Headache190.9230.9
Endocrine
  Hypothyroidism180.4270.2
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 21: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on OPDIVO and Ipilimumab -CHECKMATE-214

Laboratory AbnormalityOPDIVO and IpilimumabSunitinib
Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)
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
Hematology
  Anemia433.0649
  Lymphopenia3656314
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab 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 OPDIVO and ipilimumab group compared to the sunitinib group (31% and 61%, respectively).

Classical Hodgkin Lymphoma

The safety of OPDIVO was evaluated in 266 adult patients with cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials) [see Clinical Studies]. Patients received OPDIVO 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity.

The median age was 34 years (range: 18 to 72), 98% of patients had received autologous HSCT, none had received allogeneic HSCT, and 74% had received brentuximab vedotin. The median number of prior systemic regimens was 4 (range: 2 to 15). Patients received a median of 23 doses (cycles) of OPDIVO (range: 1 to 48), with a median duration of therapy of 11 months (range: 0 to 23 months).

Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last nivolumab dose, 2 from infection 8 to 9 months after completing nivolumab, and 6 from complications of allogeneic HSCT. Serious adverse reactions occurred in 26% of patients. Dose delay for an adverse reaction occurred in 34% of patients. OPDIVO was discontinued due to adverse reactions in 7% of patients.

The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. The most common adverse reactions (≥20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus.

Tables 22 and 23 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-205 and CHECKMATE-039.

Table 22: Adverse Reactions Occurring in ≥10% of Patients -CHECKMATE-205 and CHECKMATE-039

Adverse ReactionaOPDIVO (n=266)
All Grades (%)Grades 3-4 (%)
Infections
  Upper respiratory tract infectionb440.8
  Pneumonia/bronchopneumoniac133.8
  Nasal congestion110
General
  Fatigued391.9
  Pyrexia29<1
Respiratory, Thoracic and Mediastinal
  Cough/productive cough360
  Dyspnea/exertional dyspnea151.5
Gastrointestinal
  Diarrheae331.5
  Nausea200
  Vomiting19<1
  Abdominal painf16<1
  Constipation140.4
Musculoskeletal and Connective Tissue
  Musculoskeletal paing261.1
  Arthralgia16<1
Skin and Subcutaneous Tissue
  Rashh241.5
  Pruritus200
Nervous System
  Headache17<1
  Neuropathy peripherali12<1
Injury, Poisoning and Procedural Complications
  Infusion-related reaction14<1
Endocrine
  Hypothyroidism/thyroiditis120
Toxicity was graded per NCI CTCAE v4.
a Includes events occurring up to 30 days after last nivolumab dose, regardless of causality. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred up to 30 days after completing the initial nivolumab course.
b Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis.
c Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia.
d Includes asthenia.
e Includes colitis.
f Includes abdominal discomfort and upper abdominal pain.
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity.
h Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform.
i Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. These numbers are specific to treatment-emergent events.

Additional information regarding clinically important adverse reactions:

Immune-mediated Pneumonitis

In CHECKMATE-205 and CHECKMATE-039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO (one Grade 3 and 12 Grade 2). The median time to onset was 4.5 months (range: 5 days to 12 months). All 13 patients received systemic corticosteroids, with resolution in 12. Four patients permanently discontinued OPDIVO due to pneumonitis. Eight patients continued OPDIVO (three after dose delay), of whom two had recurrence of pneumonitis.

Peripheral Neuropathy

Treatment-emergent peripheral neuropathy was reported in 12% (31/266) of all patients receiving OPDIVO. Twenty-eight patients (11%) had new-onset peripheral neuropathy and 3 patients had worsening of neuropathy from baseline. The median time to onset was 50 (range: 1 to 309) days.

Complications of Allogeneic HSCT after OPDIVO

Of 17 patients with cHL from the CHECKMATE-205 and CHECKMATE-039 trials who underwent allogeneic HSCT after treatment with OPDIVO, 6 patients (35%) died from transplant-related complications. Five deaths occurred in the setting of severe (Grade 3 to 4) or refractory GVHD. Hyperacute GVHD occurred in 2 patients (12%) and Grade 3 or higher GVHD was reported in 5 patients (29%). Hepatic VOD occurred in 1 patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure.

Table 23 summarizes laboratory abnormalities in patients with cHL. The most common (≥20%) treatment-emergent laboratory abnormalities included cytopenias, liver function abnormalities, and increased lipase. Other common findings (≥10%) included increased creatinine, electrolyte abnormalities, and increased amylase.

Table 23: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients -CHECKMATE-205 and CHECKMATE-039

Laboratory AbnormalityOPDIVOa
(n=266)
All Grades (%)bGrades 3-4 (%)b
Hematology
  Leukopenia384.5
  Neutropenia375
  Thrombocytopenia373.0
  Lymphopenia3211
  Anemia262.6
Chemistryc
  Increased AST332.6
  Increased ALT313.4
  Increased lipase229
  Increased alkaline phosphatase201.5
  Hyponatremia201.1
  Hypokalemia161.9
  Increased creatinine16<1
  Hypocalcemia15<1
  Hyperkalemia151.5
  Hypomagnesemia14<1
  Increased amylase131.5
  Increased bilirubin111.5
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement: range: 203 to 266 patients.
b Includes events occurring up to 30 days after last nivolumab dose. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred within 30 days of completing the initial nivolumab course.
c In addition, in the safety population, fasting hyperglycemia (all grade 1-2) was reported in 27 of 69 (39%) evaluable patients and fasting hypoglycemia (all grade 1-2) in 11 of 69 (16%).

Squamous Cell Carcinoma Of The Head And Neck

The safety of OPDIVO was evaluated in CHECKMATE-141, a randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within 6 months of receiving prior platinum-based therapy [see Clinical Studies]. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either:

  • cetuximab (n=13), 400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly, or
  • methotrexate (n=46) 40 to 60 mg/m2 intravenously weekly, or
  • docetaxel (n=52) 30 to 40 mg/m2 intravenously weekly.

The median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in OPDIVO-treated patients. In this trial, 18% of patients received OPDIVO for >6 months and 2.5% of patients received OPDIVO for >1 year.

The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the OPDIVO group were ≥65 years of age and 37% in the comparator group were ≥65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy.

Serious adverse reactions occurred in 49% of patients receiving OPDIVO. OPDIVO was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.

The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.

Urothelial Carcinoma

The safety of OPDIVO was evaluated in CHECKMATE-275, a single arm trial in which 270 patients with locally advanced or metastatic urothelial carcinoma had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies]. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for an adverse reaction.

Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with OPDIVO. Serious adverse reactions occurred in 54% of patients. OPDIVO was discontinued for adverse reactions in 17% of patients.

The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite.

Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.

Table 24: Adverse Reactions Occurring in ≥10% of Patients -CHECKMATE-275

Adverse ReactionOPDIVO
(n=270)
All Grades (%)Grades 3-4 (%)
Adverse Reaction9951
General
  Asthenia/fatigue/malaise467
  Pyrexia/tumor associated fever170.4
  Edema/peripheral edema/peripheral swelling130.4
Musculoskeletal and Connective Tissue
  Musculoskeletal paina302.6
  Arthralgia100.7
Metabolism and Nutrition
  Decreased appetite222.2
Gastrointestinal
  Nausea220.7
  Diarrhea172.6
  Constipation160.4
  Abdominal painb131.5
  Vomiting121.9
Respiratory, Thoracic and Mediastinal
  Cough/productive cough180
  Dyspnea/exertional dyspnea143.3
Infections
  Urinary tract infection/escherichia/fungal urinary tract infection177
Skin and Subcutaneous Tissue
  Rashc161.5
  Pruritus120
Endocrine
  Thyroid disordersd150
Toxicity was graded per NCI CTCAE v4.
a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.
b Includes abdominal discomfort, lower and upper abdominal pain.
c Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular, maculopapular, or pruritic.
d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism, thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri-iodothyronine increased.

Table 25: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients -CHECKMATE-275

Laboratory AbnormalityOPDIVO a
All Grades (%)Grades 3-4 (%)
Chemistry
  Hyperglycemia422.4
  Hyponatremia4111
  Increased creatinine392.0
  Increased alkaline phosphatase335.5
  Hypocalcemia260.8
  Increased AST243.5
  Increased lipase207
  Hyperkalemia191.2
  Increased ALT181.2
  Increased amylase184.4
  Hypomagnesemia160
Hematology
  Lymphopenia429
  Anemia407
  Thrombocytopenia152.4
  Leukopenia110
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: range: 84 to 256 patients.

MSI-H Or dMMR Metastatic Colorectal Cancer

The safety of OPDIVO administered as a single agent or in combination with ipilimumab was evaluated in CHECKMATE-142, a multicenter, non-randomized, multiple parallel-cohort, open-label trial [see Clinical Studies]. In CHECKMATE-142, 74 patients with mCRC received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or until intolerable toxicity and 119 patients with mCRC received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses, then OPDIVO 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity.

In the OPDIVO with ipilimumab cohort, serious adverse reactions occurred in 47% of patients. OPDIVO was discontinued in 13% of patients and delayed in 45% of patients for an adverse reaction. 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 (reported in ≥20% of patients) were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting.

Tables 26 and 27 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-142. Based on the design of CHECKMATE-142, the data below cannot be used to identify statistically significant differences between the two cohorts summarized below for any adverse reaction

Table 26: Adverse Reactions Occurring in ≥10% of Patients -CHECKMATE-142

Adverse ReactionOPDIVO
(n=74)
OPDIVO and Ipilimumab
(n=119)
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
General
  Fatiguea545496
  Pyrexia240360
  Edemab12070
Gastrointestinal
  Diarrhea432.7453.4
  Abdominal painc342.7305
  Nausea341.4260.8
  Vomiting284.1201.7
  Constipation200150
Musculoskeletal and Connective Tissue
  Musculoskeletal paind281.4363.4
  Arthralgia190140.8
Respiratory, Thoracic and Mediastinal
  Cough260190.8
  Dyspnea81131.7
Skin and Subcutaneous Tissue
  Rashe231.4254.2
  Pruritus190281.7
  Dry Skin70110
Infections
  Upper respiratory tract infectionf20090
Endocrine
  Hyperglycemia192.761
  Hypothyroidism50140.8
  Hyperthyroidism40120
Nervous System
  Headache160171.7
  Dizziness140110
Metabolism and Nutrition
  Decreased appetite141.4201.7
Psychiatric
  Insomnia90130.8
Investigations
  Weight decreased80100
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.

Clinically important adverse reactions reported in <10% of patients receiving OPDIVO with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).

Table 27: Laboratory Abnormalities Worsening from BaselineOccurring in ≥10% of Patients -CHECKMATE-142

Laboratory AbnormalityOPDIVO
(n=74)
OPDIVO and Ipilimumab
(n=119)
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
Hematology
  Anemia507429
  Lymphopenia367256
  Neutropenia204.3180
  Thrombocytopenia161.4260.9
Chemistry
  Increased alkaline phosphatase372.8285
  Increased lipase33193912
  Increased ALT322.83312
  Increased AST311.44012
  Hyponatremia274.3265
  Hypocalcemia190160
  Hypomagnesemia170180
  Increased amylase164.8363.4
  Increased bilirubin144.2215
  Hypokalemia140151.8
  Increased creatinine120253.6
  Hyperkalemia110230.9
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 62 to 71 for the OPDIVO cohort and from 87 to 114 for the OPDIVO and ipilimumab cohort.

Hepatocellular Carcinoma

The safety of OPDIVO 3 mg/kg every 2 weeks as a single agent was evaluated in a 154-patient subgroup of patients with HCC and Child-Pugh Class A cirrhosis who progressed on or were intolerant to sorafenib. These patients enrolled in Cohorts 1 and 2 of CHECKMATE-040, a multicenter, multiple cohort, open-label trial [see Clinical Studies]. Patients were required to have an AST and ALT ≤5 x ULN and total bilirubin <3 mg/dL. The median duration of exposure to OPDIVO was 5 months (range: 0 to 22+ months). Serious adverse reactions occurred in 49% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, pneumonia, and anemia.

The toxicity profile observed in these patients with advanced HCC was generally similar to that observed in patients with other cancers, with the exception of a higher incidence of elevations in transaminases and bilirubin levels. Treatment with OPDIVO resulted in treatment-emergent Grade 3 or 4 AST in 27 (18%) patients, Grade 3 or 4 ALT in 16 (11%) patients, and Grade 3 or 4 bilirubin in 11 (7%) patients. Immune-mediated hepatitis requiring systemic corticosteroids occurred in 8 (5%) patients.

The safety of OPDIVO 1 mg/kg in combination with ipilimumab 3 mg/kg was evaluated in a subgroup comprising 49 patients with HCC and Child-Pugh Class A cirrhosis enrolled in Cohort 4 of the CHECKMATE-040 trial who progressed on or were intolerant to sorafenib. OPDIVO and ipilimumab were administered every 3 weeks for 4 doses, followed by single-agent OPDIVO 240 mg every 2 weeks until disease progression or unacceptable toxicity. During the OPDIVO and ipilimumab combination period, 33 of 49 (67%) patients received all 4 planned doses of OPDIVO and ipilimumab. During the entire treatment period, the median duration of exposure to OPDIVO was 5.1 months (range: 0 to 35+ months) and to ipilimumab was 2.1 months (range: 0 to 4.5 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.

The most frequent 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.

Tables 28 and 29 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-040. Based on the design of the study, the data below cannot be used to identify statistically significant differences between the cohorts summarized below for any adverse reaction.

Table 28: Adverse Reactions Occurring in ≥10% of Patients Receiving OPDIVO in Combination with Ipilimumab in Cohort 4 or OPDIVO in Cohorts 1 and 2 of CHECKMATE-040

Adverse ReactionOPDIVO and Ipilimumab
(n=49)
OPDIVO
(n=154)
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
Skin and Subcutaneous Tissue
  Rash538260.6
  Pruritus534270.6
Musculoskeletal and Connective Tissue
  Musculoskeletal pain412361.9
  Arthralgia10080.6
Gastrointestinal
  Diarrhea394271.3
  Abdominal pain226343.9
  Nausea200160
  Ascites14692.6
  Constipation140160
  Dry mouth12090
  Dyspepsia12280
  Vomiting122140
  Stomatitis10070
  Abdominal distension80110
Respiratory, Thoracic and Mediastinal
  Cough370230
  Dyspnea140131.9
  Pneumonitis1021.30.6
Metabolism and Nutrition
  Decreased appetite352221.3
General
  Fatigue272383.2
  Pyrexia270180.6
  Malaise1826.50
  Edema162120
  Influenza-like illness14090
  Chills1003.90
Nervous System
  Headache220110.6
  Dizziness20090
Endocrine
  Hypothyroidism2004.50
  Adrenal insufficiency1840.60
Investigations
  Weight decreased20070
Psychiatric
  Insomnia180100
Blood and Lymphatic System
  Anemia104192.6
Infections
  Influenza1021.90
  Upper Respiratory Tract Infection60120
Vascular
  Hypotension1000.60

Clinically important adverse reactions reported in <10% of patients who received OPDIVO with ipilimumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%).

Table 29: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients Receiving OPDIVO in Combination with Ipilimumab in Cohort 4 or OPDIVO as a Single Agent in Cohorts 1 and 2 of CHECKMATE-040

Laboratory AbnormalityOPDIVO and Ipilimumab
(n=47)
OPDIVO*
All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)
Hematology
  Lymphopenia53135915
  Anemia434.3494.6
  Neutropenia439191.3
  Leukopenia402.1263.3
  Thrombocytopenia344.3367
Chemistry
  Increased AST66405818
  Increased ALT66214811
  Increased bilirubin5511367
  Increased lipase51263714
  Hyponatremia49324011
  Hypocalcemia470280
  Increased alkaline phosphatase404.3447
  Increased amylase3815316
  Hypokalemia262.1120.7
  Hyperkalemia234.3202.6
  Increased creatinine210171.3
  Hypomagnesemia110130
* The denominator used to calculate the rate varied from 140 to 152 based on the number of patients with a baseline value and at least one post-treatment value.

In patients who received OPDIVO with ipilimumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. In patients who received single-agent OPDIVO, virologic breakthrough occurred in 5 of 47 (11%) patients and 1 of 32 (3%) 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.

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 incidence of antibodies to OPDIVO with the incidences of antibodies to other products may be misleading.

Of the 2085 patients who were treated with OPDIVO as a single agent at dose of 3 mg/kg every 2 weeks and evaluable for the presence of anti-nivolumab antibodies, 11% tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay and 0.7% had neutralizing antibodies against nivolumab. There was no evidence of altered pharmacokinetic profile or increased incidence of infusion-related reactions with anti-nivolumab antibody development.

Of the patients with melanoma, advanced renal cell carcinoma, metastatic colorectal cancer, and metastatic or recurrent non-small cell lung cancer who were treated with OPDIVO and ipilimumab and evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26% (132/516) with OPDIVO 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks, 36.7% (180/491) with OPDIVO 3 mg/kg every 2 weeks and ipilimumab 1 mg every 6 weeks, and 38% (149/394) with OPDIVO 1 mg/kg followed by ipilimumab 3 mg/kg every 3 weeks. The incidence of neutralizing antibodies against nivolumab was 0.8% (4/516) with OPDIVO 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks, 1.4% (7/491) with OPDIVO 3 mg/kg every 2 weeks and ipilimumab 1 mg every 6 weeks, and 4.6% (18/394) with OPDIVO 1 mg/kg followed by ipilimumab 3 mg/kg every 3 weeks.

Of the patients with hepatocellular carcinoma who were treated with OPDIVO and ipilimumab every 3 weeks for 4 doses followed by OPDIVO every 3 weeks and were evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 45% (20/44) with OPDIVO 3 mg/kg followed by ipilimumab 1 mg/kg and 56% (27/48) with OPDIVO 1 mg/kg followed by ipilimumab 3 mg/kg; the corresponding incidence of neutralizing antibodies against nivolumab was 14% (6/44) and 23% (11/48), respectively.

Of the patients with NSCLC who were treated with OPDIVO 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and platinum-doublet chemotherapy, and were evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 34% (104/308); the incidence of neutralizing antibodies against nivolumab was 2.6% (8/308).

There was no evidence of increased incidence of infusion-related reactions with anti-nivolumab antibody development.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of OPDIVO. 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.

Eye: Vogt-Koyanagi-Harada (VKH) syndrome

Complications of OPDIVO Treatment After Allogeneic HSCT: Treatment refractory, severe acute and chronic GVHD

Read the entire FDA prescribing information for Opdivo (Nivolumab Injection)

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