Slideshows Images Quizzes

Copyright © 2018 by RxList Inc. RxList does not provide medical advice, diagnosis or treatment. See additional information.

Opdivo

Last reviewed on RxList: 3/15/2019
Opdivo Side Effects Center

Last reviewed on RxList 3/15/2019

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. Common side effects of Opdivo include:

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

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.

Opdivo Professional Information

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of 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 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 the Warnings and Precautions section reflect exposure to OPDIVO as a single agent in 1994 patients enrolled in the CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 trials 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) or another randomized study (n=94); and OPDIVO 3 mg/kg administered with ipilimumab 1 mg/kg in 666 patients enrolled in CHECKMATE-214 or CHECKMATE-142.

The data described below reflect exposure to OPDIVO as a single agent in 13 clinical trials (n=3063), OPDIVO with 3 mg/kg ipilimumab in 1 clinical trial (n=313), and OPDIVO with 1 mg/kg ipilimumab in 2 clinical trials (n=666) [see Clinical Studies].

Unresectable Or Metastatic Melanoma

Previously Treated Metastatic Melanoma

The safety of OPDIVO as a single agent was evaluated in CHECKMATE-037, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received 3 mg/kg of OPDIVO by intravenous infusion every 2 weeks (n=268) or investigator's choice of chemotherapy (n=102), either dacarbazine 1000 mg/m² every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m² every 3 weeks [see Clinical Studies]. 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 greater than 6 months and 3% of patients received OPDIVO for greater than 1 year.

In CHECKMATE-037, 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.

The trial 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 LDH at baseline (51% vs. 38%).

OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving OPDIVO. 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 less than 5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.

Table 2 summarizes the adverse reactions that occurred in at least 10% of OPDIVOtreated patients in CHECKMATE-037. The most common adverse reaction (reported in at least 20% of patients) was rash.

Table 2: 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 Reaction OPDIVO
(n=268)
Chemotherapy
(n=102)
All Grades Grades 3-4 All Grades Grades 3-4
Percentage (%) of Patients
Skin and Subcutaneous Tissue Disorders
Rasha 21 0.4 7 0
Pruritus 19 0 3.9 0
Respiratory, Thoracic, and Mediastinal Disorders
Cough 17 0 6 0
Infections
Upper respiratory tract infectionb 11 0 2.0 0
General Disorders and Administration Site Conditions
Peripheral edema 10 0 5 0
Toxicity was graded per NCI CTCAE v4.
a Rash is a composite term which includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis.
b Upper respiratory tract infection is a composite term which includes rhinitis, pharyngitis, and nasopharyngitis.

Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO in CHECKMATE-037 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 3: Laboratory Abnormalities Worsening from Baseline 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 Abnormality Percentage of Patients with Worsening Laboratory Test from Baselinea
OPDIVO Chemotherapy
All Grades Grades 3-4 All Grades Grades 3-4
Increased AST 28 2.4 12 1.0
Increased alkaline phosphatase 22 2.4 13 1.1
Hyponatremia 25 5 18 1.1
Increased ALT 16 1.6 5 0
Hyperkalemia 15 2.0 6 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 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 which 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma received 3 mg/kg of OPDIVO by intravenous infusion every 2 weeks (n=206) or dacarbazine 1000 mg/m² every 3 weeks (n=205) [see Clinical Studies]. 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 greater than 6 months and 12% of patients received OPDIVO for greater than 1 year.

The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications.

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%).

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. Serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%).

Table 4 summarizes selected adverse reactions that occurred in at least 10% of OPDIVO-treated patients. The most common adverse reactions (reported in at least 20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.

Table 4: 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 Reaction OPDIVO
(n=206)
Dacarbazine
(n=205)
All Grades Grades 3-4 All Grades Grades 3-4
Percentage (%) of Patients
General Disorders and Administration Site Conditions
Fatigue 49 1.9 39 3.4
Edemaa 12 1.5 4.9 0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painb 32 2.9 25 2.4
Skin and Subcutaneous Tissue Disorders
Rashc 28 1.5 12 0
Pruritus 23 0.5 12 0
Erythema 10 0 2.9 0
Vitiligo 11 0 0.5 0
Infections
Upper respiratory tract infectiond 17 0 6 0
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.

Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO in CHECKMATE-066 were:

Nervous System Disorders: peripheral neuropathy

Table 5: Laboratory Abnormalities Worsening from Baseline 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 Abnormality Percentage of Patients with Worsening Laboratory Test from Baselinea
OPDIVO   Dacarbazine
All Grades Grades 3-4 All Grades Grades 3-4
Increased ALT 25 3.0 19 0.5
Increased AST 24 3.6 19 0.5
Increased alkaline phosphatase 21 2.6 14 1.6
Increased bilirubin 13 3.1 6 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 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 [see Clinical Studies], a randomized (1:1:1), a double-blind trial in which 937 patients with previously untreated, unresectable or metastatic melanoma received:

  • OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by OPDIVO 3 mg/kg as a single agent every 2 weeks (OPDIVO plus ipilimumab arm; n=313),
  • OPDIVO 3 mg/kg every 2 weeks (OPDIVO arm; n=313), or
  • Ipilimumab 3 mg/kg 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 18.8 months) for the OPDIVO plus ipilimumab arm and 6.6 months (range: 1 day to 17.3 months) for the OPDIVO arm. In the OPDIVO plus ipilimumab arm, 39% were exposed to OPDIVO for ≥6 months and 24% exposed for >1 year. In the OPDIVO arm, 53% were exposed for ≥6 months and 32% for >1 year.

CHECKMATE-067 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.

The trial population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with 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.

In CHECKMATE-067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus ipilimumab arm relative to the OPDIVO arm.

The most frequent (≥10%) serious adverse reactions in the OPDIVO plus ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO plus ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were diarrhea (8% and 1.9%), colitis (8% and 0.6%), increased ALT (4.8% and 1.3%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%). The most common (≥20%) adverse reactions in the OPDIVO plus ipilimumab arm were fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea. The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue, rash, diarrhea, and nausea. Table 6 summarizes the incidence of adverse reactions occurring in at least 10% of patients in either OPDIVO-containing arm in CHECKMATE-067.

Table 6: Adverse Reactions Occurring in ≥10% of Patients on the OPDIVO plus 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 Reaction Percentage (%) of Patients
OPDIVO plus 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 Disorders and Administration Site Conditions
Fatiguea 59 6 53 1.9 50 3.9
Pyrexia 37 1.6 14 0 17 0.6
Skin and Subcutaneous Tissue Disorders
Rashb 53 5 40 1.6 42 3.9
Gastrointestinal Disorders
Diarrhea 52 11 31 3.8 46 8
Nausea 40 3.5 28 0.6 29 1.9
Vomiting 28 3.5 17 1.0 16 1.6
Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea 20 2.2 12 1.3 13 0.6
Toxicity was graded per NCI CTCAE v4.
a Fatigue is a composite term which includes asthenia and fatigue.
b Rash is a composite term which includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, erythema, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, pruritic rash, and seborrheic dermatitis.

Other clinically important adverse reactions in less than 10% of patients treated with either OPDIVO with ipilimumab or single-agent OPDIVO in CHECKMATE-067 were:

Gastrointestinal Disorders: stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders: vitiligo

Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren's syndrome, spondyloarthropathy

Nervous System Disorders: neuritis, peroneal nerve palsy

Table 7: Laboratory Abnormalities Worsening from Baseline 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 Abnormality Percentage (%) of Patientsa
OPDIVO plus Ipilimumab OPDIVO Ipilimumab
Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4
Chemistry
Increased ALT 53 15 23 3.0 28 2.7
Increased AST 47 13 27 3.7 27 1.7
Hyponatremia 42 9 20 3.3 25 7
Increased lipase 41 20 29 9 23 7
Increased alkaline phosphatase 40 6 24 2.0 22 2.0
Hypocalcemia 29 1.1 13 0.7 21 0.7
Increased amylase 25 9.1 15 1.9 14 1.6
Increased creatinine 23 2.7 16 0.3 16 1.3
Hematology
Anemia 50 2.7 39 2.6 40 6
Lymphopenia 35 4.8 39 4.3 27 3.4
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 plus ipilimumab (range: 241 to 297); OPDIVO (range: 260 to 306); ipilimumab (range: 253 to 304).

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 which 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received 3 mg/kg of OPDIVO by intravenous infusion every 2 weeks (n=452) or 10 mg/kg ipilimumab (n=453), by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to a 1 year [see Clinical Studies]. The median duration of exposure was 11.5 months in OPDIVO-treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received OPDIVO for greater than 6 months.

Study therapy was discontinued for adverse reactions in 9% of OPDIVO-treated patients and 42% of ipilimumab-treated 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 at least 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

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

Table 8 summarizes the adverse reactions that occurred in at least 10% of OPDIVO-treated patients in CHECKMATE-238.

Table 8: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients (CHECKMATE-238)

Adverse Reaction OPDIVO
(n=452)
Ipilimumab 10 mg/kg
(n=453)
All Grades Grades 3-4 All Grades Grades 3-4
Percentage (%) of Patients
General Disorders and Administration Site Conditions
Fatiguea 57 0.9 55 2.4
Gastrointestinal Disorders
Diarrhea 37 2.4 55 11
Nausea 23 0.2 28 0
Abdominal painb 21 0.2 23 0.9
Constipation 10 0 9 0
Skin and Subcutaneous Tissue Disorders
Rashc 35 1.1 47 5.3
Pruritus 28 0 37 1.1
Infections and Infestations
Upper respiratory tract infectiond 22 0 15 0.2
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paine 32 0.4 27 0.4
Arthralgia 19 0.4 13 0.4
Nervous System Disorders
Headache 23 0.4 31 2.0
Dizzinessf 11 0 8 0
Respiratory, Thoracic and Mediastinal Disorders
Cough/productive cough 19 0 19 0
Dyspnea/exertional dyspnea 10 0.4 10 0.2
Endocrine Disorders
Hypothyroidismg 12 0.2 7.5 0.4
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 also 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 upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis.
e Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity.
f Includes postural dizziness and vertigo.
g Includes secondary hypothyroidism and autoimmune hypothyroidism.

Table 9: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO-Treated Patients (CHECKMATE-238)

Laboratory Abnormality Percentage of Patients with Worsening Laboratory Test from Baselinea
OPDIVO Ipilimumab 10 mg/kg
All Grades Grades 3-4 All Grades Grades 3-4
Hematology
Lymphopenia 27 0.4 12 0.9
Anemia 26 0 34 0.5
Leukopenia 14 0 2.7 0.2
Neutropenia 13 0 6 0.5
Chemistry
Increased Lipase 25 7 23 9
Increased ALT 25 1.8 40 12
Increased AST 24 1.3 33 9
Increased Amylase 17 3.3 13 3.1
Hyponatremia 16 1.1 22 3.2
Hyperkalemia 12 0.2 9 0.5
Increased Creatinine 12 0 13 0
Hypocalcemia 10 0.7 16 0.5
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

The safety of OPDIVO in metastatic NSCLC 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]. Patients received 3 mg/kg of OPDIVO over 60 minutes by intravenous infusion every 2 weeks or docetaxel administered intravenously at 75 mg/m² 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 greater than 6 months and 20% of patients received OPDIVO for greater than 1 year.

CHECKMATE-017 and CHECKMATE-057 excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease.

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%).

OPDIVO was discontinued in 11% of patients, and was delayed in 28% of patients for an adverse reaction. Serious adverse reactions occurred in 46% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. 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. Across both trials, the most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

Table 10 summarizes selected adverse reactions occurring more frequently in at least 10% of OPDIVO-treated patients.

Table 10: 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 Reaction OPDIVO
(n=418)
Docetaxel
(n=397)
All Grades Grades 3-4 All Grades Grades 3-4
Percentage (%) of Patients
Respiratory, Thoracic, and Mediastinal Disorders
Cough 31 0.7 24 0
Metabolism and Nutrition Disorders
Decreased appetite 28 1.4 23 1.5
Skin and Subcutaneous Tissue Disorders
Pruritus 10 0.2 2.0 0
Toxicity was graded per NCI CTCAE v4.

Other clinically important adverse reactions observed in patients treated with OPDIVO and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% Grade 1-4, 5% Grade 3-4), musculoskeletal pain (33%), pleural effusion (4.5%), pulmonary embolism (3.3%).

Table 11: Laboratory Abnormalities Worsening from Baseline 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 Abnormality Percentage of Patients with Worsening Laboratory Test from Baselinea
OPDIVO Docetaxel
All Grades Grades 3-4 All Grades Grades 3-4
Chemistry
Hyponatremia 35 7 34 4.9
Increased AST 27 1.9 13 0.8
Increased alkaline phosphatase 26 0.7 18 0.8
Increased ALT 22 1.7 17 0.5
Increased creatinine 18 0 12 0.5
Increased TSHb 14 N/A 6 N/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); 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 in SCLC was evaluated in CHECKMATE-032, a multicenter, multicohort, open-label, ongoing trial that enrolled 245 patients with SCLC with disease progression after platinum-based chemotherapy who received OPDIVO 3 mg/kg administered intravenously over 60 minutes every 2 weeks [see Clinical Studies]. The median duration of therapy in OPDIVO-treated patients was 1 month (range: 0 to 44.2+ months): 17% of patients received OPDIVO for greater than 6 months and 9% of patients received OPDIVO for greater than one year.

The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease.

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.

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

Renal Cell Carcinoma

Previously Treated Renal Cell Carcinoma

The safety of OPDIVO was evaluated in CHECKMATE-025, a randomized open-label trial in which 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received 3 mg/kg of OPDIVO 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.

Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients and 19% of everolimus patients. Forty-four percent (44%) of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

Rate of death on treatment or within 30 days of the last dose of study drug was 4.7% on the OPDIVO arm versus 8.6% on the everolimus arm.

The most common adverse reactions (reported in at least 20% of patients) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. Table 12 summarizes adverse reactions that occurred in greater than 15% of OPDIVO-treated patients.

Table 12: Grade 1-4 Adverse Reactions in >15% of Patients Receiving OPDIVO (CHECKMATE-025)

  OPDIVO
(n=406)
Everolimus
(n=397)
Percentage (%) of Patients
Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4
Adverse Reaction 98 56 96 62
General Disorders and Administration Site Conditions
Fatiguea 56 6 57 7
Pyrexia 17 0.7 20 0.8
Respiratory, Thoracic and Mediastinal Disorders
Cough/productive cough 34 0 38 0.5
Dyspnea/exertional dyspnea 27 3.0 31 2.0
Upper respiratory infectionb 18 0 11 0
Gastrointestinal Disorders
Nausea 28 0.5 29 1
Diarrheac 25 2.2 32 1.8
Constipation 23 0.5 18 0.5
Vomiting 16 0.5 16 0.5
Skin and Subcutaneous Tissue Disorders
Rashd 28 1.5 36 1.0
Pruritus/generalized pruritus 19 0 14 0
Metabolism and Nutrition Disorders
Decreased appetite 23 1.2 30 1.5
Musculoskeletal and Connective Tissue Disorders
Arthralgia 20 1.0 14 0.5
Back pain 21 3.4 16 2.8
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia, decreased activity, fatigue, and malaise.
b Includes nasopharyngitis, pharyngitis, rhinitis, and viral 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

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, elevated triglycerides, and hyperkalemia. Table 13 summarizes the laboratory abnormalities that occurred in greater than 15% of OPDIVO-treated patients.

Table 13: Grade 1-4 Laboratory Values Worsening from Baseline Occurring in >15% of Patients on OPDIVO (CHECKMATE-025)

Laboratory Abnormality Percentage of Patients with Worsening Laboratory Test from Baselinea
OPDIVO Everolimus
Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4
Hematology
Lymphopenia 42 6 53 11
Anemia 39 8 69 16
Chemistry
Increased creatinine 42 2.0 45 1.6
Increased AST 33 2.8 39 1.6
Increased alkaline phosphatase 32 2.3 32 0.8
Hyponatremia 32 7 26 6
Hyperkalemia 30 4.0 20 2.1
Hypocalcemia 23 0.9 26 1.3
Increased ALT 22 3.2 31 0.8
Hypercalcemia 19 3.2 6 0.3
Lipids
Increased triglycerides 32 1.5 67 11
Increased cholesterol 21 0.3 55 1.4
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).

In addition, among patients with TSH less than ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH greater than ULN in the OPDIVO group compared to the everolimus group (26% and 14%, respectively).

Previously Untreated Renal Cell Carcinoma

The safety of OPDIVO 3 mg/kg, administered with ipilimumab 1 mg/kg was evaluated in CHECKMATE-214, a randomized open-label trial in which 1082 patients with previously untreated advanced RCC received OPDIVO 3 mg/kg in combination with ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by OPDIVO monotherapy at the 3 mg/kg dose (n=547) every 2 weeks or sunitinib administered orally 50 mg daily for 4 weeks followed by 2 weeks off, every cycle (n=535) [see Clinical Studies]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in OPDIVO plus 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 plus ipilimumab arm were exposed to treatment for greater than 6 months, and 38% of patients were exposed to treatment for greater than 1 year.

Study therapy was discontinued for adverse reactions in 31% of OPDIVO plus ipilimumab patients and in 21% of sunitinib patients. Fifty-four percent (54%) of patients receiving OPDIVO plus ipilimumab and 43% of patients receiving sunitinib had a drug delay for an adverse reaction. In the sunitinib group, 53% of patients required a dose reduction; dose reductions were not permitted in the OPDIVO plus ipilimumab treatment group. Serious adverse reactions occurred in 59% of patients receiving OPDIVO plus ipilimumab and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in at least 2% of patients treated with OPDIVO plus 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 at least 20% of OPDIVO plus ipilimumab-treated patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. Table 14 summarizes adverse reactions that occurred in greater than 15% of OPDIVO plus ipilimumab-treated patients.

Table 14: Grade 1-4 Adverse Reactions in >15% of Patients Receiving OPDIVO plus Ipilimumab (CHECKMATE-214)

  OPDIVO plus Ipilimumab Cohort
(n=547)
Sunitinib
(n=535)
Percentage (%) of Patients
Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4
Adverse Reaction 99 65 99 76
General Disorders and Administration Site Conditions
Fatiguea 58 8 69 13
Pyrexia 25 0.7 17 0.6
Edemab 16 0.5 17 0.6
Respiratory, Thoracic, and Mediastinal Disorders
Cough/productive cough 28 0.2 25 0.4
Dyspnea/exertional dyspnea 20 2.4 21 2.1
Gastrointestinal Disorders
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
Skin and Subcutaneous Tissue Disorders
Rashc 39 3.7 25 1.1
Pruritus/generalized pruritus 33 0.5 11 0
Endocrine Disorders
Hypothyroidism 18 0.4 27 0.2
Nervous System Disorders
Headache 19 0.9 23 0.9
Metabolism and Nutrition Disorders
Decreased appetite 21 1.8 29 0.9
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paind 37 4.0 40 2.6
Arthralgia 23 1.3 16 0
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema, peripheral swelling.
c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.

The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of OPDIVO plus ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia. Table 15 summarizes the laboratory abnormalities that occurred in greater than 15% of OPDIVO plus ipilimumab-treated patients.

Table 15: Grade 1-4 Laboratory Values Worsening from Baseline Occurring in >15% of Patients on OPDIVO plus Ipilimumab (CHECKMATE-214)

Laboratory Abnormality Percentage of Patients with Worsening Laboratory Test from Baselinea
OPDIVO plus Ipilimumab Cohort Sunitinib
Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4
Hematology
Anemia 43 3.0 64 9
Lymphopenia 36 5 63 14
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
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 plus ipilimumab group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).

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

Classical Hodgkin Lymphoma

The safety of 3 mg/kg of OPDIVO by intravenous infusion every 2 weeks was evaluated in 266 adult patients with cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials). Treatment could continue 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).

OPDIVO was discontinued due to adverse reactions in 7% of patients. Dose delay for an adverse reaction occurred in 34% of patients. Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in at least 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. 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.

The most common adverse reactions (reported in at least 20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus.

Table 16 summarizes the adverse reactions, excluding laboratory terms, that occurred in at least 10% of patients in the safety population.

Table 16: Non-Laboratory Adverse Reactions Occurring in ≥10% of Patients with cHL (CHECKMATE-205 and CHECKMATE-039)

Adverse Reactiona OPDIVO cHL Safety Population
(n=266)
Percentage (%)
All Grades Grades 3-4
General Disorders and Administration Site Conditions
Fatigueb 39 1.9
Pyrexia 29 <1
Gastrointestinal Disorders
Diarrheac 33 1.5
Nausea 20 0
Vomiting 19 <1
Abdominal paind 16 <1
Constipation 14 0.4
Infections
Upper respiratory tract infectione 44 0.8
Pneumonia/bronchopneumoniaf 13 3.8
Nasal congestion 11 0
Respiratory, Thoracic and Mediastinal Disorders
Cough/productive cough 36 0
Dyspnea/exertional dyspnea 15 1.5
Skin and Subcutaneous Tissue Disorders
Rashg 24 1.5
Pruritus 20 0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painh 26 1.1
Arthralgia 16 <1
Endocrine Disorders
Hypothyroidism/thyroiditis 12 0
Nervous System Disorders
Headache 17 <1
Neuropathy peripherali 12 <1
Injury, Poisoning and Procedural Complications
Infusion-related reaction 14 <1
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 asthenia.
c Includes colitis.
d Includes abdominal discomfort and upper abdominal pain.
e Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis.
f Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia.
g Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform.
h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity.
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

In CHECKMATE-205 and CHECKMATE-039, treatmentemergent peripheral neuropathy was reported in 14% (31/266) of all patients receiving OPDIVO. Twenty-eight patients (11%) had new-onset peripheral neuropathy, and 3 of 40 patients had worsening of neuropathy from baseline. These adverse reactions were Grade 1 or 2, except for 1 Grade 3 event (<1%). 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 reducedintensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure.

Table 17 summarizes laboratory abnormalities that developed or worsened in at least 10% of patients with cHL. The most common (reported in at least 20%) treatmentemergent laboratory events included cytopenias, liver function abnormalities, and elevated lipase. Other common findings (reported in at least 10%) included elevated creatinine, electrolyte abnormalities, and elevated amylase.

Table 17: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO-Treated Patients with cHL (CHECKMATE-205 and CHECKMATE-039)

Laboratory Abnormality OPDIVO cHL Safety Populationa
(n=266)
Percentage (%)b
All Grades Grades 3-4
Hematology
Leukopenia 38 4.5
Neutropenia 37 5
Thrombocytopenia 37 3.0
Lymphopenia 32 11
Anemia 26 2.6
Chemistryc
Increased AST 33 2.6
Increased ALT 31 3.4
Increased lipase 22 9
Increased alkaline phosphatase 20 1.5
Hyponatremia 20 1.1
Hypokalemia 16 1.9
Increased creatinine 16 <1
Hypocalcemia 15 <1
Hypomagnesemia 14 <1
Hyperkalemia 15 1.5
Increased amylase 13 1.5
Increased bilirubin 11 1.5
a Number of evaluable patients for the safety population ranges from 203 to 266.
b Includes events occurring up to 30 days after last nivolumab dose. After an immunemediated 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%).

Recurrent Or Metastatic Squamous Cell Carcinoma Of The Head And Neck

The safety of OPDIVO was evaluated in CHECKMATE-141, a randomized, activecontrolled, 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]. Patients received 3 mg/kg of OPDIVO (n=236) over 60 minutes by intravenous infusion every 2 weeks or investigator's choice of either:

  • cetuximab (n=13), 400 mg/m² loading dose IV followed by 250 mg/m² weekly
  • or methotrexate (n=46) 40 to 60 mg/m² IV weekly, or
  • docetaxel (n=52) 30 to 40 mg/m² IV 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 greater than 6 months and 2.5% of patients received OPDIVO for greater than 1 year.

CHECKMATE-141 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).

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.

OPDIVO was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC. 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 study 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 platinumcontaining chemotherapy received OPDIVO 3 mg/kg 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 drug delay 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. OPDIVO was discontinued for adverse reactions in 17% of patients. Serious adverse reactions occurred in 54% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

Twenty-five (9%) patients received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction [see WARNINGS AND PRECAUTIONS].

The most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite.

Table 18 summarizes adverse reactions that occurred in greater than 10% of patients.

Table 18: Adverse Reactions Occurring in ≥10% of Patients (CHECKMATE-275)

  OPDIVO Urothelial Carcinoma
Percentage (%) of Patients
All Grades Grades 3-4
Adverse Reaction 99 51
General Disorders and Administration Site Conditions
Asthenia/fatigue/malaise 46 7
Pyrexia/tumor associated fever 17 0.4
Edema/peripheral edema/peripheral swelling 13 0.4
Infections and Infestations
Urinary Tract Infection/escherichia/ fungal urinary tract infection 17 7
Respiratory, Thoracic, and Mediastinal Disorders
Cough/productive cough 18 0
Dyspnea/exertional dyspnea 14 3.3
Gastrointestinal Disorders
Nausea 22 0.7
Diarrhea 17 2.6
Constipation 16 0.4
Abdominal paina 13 1.5
Vomiting 12 1.9
Skin and Subcutaneous Tissue Disorders
Rashb 16 1.5
Pruritus 12 0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painc 30 2.6
Arthralgia 10 0.7
Metabolism and Nutrition Disorders
Decreased appetite 22 2.2
Endocrine Disorders
Thyroid disordersd 15 0
Toxicity was graded per NCI CTCAE v4.
a Includes abdominal discomfort, lower and upper abdominal pain.
b Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular, maculopapular, or pruritic.
c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.
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 19: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients (CHECKMATE-275)

Laboratory Abnormality OPDIVO Urothelial Carcinomaa
Percentage (%) of Patients
All Grades Grades 3-4
Hematology
Lymphopenia 42 9
Anemia 40 7
Thrombocytopenia 15 2.4
Leucopenia 11 0
Chemistry
Hyperglycemia 42 2.4
Hyponatremia 41 11
Increased creatinine 39 2.0
Increased alkaline phosphatase 33 5.5
Hypocalcemia 26 0.8
Increased AST 24 3.5
Hyperkalemia 19 1.2
Increased ALT 18 1.2
Hypomagnesemia 16 0
Increased lipase 20 7
Increased amylase 18 4.4
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: range: 84 to 256 patients.

Previously Treated 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 parallelcohort, open-label study. In CHECKMATE-142, 74 patients with mCRC received OPDIVO 3 mg/kg 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 on Day 1 of each 21-day cycle for 4 doses, then OPDIVO 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity. [See Clinical Studies]

OPDIVO was discontinued in 13% of patients and delayed in 45% of patients for an adverse reaction. Serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were colitis/ diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (reported in at least 20% of patients) were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting.

Table 20 summarizes adverse reactions that occurred in greater than 10% of patients receiving OPDIVO with ipilimumab. Table 21 summarizes laboratory tests that worsened from baseline in greater than 10% of patients receiving OPDIVO with ipilimumab. 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 20: Adverse Reactions Occurring in ≥10% of Patients (CHECKMATE-142)

Adverse Reaction OPDIVOMSI-H/dMMR Cohort
(n=74)
OPDIVO plus IpilimumabMSI-H/dMMR Cohort
(n=119)
Percentage (%) of Patients
All Grades Grades 3-4 All Grades Grades 3-4
General Disorders and Administration Site Conditions
Fatiguea 54 5 49 6
Pyrexia 24 0 36 0
Edemab 12 0 7 0
Gastrointestinal Disorders
Diarrhea 43 2.7 45 3.4
Abdominal painc 34 2.7 30 5
Nausea 34 1.4 26 0.8
Vomiting 28 4.1 20 1.7
Constipation 20 0 15 0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paind 28 1.4 36 3.4
Arthralgia 19 0 14 0.8
Skin and Subcutaneous Tissue Disorders
Pruritus 19 0 28 1.7
Rashe 23 1.4 25 4.2
Dry Skin 7 0 11 0
Infections and Infestations
Upper respiratory tract infectionf 20 0 9 0
Metabolism and Nutrition Disorders
Decreased appetite 14 1.4 20 1.7
Respiratory, Thoracic, and Mediastinal Disorders
Cough 26 0 19 0.8
Dyspnea 8 1 13 1.7
Nervous System Disorders
Headache 16 0 17 1.7
Dizziness 14 0 11 0
Endocrine Disorders
Hyperglycemia 19 2.7 6 1
Hypothyroidism 5 0 14 0.8
Hyperthyroidism 4 0 12 0
Investigations
Weight decreased 8 0 10 0
Psychiatric Disorders
Insomnia 9 0 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 less than 10% of patients receiving OPDIVO with ipilimumab in CHECKMATE-142 were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).

Table 21: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients (CHECKMATE-142)

Laboratory Abnormality Percentage of Patients with Worsening Laboratory Test from Baselinea
OPDIVO MSI-H/dMMR Cohort
(n=74)
OPDIVO + Ipilimumab MSI-H/dMMR Cohort
(n=119)
All Grades Grades 3-4 All Grades Grades 3-4
Hematology
Anemia 50 7 42 9
Thrombocytopenia 16 1.4 26 0.9
Lymphopenia 36 7 25 6
Neutropenia 20 4.3 18 0
Chemistry
Increased AST 31 1.4 40 12
Increased lipase 33 19 39 12
Increased amylase 16 4.8 36 3.4
Increased ALT 32 2.8 33 12
Increased alkaline phosphatase 37 2.8 28 5
Hyponatremia 27 4.3 26 5
Increased creatinine 12 0 25 3.6
Hyperkalemia 11 0 23 0.9
Increased bilirubin 14 4.2 21 5
Hypomagnesemia 17 0 18 0
Hypocalcemia 19 0 16 0
Hypokalemia 14 0 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 62 to 71 for the OPDIVO cohort and from 87 to 114 for the OPDIVO plus ipilimumab cohort.

Hepatocellular Carcinoma

The safety of OPDIVO was evaluated in a 154-patient subgroup of patients with HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib enrolled in CHECKMATE-040, a multicenter, open-label trial. Patients were required to have an AST and ALT of no more than five times the upper limit of normal and total bilirubin of less than 3 mg/dL. The median duration of exposure to OPDIVO was 6 months.

The toxicity profile observed in 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval 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 disorders: Vogt-Koyanagi-Harada (VKH) syndrome

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

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.

Of 2085 patients who were treated with OPDIVO as a single agent 3 mg/kg every 2 weeks and evaluable for the presence of anti-nivolumab antibodies, 233 patients (11.2%) tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay and 15 patients (0.7%) had neutralizing antibodies against nivolumab. There was no evidence of altered pharmacokinetic profile or increased incidence of infusion reactions with anti-nivolumab antibody development.

Of the patients who were treated with OPDIVO and ipilimumab and evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 23.8% to 26.0% with nivolumab 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks and 37.8% with nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg every 3 weeks. The incidence of neutralizing antibodies against nivolumab was 0.5% to 1.9% with nivolumab 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks and 4.6% with nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg every 3 weeks. Of patients evaluable for the presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged from 4.1% to 8.4% and neutralizing antibodies against ipilimumab ranged from 0 to 0.3%.

Overall, there was no evidence of increased incidence of infusion reactions or effects on efficacy with anti-nivolumab antibody development.

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.

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

Related Resources for Opdivo

Related Health

© Opdivo Patient Information is supplied by Cerner Multum, Inc. and Opdivo Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Health Solutions From Our Sponsors

CONTINUE SCROLLING FOR RELATED ARTICLE