Opdivo

Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 8/9/2021
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:

  • fatigue
  • rash
  • itching
  • cough
  • upper respiratory tract infection
  • swelling of the extremities
  • shortness of breath
  • muscle pain
  • decreased appetite
  • nausea
  • vomiting
  • constipation
  • diarrhea
  • weakness
  • swelling
  • fever
  • abdominal pain
  • chest pain
  • joint pain
  • weight loss
  • irregular heartbeat
  • eye inflammation
  • infusion-related reactions
  • increased amylase
  • increased lipase
  • dizziness
  • numbness and tingling
  • skin peeling
  • skin redness and
  • psoriasis.

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.

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Opdivo Consumer Information

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

Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, light-headed, short of breath, itchy, or tingly, or if you have a fever, chills, back pain or neck pain.

Call your doctor at once if you have:

  • severe or ongoing diarrhea, severe stomach pain, bloody or tarry stools;
  • eye pain, vision changes, sensitivity to light;
  • severe muscle pain or weakness;
  • confusion, memory problems, neck stiffness, drowsiness, balance problems;
  • numbness or tingling in your arms or legs;
  • kidney problems--little or no urination, swelling in your feet or ankles, blood in your urine;
  • liver problems--severe nausea or vomiting, right-sided upper stomach pain, easy bruising or bleeding, dark urine, jaundice (yellowing of the skin or eyes);
  • lung problems--new or worsening cough, chest pain, feeling short of breath;
  • skin problems--rash, itching, redness, swelling, pain, sores, blisters, sores in your mouth or nose or on your genitals;
  • signs of a hormonal disorder--frequent or unusual headaches, vision problems, fast heartbeats, dizziness, fainting, tiredness, mood or behavior changes, hunger, increased thirst or urination, constipation, hair loss, hoarse or deepened voice, sweating, feeling cold, weight gain or loss; or
  • (if you have had a stem cell transplant) feeling sick or uneasy, with pain or swelling near your transplanted organ.

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

Common side effects may include:

  • nausea, vomiting, stomach pain, loss of appetite, diarrhea, constipation;
  • mouth sores, altered sense of taste;
  • itching, rash, redness or blisters on your hands or feet;
  • hormonal problems;
  • liver problems;
  • numbness, tingling, or burning pain in your hands or feet;
  • fever, body aches;
  • feeling weak, tired, or short of breath;
  • cold symptoms such as runny or stuffy nose, cough, sore throat;
  • headache, dizziness, increased blood pressure; or
  • weight loss.

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.

Read the entire detailed patient monograph for Opdivo (Nivolumab Injection)

SLIDESHOW

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

SIDE EFFECTS

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

  • Severe and Fatal Immune-Mediated Adverse Reactions [see WARNINGS AND PRECAUTIONS]
  • Infusion-Related Reactions [see WARNINGS AND PRECAUTIONS]
  • 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 in patients enrolled in CHECKMATE- 227 (n=576) or CHECKMATE-743 (n=300); OPDIVO 360 mg with ipilimumab 1 mg/kg and 2 cycles of platinum-doublet chemotherapy in CHECKMATE-9LA (n=361); and OPDIVO 240 mg with cabozantinib 40 mg in patients enrolled in CHECKMATE-9ER (n=320).

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 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.

Table 5: 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
(%)
Skin and Subcutaneous Tissue
  Rasha 21 0.4 7 0
  Pruritus 19 0 3.9 0
Respiratory, Thoracic and Mediastinal
  Cough 17 0 6 0
Infections
  Upper respiratory tract infectionb 11 0 2.0 0
General
  Peripheral edema 10 0 5 0
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 6: 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 Abnormality OPDIVO Chemotherapy
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Increased AST 28 2.4 12 1.0
Hyponatremia 25 5 18 1.1
Increased alkaline phosphatase 22 2.4 13 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 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 7 and 8 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.

Table 7: 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
(%)
General
  Fatigue 49 1.9 39 3.4
  Edemaa 12 1.5 4.9 0
Musculoskeletal and Connective Tissue
  Musculoskeletal painb 32 2.9 25 2.4
Skin and Subcutaneous Tissue
  Rashc 28 1.5 12 0
  Pruritus 23 0.5 12 0
  Vitiligo 11 0 0.5 0
  Erythema 10 0 2.9 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.

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

Nervous System Disorders: peripheral neuropathy

Table 8: 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 Abnormality 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, 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 9 and 10 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.

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

Clinically important adverse reactions in <10% of patients who received 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 10: 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 Abnormality OPDIVO and Ipilimumab OPDIVO Ipilimumab
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Chemistry
  Increased ALT 55 16 25 3.0 29 2.7
  Hyperglycemia 53 5.3 46 7 26 0
  Increased AST 52 13 29 3.7 29 1.7
  Hyponatremia 45 10 22 3.3 26 7
  Increased lipase 43 22 32 12 24 7
  Increased alkaline phosphatase 41 6 27 2.0 23 2.0
  Hypocalcemia 31 1.1 15 0.7 20 0.7
  Increased amylase 27 10 19 2.7 15 1.6
  Increased creatinine 26 2.7 19 0.7 17 1.3
Hematology
  Anemia 52 2.7 41 2.6 41 6
  Lymphopenia 39 5 41 4.9 29 4.0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: 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 ipilimumab-treated 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 11 and 12 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238.

Table 11: 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 (%)
General
  Fatiguea 57 0.9 55 2.4
Gastrointestinal
  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
  Rashc 35 1.1 47 5.3
  Pruritus 28 0 37 1.1
Musculoskeletal and Connective Tissue
  Musculoskeletal paind 32 0.4 27 0.4
  Arthralgia 19 0.4 13 0.4
Nervous System
  Headache 23 0.4 31 2.0
  Dizzinesse 11 0 8 0
Infections
  Upper respiratory tract infectionf 22 0 15 0.2
Respiratory, Thoracic and Mediastinal
  Cough/productive cough 19 0 19 0
  Dyspnea/exertional dyspnea 10 0.4 10 0.2
Endocrine
  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 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 12: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of OPDIVO-Treated Patients - CHECKMATE-238

Laboratory Abnormality 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

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

Table 13: Adverse Reactions in ≥10% of Patients Receiving OPDIVO and Ipilimumab - CHECKMATE-227

Adverse Reaction OPDIVO and Ipilimumab
(n=576)
Platinum-doublet Chemotherapy
(n=570)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
General
  Fatiguea 44 6 42 4.4
  Pyrexia 18 0.5 11 0.4
  Edemab 14 0.2 12 0.5
Skin and Subcutaneous Tissue
  Rashc 34 4.7 10 0.4
  Pruritusd 21 0.5 3.3 0
Metabolism and Nutrition
  Decreased appetite 31 2.3 26 1.4
Musculoskeletal and Connective Tissue
  Musculoskeletal paine 27 1.9 16 0.7
  Arthralgia 13 0.9 2.5 0.2
Gastrointestinal
  Diarrhea/colitisf 26 3.6 16 0.9
  Nausea 21 1.0 42 2.5
  Constipation 18 0.3 27 0.5
  Vomiting 13 1.0 18 2.3
  Abdominal paing 10 0.2 9 0.7
Respiratory, Thoracic, and Mediastinal
  Dyspneah 26 4.3 16 2.1
  Coughi 23 0.2 13 0
Hepatobiliary
  Hepatitisj 21 9 10 1.2
Endocrine
  Hypothyroidismk 16 0.5 1.2 0
  Hyperthyroidisml 10 0 0.5 0
Infections and Infestations
  Pneumoniam 13 7 8 4.0
Nervous System
  Headache 11 0.5 6 0
a Includes fatigue and asthenia.
b Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, and periorbital edema.
c Includes autoimmune dermatitis, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, granulomatous dermatitis, rash generalized, drug eruption, dyshidrotic eczema, eczema, exfoliative rash, nodular rash, rash, rash erythematous, rash 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 14: Laboratory Values Worsening from Baselinea Occurring in ≥20% of Patients on OPDIVO and Ipilimumab - CHECKMATE-227

Laboratory Abnormality OPDIVO and Ipilimumab Platinum-doublet Chemotherapy
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Hematology
  Anemia 46 3.6 78 14
  Lymphopenia 46 5 60 15
Chemistry
  Hyponatremia 41 12 26 4.9
  Increased AST 39 5 26 0.4
  Increased ALT 36 7 27 0.7
  Increased lipase 35 14 14 3.4
  Increased alkaline phosphatase 34 3.8 20 0.2
  Increased amylase 28 9 18 1.9
  Hypocalcemia 28 1.7 17 1.3
  Hyperkalemia 27 3.4 22 0.4
  Increased creatinine 22 0.9 17 0.2
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: 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 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.

Table 15: Adverse Reactions in >10% of Patients Receiving OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA

Adverse Reaction OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy
(n=358)
Platinum-Doublet Chemotherapy
(n=349)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
General
  Fatiguea 49 5 40 4.9
  Pyrexia 14 0.6 10 0.6
Musculoskeletal and Connective Tissue
  Musculoskeletal painb 39 4.5 27 2.0
Gastrointestinal
  Nausea 32 1.7 41 0.9
  Diarrheac 31 6 18 1.7
  Constipation 21 0.6 23 0.6
  Vomiting 18 2.0 17 1.4
  Abdominal paind 12 0.6 11 0.9
Skin and Subcutaneous Tissue
  Rashe 30 4.7 10 0.3
  Pruritusf 21 0.8 2.9 0
  Alopecia 11 0.8 10 0.6
Metabolism and Nutrition
  Decreased appetite 28 2.0 22 1.7
Respiratory, Thoracic and Mediastinal
  Coughg 19 0.6 15 0.9
  Dyspneah 18 4.7 14 3.2
Endocrine
  Hypothyroidismi 19 0.3 3.4 0
Nervous System
  Headache 11 0.6 7 0
  Dizzinessj 11 0.6 6 0
Toxicity was graded per NCI CTCAE v4.
a Includes fatigue and asthenia
b Includes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, synovitis
c Includes colitis, ulcerative colitis, diarrhea, and enterocolitis
d Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain
e Includes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blenorrhagica, palmar-plantar erythrodysaesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, urticaria
f Includes pruritus and generalized pruritus
g Includes cough, productive cough, and upper-airway cough syndrome
h Includes dyspnea, dyspnea at rest, and exertional dyspnea
i Includes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine
j Includes dizziness, vertigo and positional vertigo

Table 16: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA

Laboratory Abnormality OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Hematology
  Anemia 70 9 74 16
  Lymphopenia 41 6 40 11
  Neutropenia 40 15 42 15
  Leukopenia 36 10 40 9
  Thrombocytopenia 23 4.3 24 5
Chemistry
  Hyperglycemia 45 7 42 2.6
  Hyponatremia 37 10 27 7
  Increased ALT 34 4.3 24 1.2
  Increased lipase 31 12 10 2.2
  Increased alkaline phosphatase 31 1.2 26 0.3
  Increased amylase 30 7 19 1.3
  Increased AST 30 3.5 22 0.3
  Hypomagnesemia 29 1.2 33 0.6
  Hypocalcemia 26 1.4 22 1.8
  Increased creatinine 26 1.2 23 0.6
  Hyperkalemia 22 1.7 21 2.1
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: 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 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.

Table 17: 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
(%)
Respiratory, Thoracic and Mediastinal
  Cough 31 0.7 24 0
Metabolism and Nutrition
  Decreased appetite 28 1.4 23 1.5
Skin and Subcutaneous Tissue
  Pruritus 10 0.2 2.0 0
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 18: 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 Abnormality 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), except for TSH: OPDIVO group n=314 and docetaxel group n=297.
b Not graded per NCI CTCAE v4.

Malignant Pleural Mesothelioma

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

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

Both OPDIVO and ipilimumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction.

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

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

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

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

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

Laboratory Abnormality OPDIVO and Ipilimumab Chemotherapy
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Chemistry
  Hyperglycemia 53 3.7 34 1.1
  Increased AST 38 7 17 0
  Increased ALT 37 7 15 0.4
  Increased lipase 34 13 9 0.8
  Hyponatremia 32 8 21 2.9
  Increased alkaline phosphatase 31 3.1 12 0
  Hyperkalemia 30 4.1 16 0.7
  Hypocalcemia 28 0 16 0
  Increased amylase 26 5 13 0.9
  Increased creatinine 20 0.3 20 0.4
Hematology
  Lymphopenia 43 8 57 14
  Anemia 43 2.4 75 15
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 109 to 297 patients) and chemotherapy group (range: 90 to 276 patients).

Advanced Renal Cell Carcinoma

First-line Renal Cell Carcinoma

CHECKMATE-214

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 21 and 22 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of OPDIVO and ipilimumab-treated patients in CHECKMATE-214.

Table 21: Adverse Reactions in >15% of Patients Receiving OPDIVO and Ipilimumab - CHECKMATE-214

Adverse Reaction OPDIVO and Ipilimumab
(n=547)
Sunitinib
(n=535)
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Adverse Reaction 99 65 99 76
General
  Fatiguea 58 8 69 13
  Pyrexia 25 0.7 17 0.6
  Edemab 16 0.5 17 0.6
Skin and Subcutaneous Tissue
  Rashc 39 3.7 25 1.1
  Pruritus/generalized pruritus 33 0.5 11 0
Gastrointestinal
  Diarrhea 38 4.6 58 6
  Nausea 30 2.0 43 1.5
  Vomiting 20 0.9 28 2.1
  Abdominal pain 19 1.6 24 1.9
  Constipation 17 0.4 18 0
Musculoskeletal and Connective Tissue
  Musculoskeletal paind 37 4.0 40 2.6
  Arthralgia 23 1.3 16 0
Respiratory, Thoracic and Mediastinal
  Cough/productive cough 28 0.2 25 0.4
  Dyspnea/exertional dyspnea 20 2.4 21 2.1
Metabolism and Nutrition
  Decreased appetite 21 1.8 29 0.9
Nervous System
  Headache 19 0.9 23 0.9
Endocrine
  Hypothyroidism 18 0.4 27 0.2
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema, peripheral swelling.
c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.

Table 22: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on OPDIVO and Ipilimumab - CHECKMATE-214

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

CHECKMATE-9ER

The safety of OPDIVO with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received OPDIVO 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Clinical Studies]. Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in OPDIVO and cabozantinib-treated patients. In this trial, 82% of patients in the OPDIVO and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.

Serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.

Adverse reactions leading to discontinuation of either OPDIVO or cabozantinib occurred in 20% of patients: 7% OPDIVO only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either OPDIVO or cabozantinib occurred in 83% of patients: 3% OPDIVO only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially.

The most common adverse reactions reported in ≥20% of patients treated with OPDIVO and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysaesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

Tables 23 and 24 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER.

Table 23: Adverse Reactions in >15% of Patients Receiving OPDIVO and Cabozantinib - CHECKMATE-9ER

Adverse Reaction OPDIVO and Cabozantinib
(n=320)
Sunitinib
(n=320)
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Gastrointestinal
  Diarrhea 64 7 47 4.4
  Nausea 27 0.6 31 0.3
  Abdominal paina 22 1.9 15 0.3
  Vomiting 17 1.9 21 0.3
  Dyspepsiab 15 0 22 0.3
General
  Fatiguec 51 8 50 8
Hepatobiliary
  Hepatotoxicityd 44 11 26 5
Skin and Subcutaneous Tissue
  Palmar-plantar erythrodysaesthesia syndrome 40 8 41 8
  Stomatitise 37 3.4 46 4.4
  Rashf 36 3.1 14 0
  Pruritus 19 0.3 4.4 0
Vascular
  Hypertensiong 36 13 39 14
Endocrine
  Hypothyroidismh 34 0.3 30 0.3
Musculoskeletal and Connective Tissue
  Musculoskeletal paini 33 3.8 29 3.1
  Arthralgia 18 0.3 9 0.3
Metabolism and Nutrition
  Decreased appetite 28 1.9 20 1.3
Nervous System
  Dysgeusia 24 0 22 0
  Headache 16 0 12 0.6
Respiratory, Thoracic and Mediastinal
  Coughj 20 0.3 17 0
  Dysphonia 17 0.3 3.4 0
Infections and Infestations
  Upper respiratory tract infectionk 20 0.3 8 0.3
Toxicity was graded per NCI CTCAE v4.
a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper.
b Includes gastroesophageal reflux disease.
c Includes asthenia.
d Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure.
e Includes mucosal inflammation, aphthous ulcer, mouth ulceration.
f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic.
g Includes blood pressure increased, blood pressure systolic increased.
h Includes primary hypothyroidism.
i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.
j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, rhinitis.

Table 24: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on OPDIVO and Cabozantinib - CHECKMATE-9ER

Laboratory Abnormality OPDIVO and Cabozantinib Sunitinib
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Chemistry
  Increased ALT 79 9.8 39 3.5
  Increased AST 77 7.9 57 2.6
  Hypophosphatemia 69 28 48 10
  Hypocalcemia 54 1.9 24 0.6
  Hypomagnesemia 47 1.3 25 0.3
  Hyperglycemia 44 3.5 44 1.7
  Hyponatremia 43 11 36 12
  Increased lipase 41 14 38 13
  Increased amylase 41 10 28 6
  Increased alkaline phosphatase 41 2.8 37 1.6
  Increased creatinine 39 1.3 42 0.6
  Hyperkalemia 35 4.7 27 1
  Hypoglycemia 26 0.8 14 0.4
Hematology
  Lymphopenia 42 6.6 45 10
  Thrombocytopenia 41 0.3 70 9.7
  Anemia 37 2.5 61 4.8
  Leukopenia 37 0.3 66 5.1
  Neutropenia 35 3.2 67 12
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 cabozantinib group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients).

Previously Treated Renal Cell Carcinoma

CHECKMATE-025

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 everolimustreated 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 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025.

Table 25: Adverse Reactions in >15% of Patients Receiving OPDIVO - CHECKMATE- 025

Adverse Reaction OPDIVO
(n=406)
Everolimus
(n=397)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Adverse Reaction 98 56 96 62
General
  Fatiguea 56 6 57 7
  Pyrexia 17 0.7 20 0.8
Respiratory, Thoracic and Mediastinal
  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
  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
  Rashd 28 1.5 36 1.0
  Pruritus/generalized pruritus 19 0 14 0
Metabolism and Nutrition
  Decreased appetite 23 1.2 30 1.5
Musculoskeletal and Connective Tissue
  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 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 26: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on OPDIVO - CHECKMATE-025

Laboratory Abnormality 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).

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 27 and 28 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-205 and CHECKMATE-039.

Table 27: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-205 and CHECKMATE-039

Adverse Reactiona OPDIVO (n=266)
All Grades (%) Grades 3-4 (%)
Infections
  Upper respiratory tract infectionb 44 0.8
  Pneumonia/bronchopneumoniac 13 3.8
  Nasal congestion 11 0
General
  Fatigued 39 1.9
  Pyrexia 29 <1
Respiratory, Thoracic and Mediastinal
  Cough/productive cough 36 0
  Dyspnea/exertional dyspnea 15 1.5
Gastrointestinal
  Diarrheae 33 1.5
  Nausea 20 0
  Vomiting 19 <1
  Abdominal painf 16 <1
  Constipation 14 0.4
Musculoskeletal and Connective Tissue
  Musculoskeletal paing 26 1.1
  Arthralgia 16 <1
Skin and Subcutaneous Tissue
  Rashh 24 1.5
  Pruritus 20 0
Nervous System
  Headache 17 <1
  Neuropathy peripherali 12 <1
Injury, Poisoning and Procedural Complications
  Infusion-related reaction 14 <1
Endocrine
  Hypothyroidism/thyroiditis 12 0
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 28 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 28: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-205 and CHECKMATE-039

Laboratory Abnormality OPDIVOa
(n=266)
All Grades (%)b Grades 3-4 (%)b
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
  Hyperkalemia 15 1.5
  Hypomagnesemia 14 <1
  Increased amylase 13 1.5
  Increased bilirubin 11 1.5
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 nonsquamous 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 (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (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 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.

Table 29: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-275

Adverse Reaction OPDIVO
(n=270)
All Grades (%) Grades 3-4 (%)
Adverse Reaction 99 51
General
  Asthenia/fatigue/malaise 46 7
  Pyrexia/tumor associated fever 17 0.4
  Edema/peripheral edema/peripheral swelling 13 0.4
Musculoskeletal and Connective Tissue
  Musculoskeletal paina 30 2.6
  Arthralgia 10 0.7
Metabolism and Nutrition
  Decreased appetite 22 2.2
Gastrointestinal
  Nausea 22 0.7
  Diarrhea 17 2.6
  Constipation 16 0.4
  Abdominal painb 13 1.5
  Vomiting 12 1.9
Respiratory, Thoracic and Mediastinal
  Cough/productive cough 18 0
  Dyspnea/exertional dyspnea 14 3.3
Infections
  Urinary tract infection/escherichia/fungal urinary tract infection 17 7
Skin and Subcutaneous Tissue
  Rashc 16 1.5
  Pruritus 12 0
Endocrine
  Thyroid disordersd 15 0
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 30: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients - CHECKMATE-275

Laboratory Abnormality OPDIVOa
All Grades (%) Grades 3-4 (%)
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
  Increased lipase 20 7
  Hyperkalemia 19 1.2
  Increased ALT 18 1.2
  Increased amylase 18 4.4
  Hypomagnesemia 16 0
Hematology
  Lymphopenia 42 9
  Anemia 40 7
  Thrombocytopenia 15 2.4
  Leukopenia 11 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: 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, openlabel 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. Treatment 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 31 and 32 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 31: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-142

Adverse Reaction OPDIVO
(n=74)
OPDIVO and Ipilimumab
(n=119)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
General
  Fatiguea 54 5 49 6
  Pyrexia 24 0 36 0
  Edemab 12 0 7 0
Gastrointestinal
  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
  Musculoskeletal paind 28 1.4 36 3.4
  Arthralgia 19 0 14 0.8
Respiratory, Thoracic and Mediastinal
  Cough 26 0 19 0.8
  Dyspnea 8 1 13 1.7
Skin and Subcutaneous Tissue
  Rashe 23 1.4 25 4.2
  Pruritus 19 0 28 1.7
  Dry Skin 7 0 11 0
Infections
  Upper respiratory tract infectionf 20 0 9 0
Endocrine
  Hyperglycemia 19 2.7 6 1
  Hypothyroidism 5 0 14 0.8
  Hyperthyroidism 4 0 12 0
Nervous System
  Headache 16 0 17 1.7
  Dizziness 14 0 11 0
Metabolism and Nutrition
  Decreased appetite 14 1.4 20 1.7
Psychiatric
  Insomnia 9 0 13 0.8
Investigations
  Weight decreased 8 0 10 0
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 32: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-142

Laboratory Abnormality OPDIVO
(n=74)
OPDIVO and Ipilimumab
(n=119)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Hematology
  Anemia 50 7 42 9
  Lymphopenia 36 7 25 6
  Neutropenia 20 4.3 18 0
  Thrombocytopenia 16 1.4 26 0.9
Chemistry
  Increased alkaline phosphatase 37 2.8 28 5
  Increased lipase 33 19 39 12
  Increased ALT 32 2.8 33 12
  Increased AST 31 1.4 40 12
  Hyponatremia 27 4.3 26 5
  Hypocalcemia 19 0 16 0
  Hypomagnesemia 17 0 18 0
  Increased amylase 16 4.8 36 3.4
  Increased bilirubin 14 4.2 21 5
  Hypokalemia 14 0 15 1.8
  Increased creatinine 12 0 25 3.6
  Hyperkalemia 11 0 23 0.9
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 singleagent 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 33 and 34 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 33: 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 Reaction OPDIVO and Ipilimumab
(n=49)
OPDIVO
(n=154)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Skin and Subcutaneous Tissue
  Rash 53 8 26 0.6
  Pruritus 53 4 27 0.6
Musculoskeletal and Connective Tissue
  Musculoskeletal pain 41 2 36 1.9
  Arthralgia 10 0 8 0.6
Gastrointestinal
  Diarrhea 39 4 27 1.3
  Abdominal pain 22 6 34 3.9
  Nausea 20 0 16 0
  Ascites 14 6 9 2.6
  Constipation 14 0 16 0
  Dry mouth 12 0 9 0
  Dyspepsia 12 2 8 0
  Vomiting 12 2 14 0
  Stomatitis 10 0 7 0
  Abdominal distension 8 0 11 0
Respiratory, Thoracic and Mediastinal
  Cough 37 0 23 0
  Dyspnea 14 0 13 1.9
  Pneumonitis 10 2 1.3 0.6
Metabolism and Nutrition
  Decreased appetite 35 2 22 1.3
General
  Fatigue 27 2 38 3.2
  Pyrexia 27 0 18 0.6
  Malaise 18 2 6.5 0
  Edema 16 2 12 0
  Influenza-like illness 14 0 9 0
  Chills 10 0 3.9 0
Nervous System
  Headache 22 0 11 0.6
  Dizziness 20 0 9 0
Endocrine
  Hypothyroidism 20 0 4.5 0
  Adrenal insufficiency 18 4 0.6 0
Investigations
  Weight decreased 20 0 7 0
Psychiatric
  Insomnia 18 0 10 0
Blood and Lymphatic System
  Anemia 10 4 19 2.6
Infections
  Influenza 10 2 1.9 0
  Upper Respiratory Tract Infection 6 0 12 0
Vascular
  Hypotension 10 0 0.6 0

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 34: 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 Abnormality OPDIVO and Ipilimumab
(n=47)
OPDIVO*
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Hematology
  Lymphopenia 53 13 59 15
  Anemia 43 4.3 49 4.6
  Neutropenia 43 9 19 1.3
  Leukopenia 40 2.1 26 3.3
  Thrombocytopenia 34 4.3 36 7
Chemistry
  Increased AST 66 40 58 18
  Increased ALT 66 21 48 11
  Increased bilirubin 55 11 36 7
  Increased lipase 51 26 37 14
  Hyponatremia 49 32 40 11
  Hypocalcemia 47 0 28 0
  Increased alkaline phosphatase 40 4.3 44 7
  Increased amylase 38 15 31 6
  Hypokalemia 26 2.1 12 0.7
  Hyperkalemia 23 4.3 20 2.6
  Increased creatinine 21 0 17 1.3
  Hypomagnesemia 11 0 13 0
* 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.

Esophageal Cancer

Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer

The safety of OPDIVO was evaluated in CHECKMATE-577, a randomized, placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following chemoradiotherapy (CRT) [see Clinical Studies]. The trial excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Patients received either OPDIVO 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease recurrence, unacceptable toxicity, or for up to 1 year total duration. The median duration of exposure was 10.1 months (range: <0.1 to 14 months) in OPDIVO-treated patients and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received OPDIVO, 61% were exposed for >6 months and 54% were exposed for >9 months.

Serious adverse reactions occurred in 33% of patients receiving OPDIVO. A serious adverse reaction reported in ≥2% of patients who received OPDIVO was pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who received OPDIVO.

OPDIVO was discontinued in 12% of patients and was delayed in 28%of patients for an adverse reaction.

Tables 35 and 36 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577.

Table 35: Adverse Reactions Occurring in ≥10% of Patients Receiving OPDIVO - CHECKMATE-577

Adverse Reaction OPDIVO
(n=532)
Placebo
(n=260)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Adverse Reaction 96 34 93 32
Gastrointestinal
  Diarrhea 29 0.9 29 0.8
  Nausea 23 0.8 21 0
  Abdominal Paina 17 0.8 20 1.5
  Vomiting 15 0.6 16 1.2
  Dysphagia 13 0.8 17 3.5
  Dyspepsiab 12 0.2 16 0.4
  Constipation 11 0 12 0
General
  Fatiguec 34 1.3 29 1.5
Respiratory, Thoracic and Mediastinal
  Coughd 20 0.2 21 0.4
  Dyspneae 12 0.8 12 0.4
Skin and Subcutaneous Tissue
  Rashf 21 0.9 10 0.4
  Pruritus 13 0.4 6 0
Investigations
  Weight decreased 13 0.4 9 0
Musculoskeletal and Connective Tissue
  Musculoskeletal paing 21 0.6 20 0.8
  Arthralgia 10 0.2 8 0
Metabolism and Nutrition
  Decreased appetite 15 0.9 10 0.8
Endocrine
  Hypothyroidism 11 0 1.5 0
a Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
b Includes gastroesophageal reflux.
c Includes asthenia.
d Includes productive cough.
e Includes dyspnea exertional.
f Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash erythematous, rash macular, rash maculo-papular, rash popular, rash pruritic.
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, spinal pain.

Table 36: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-577

Laboratory Abnormality OPDIVO
(n=532)
Placebo
(n=260)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Chemistry
  Increased AST 27 2.1 22 0.8
  Increased alkaline phosphatase 25 0.8 18 0.8
  Increased albumin 21 0.2 18 0
  Increased ALT 20 1.9 16 1.2
  Increased amylase 20 3.9 13 1.3
  Hyponatremia 19 1.7 12 1.2
  Hyperkalemia 17 0.8 15 1.6
  Hypokalemia 12 1 11 1.2
  Transaminases increasedb 11 1.5 6 1.2
Hematology
  Lymphopenia 44 17 35 12
  Anemia 27 0.8 21 0.4
  Neutropenia 24 1.5 23 0.4
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: 163 to 526 patients) and Placebo group (range: 86 to 256 patients).
b Includes alanine aminotransferase increased, aspartate aminotransferase increased.

Esophageal Squamous Cell Carcinoma

The safety of OPDIVO was evaluated in ATTRACTION-3, a randomized, active-controlled, open-label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum-based chemotherapy [see Clinical Studies]. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients received OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m2 intravenously every 3 weeks (n=65) or paclitaxel 100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in OPDIVO-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel-treated patients. Among patients who received OPDIVO, 26% were exposed for >6 months and 10% were exposed for >1 year.

Serious adverse reactions occurred in 38% of patients receiving OPDIVO. Serious adverse reactions reported in ≥2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

OPDIVO was discontinued in 13% of patients and was delayed in 27%of patients for an adverse reaction.

Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in ATTRACTION-3.

Table 37: Adverse Reactions Occurring in ≥10% of Patients Receiving OPDIVO - ATTRACTION-3

Adverse Reaction OPDIVO
(n=209)
Docetaxel or Paclitaxel
(n=208)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Skin and Subcutaneous Tissue
  Rasha 22 1.9 28 1
  Pruritus 12 0 7 0
Metabolism and Nutrition
  Decreased appetiteb 21 1.9 35 5
Gastrointestinal
  Diarrheac 18 1.9 17 1.4
  Constipation 17 0 19 0
  Nausea 11 0 20 0.5
Musculoskeletal and Connective Tissue
  Musculoskeletal paind 17 0 26 1.4
Infections
  Upper respiratory tract infectione 17 1.0 14 0
  Pneumoniaf 13 5 19 9
Respiratory, Thoracic and Mediastinal
  Coughg 16 0 14 0.5
General
  Pyrexiah 16 0.5 19 0.5
  Fatiguei 12 1.4 27 4.8
Blood and Lymphatic System
  Anemiaj 13 8 30 13
Endocrine
  Hypothyroidismk 11 0 1.4 0
Toxicity was graded per NCI CTCAE v4.
a Includes urticaria, drug eruption, eczema, eczema asteatotic, eczema nummular, palmar-plantar erythrodysaesthesia syndrome, erythema, erythema multiforme, blister, skin exfoliation, Stevens-Johnson syndrome, dermatitis, dermatitis described as acneiform, bullous, or contact, and rash described as maculo-papular, generalized, or pustular.
b Includes hypophagia, and food aversion.
c Includes colitis.
d Includes spondylolisthesis, periarthritis, musculoskeletal chest pain, neck pain, arthralgia, back pain, myalgia, pain in extremity, arthritis, bone pain, and periarthritis calcarea.
e Includes influenza, influenza like illness, pharyngitis, nasopharyngitis, tracheitis, and bronchitis and upper respiratory infection with bronchitis.
f Includes pneumonia aspiration, pneumonia bacterial, and lung infection. Two patients (1.0%) died of pneumonia in the OPDIVO treatment arm. Two patients (1.0%) died of pneumonia in the chemotherapy treatment arm; these deaths occurred with paclitaxel only.
g Includes productive cough.
h Includes tumor-associated fever.
i Includes asthenia.
j Includes hemoglobin decreased, and iron deficiency anemia.
k Includes blood thyroid stimulating hormone increased.

Table 38: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - ATTRACTION-3

Laboratory Abnormality OPDIVO
(n=209)
Docetaxel or Paclitaxel
(n=208)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Chemistry
  Increased creatinine 78 0.5 68 0.5
  Hyperglycemia 52 5 62 5
  Hyponatremia 42 11 50 12
  Increased AST 40 6 30 1.0
  Increased alkaline phosphatase 33 4.8 24 1.0
  Increased ALT 31 5 22 1.9
  Hypercalcemia 22 6 14 2.9
  Hyperkalemia 22 0.5 31 1.0
  Hypoglycemia 14 1.4 14 0.5
  Hypokalemia 11 2.9 13 3.4
Hematology
  Lymphopenia 46 19 72 43
  Anemia 42 9 71 17
  Leukopenia 11 0.5 79 45
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 (209 patients) and Docetaxel or Paclitaxel group (range: 207 to 208 patients).

Gastric Cancer, Gastroesophageal Junction Cancer, And Esophageal Adenocarcinoma

The safety of OPDIVO in combination with chemotherapy was evaluated in CHECKMATE- 649, a randomized, multicenter, open-label trial in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma [see Clinical Studies]. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive, or had untreated CNS metastases. Patients were randomized to receive OPDIVO in combination with chemotherapy or chemotherapy. Patients received one of the following treatments:

  • OPDIVO 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
  • OPDIVO 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks.

Patients were treated with OPDIVO in combination with chemotherapy or chemotherapy until disease progression, unacceptable toxicity, or up to 2 years. The median duration of exposure was 6.8 months (range: 0 to 33.5 months) in OPDIVO and chemotherapy-treated patients. Among patients who received OPDIVO and chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year.

Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy. OPDIVO and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.

Tables 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-649.

Table 39: Adverse Reactions in ≥10% of Patients Receiving OPDIVO and Chemotherapy - CHECKMATE-649

Adverse Reaction OPDIVO and mFOLFOX6 or CapeOX
(n=782)
mFOLFOX6 or CapeOX
(n=767)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4 (%)
Adverse Reaction 99 69 98 59
Nervous System
  Peripheral neuropathya 53 7 46 4.8
  Headache 11 0.8 6 0.3
Gastrointestinal
  Nausea 48 3.2 44 3.7
  Diarrhea 39 5 34 3.7
  Vomiting 31 4.2 29 4.2
  Abdominal painb 27 2.8 24 2.6
  Constipation 25 0.6 21 0.4
  Stomatitisc 17 1.8 13 0.8
General
  Fatigued 44 7 40 5
  Pyrexiae 19 1.0 11 0.4
  Edemaf 12 0.5 8 0.1
Metabolism and Nutrition
  Decreased appetite 29 3.6 26 2.5
  Hypoalbuminemiag 14 0.3 9 0.3
Investigations
  Weight decreased 17 1.3 15 0.7
  Increased lipase 14 7 8 3.7
  Increased amylase 12 3.1 5 0.4
Musculoskeletal and Connective Tissue
  Musculoskeletal painh 20 1.3 14 2.0
Skin and Subcutaneous Tissue
  Rashi 18 1.7 4.4 0.1
  Palmar-plantar erythrodysesthesia syndrome 13 1.5 12 0.8
Respiratory, Thoracic and Mediastinal
  Coughj 13 0.1 9 0
Infections and Infestations
  Upper respiratory tract infectionk 10 0.1 7 0.1
Toxicity was graded per NCI CTCAE v4.
a Includes dysaesthesia, hypoaesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy.
b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
d Includes asthenia.
e Includes tumor associated fever.
f Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
g Includes blood albumin decreased.
h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
i Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, nodular rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash vesicular.
j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, and rhinitis.

Table 40: Laboratory Values Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-649

Laboratory Abnormality OPDIVO and mFOLFOX6 or CapeOX
(n=782)
mFOLFOX6 or CapeOX
(n=767)
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
Hematology
  Neutropenia 73 29 62 23
  Leukopenia 69 12 59 9
  Thrombocytopenia 68 7 63 4.4
  Anemia 59 14 60 10
  Lymphopenia 59 12 49 9
Chemistry
  Increased AST 52 4.6 47 1.9
  Hypocalcemia 42 1.6 37 1.0
  Hyperglycemia 41 3.9 38 2.7
  Increased ALT 37 3.4 30 1.9
  Hyponatremia 34 6 24 5
  Hypokalemia 27 7 24 4.8
  Hyperbilirubinemia 24 2.8 21 2.0
  Increased creatinine 15 1.0 9 0.5
  Hyperkalemia 14 1.4 11 0.7
  Hypoglycemia 12 0.7 9 0.2
  Hypernatremia 11 0.5 7.1 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 mFOLFOX6 or CapeOX group (407 to 767 patients) or mFOLFOX6 or CapeOX group (range: 405 to 735 patients).

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of 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, metastatic or recurrent non-small cell lung cancer, and malignant pleural mesothelioma 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) and 25.7% (69/269) with OPDIVO 3 mg/kg every 2 weeks and ipilimumab 1 mg every 6 weeks in non-small cell lung cancer and malignant pleural mesothelioma patients, respectively, 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) and 0.7% (2/269) with OPDIVO 3 mg/kg every 2 weeks and ipilimumab 1 mg every 6 weeks in non-small cell lung cancer and malignant pleural mesothelioma patients, respectively, 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 2 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

Blood and lymphatic system disorders: hemophagocytic lymphohistiocytosis (HLH) (including fatal cases), autoimmune hemolytic anemia (including fatal cases)

DRUG INTERACTIONS

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