Opdivo

Contraindications

None

Cautions

Immune-mediated pneumonitis may occur; withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis

Immune-mediated colitis reported; withhold for moderate or severe and permanently discontinue for life-threatening colitis

Immune-mediated hepatitis observed in clinical trials; monitor for changes in liver function; withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation

Immune-mediated nephritis and renal dysfunction may occur; monitor for changes in renal function; withhold for moderate and permanently discontinue for severe or life-threatening serum creatinine elevation; withhold therapy for moderate (Grade 2) or severe (Grade 3) increased serum creatinine; permanently discontinue therapy for life-threatening (Grade 4) increased serum creatinine

Immune-mediated encephalitis can occur; withhold therapy in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration; evaluation may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture; if other etiologies ruled out, administer corticosteroids at a dose of 1 - 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper; permanently discontinue therapy for immune-mediated encephalitis

Other clinically significant and potentially fatal immune-mediated adverse reactions (eg, myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis) can occur after therapy discontinuation

Severe infusion reactions reported (rare, <1%); discontinue if severe or life-threatening, interrupt or slow infusion rate if mild or moderate reaction

Can cause fetal harm; advise of potential risk to a fetus and use of effective contraception (see Pregnancy and Lactation)

Monitor for hyperacute graft-versus-host-disease (GVHD), grade 3-4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions; transplant-related mortality has occurred

Immune-mediated endocrinopathies

• Immune-mediated hypophysitis; monitor; withhold therapy for moderate (Grade 2) or severe (Grade 3); permanently discontinue therapy for life-threatening (Grade 4
• Immune-mediated hypothyroidism and hyperthyroidism reported; monitor for changes in thyroid function and initiate thyroid hormone replacement as needed;administer hormone-replacement therapy for hypothyroidism; initiate medical management for control of hyperthyroidism
• Adrenal insufficiency may occur; monitor for signs and symptoms of adrenal insufficiency during and after treatment
• May cause type 1 diabetes mellitus; monitor for hyperglycemia, withhold if severe (Grade 3) hyperglycemia until metabolic control is achieved, permanently discontinue if life-threatening (Grade 4) hyperglycemia

Immune-Mediated Skin Reactions

• May cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN); for symptoms or signs of SJS or TEN, withhold therapy and refer patient for specialized care for assessment and treatment; if SJS or TEN is confirmed, permanently discontinue therapy; for immune-mediated rash, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) rash
• Immune mediated rash reported in combination with ipilimumab; withhold for severe and permanently discontinue for life-threatening rash

Mechanism of Action

Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2

PD-1 and PD-L1

• PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions; PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound
• This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation
• Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells

Absorption

Time to steady state: 12 wk (monotherapy)

Distribution

Vd: 6.8L (monotherapy); 7.92 L (combined with ipilimumab)

Elimination

Clearance: 8.2 mL/h (monotherapy); 10 mL/hr (combined with ipilimumab)

Half-life: 25 days (monotherapy); 24.8 days (combined with ipilimumab)

If Opdivo is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if an overdose is suspected, seek emergency medical attention.

Other drugs may interact with nivolumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Melanoma

Treatment of unresectable or metastatic melanoma following failure of ipilimumab and, in patients with tumors bearing the b-Raf serine-threonine kinase (BRAF) V600 mutation, therapy with a BRAF inhibitor1 2 (designated an orphan drug by FDA for this use).4

Efficacy based on overall response rate and response duration; improvement in patient-reported outcomes and overall survival not demonstrated.1

Non-small Cell Lung Cancer (NSCLC)

Treatment of metastatic squamous NSCLC that has progressed during or following therapy with platinum-based chemotherapy.1 3

Nivolumab injection is used alone or together with other medicines (eg, ipilimumab) to treat melanoma (skin cancer) that has spread throughout the body (metastatic) or that cannot be removed by surgery. It is also used to treat non-small cell lung cancer that has spread throughout the body and after other cancer medicines have been tried. Nivolumab injection is also used to treat kidney cancer in patients who have received other medicines. It is also used to treat classical Hodgkin lymphoma (white blood cell cancer) that has come back or spread after autologous hematopoietic stem cell transplantation (HSCT) and used brentuximab vedotin after stem cell transplant, or after you received at least 3 kinds of treatment including autologous HSCT. This medicine is also used to treat squamous cell cancer of the head and neck that has come back or spread throughout the body after receiving medicines containing platinum. It is also used to treat patients with urothelial cancer (bladder cancer) that has spread or grown and have tried cancer medicines containing platinum but did not work well.

Nivolumab is a monoclonal antibody that affects the immune system and helps control the growth of cancer cells.

This medicine is to be given only by or under the supervision of your doctor.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.
• Tell all of your health care providers that you take Opdivo. This includes your doctors, nurses, pharmacists, and dentists.
• This medicine may be used with another drug called ipilimumab. Some side effects that can happen may happen more often if this medicine is used with ipilimumab. If you are also using ipilimumab, talk with your doctor about the risks and side effects that may happen.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Injection: 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL) solution in a single-dose vial.

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Immune-Mediated Pneumonitis [see Warnings and Precautions (5.1)] • Immune-Mediated Colitis [see Warnings and Precautions (5.2)] • Immune-Mediated Hepatitis [see Warnings and Precautions (5.3)] • Immune-Mediated Endocrinopathies [see Warnings and Precautions (5.4)] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions (5.5)] • Immune-Mediated Skin Adverse Reactions [see Warnings and Precautions (5.6)] • Immune-Mediated Encephalitis [see Warnings and Precautions (5.7)] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.8)] • Infusion Reactions [see Warnings and Precautions (5.9)] • Complications of Allogeneic HSCT after Opdivo [see Warnings and Precautions (5.10)]

Clinical Trials Experience

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

The data in the Warnings and Precautions section reflect exposure to Opdivo, as a single agent, for clinically significant adverse reactions in 1994 patients enrolled in the CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 trials or a single-arm trial in NSCLC (n=117) administering Opdivo as a single agent [see Warnings and Precautions (5.1, 5.8)]. In addition, clinically significant adverse reactions of Opdivo administered with ipilimumab were evaluated in 407 patients with melanoma enrolled in CHECKMATE-067 (n=313) or a Phase 2 randomized study (n=94), administering Opdivo with ipilimumab, supplemented by immune-mediated adverse reaction reports in ongoing clinical trials [see Warnings and Precautions (5.1, 5.8)].

The data described below reflect exposure to Opdivo as a single agent in CHECKMATE-037, CHECKMATE-066, and CHECKMATE-067, and to Opdivo with ipilimumab in CHECKMATE-067, which are randomized, active-controlled trials conducted in patients with unresectable or metastatic melanoma. Also described below are single-agent Opdivo data from CHECKMATE-017 and CHECKMATE-057, which are randomized trials in patients with metastatic NSCLC, CHECKMATE-025, which is a randomized trial in patients with advanced RCC, CHECKMATE-205 and CHECKMATE-039, which are open-label, multiple-cohort trials in patients with cHL, CHECKMATE-141, a randomized trial in patients with recurrent or metastatic SCCHN, and CHECKMATE-275, which is a single-arm trial in patients with urothelial carcinoma.

Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

The safety of Opdivo as a single agent was evaluated in CHECKMATE-037, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received Opdivo 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks [see Clinical Studies (14.1)]. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in Opdivo-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received Opdivo for greater than 6 months and 3% of patients received Opdivo for greater than 1 year.

In CHECKMATE-037, patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV.

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

Opdivo was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving Opdivo had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving Opdivo. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving Opdivo. The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving Opdivo were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.

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

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

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

Other clinically important adverse reactions in less than 10% of patients treated with Opdivo in CHECKMATE-037 were:

Cardiac Disorders: ventricular arrhythmia

Eye Disorders: iridocyclitis

General Disorders and Administration Site Conditions: infusion-related reactions

Investigations: increased amylase, increased lipase

Nervous System Disorders: dizziness, peripheral and sensory neuropathy

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

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

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).
Laboratory Abnormality	Percentage of Patients with Worsening Laboratory Test from Baselinea
	Opdivo		Chemotherapy
	All Grades	Grades 3-4	All Grades	Grades 3-4
Increased AST	28	2.4	12	1.0
Increased alkaline phosphatase	22	2.4	13	1.1
Hyponatremia	25	5	18	1.1
Increased ALT	16	1.6	5	0
Hyperkalemia	15	2.0	6	0

Previously Untreated Metastatic Melanoma

CHECKMATE-066

The safety of Opdivo was also evaluated in CHECKMATE-066, a randomized, double-blind, active-controlled trial in which 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma received Opdivo 3 mg/kg every 2 weeks (n=206) or dacarbazine 1000 mg/m2 every 3 weeks (n=205) [see Clinical Studies (14.1)]. The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in Opdivo-treated patients. In this trial, 47% of patients received Opdivo for greater than 6 months and 12% of patients received Opdivo for greater than 1 year.

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

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

Adverse reactions led to permanent discontinuation of Opdivo in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of Opdivo discontinuations. Serious adverse reactions occurred in 36% of patients receiving Opdivo. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving Opdivo. The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of patients receiving Opdivo were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%).

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

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

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

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

Nervous System Disorders: peripheral neuropathy

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

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).
Laboratory Abnormality	Percentage of Patients with Worsening Laboratory Test from Baselinea
	Opdivo		Dacarbazine
	All Grades	Grades 3-4	All Grades	Grades 3-4
Increased ALT	25	3.0	19	0.5
Increased AST	24	3.6	19	0.5
Increased alkaline phosphatase	21	2.6	14	1.6
Increased bilirubin	13	3.1	6	0

CHECKMATE-067

The safety of Opdivo, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067 [see Clinical Studies (14.1)], a randomized (1:1:1), a double-blind trial in which 937 patients with previously untreated, unresectable or metastatic melanoma received:

• Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by Opdivo 3 mg/kg as a single agent every 2 weeks (Opdivo plus ipilimumab arm; n=313), • Opdivo 3 mg/kg every 2 weeks (Opdivo arm; n=313), or • Ipilimumab 3 mg/kg every 3 weeks for up to 4 doses (ipilimumab arm; n=311).

The median duration of exposure to Opdivo was 2.8 months (range: 1 day to 18.8 months) for the Opdivo plus ipilimumab arm and 6.6 months (range: 1 day to 17.3 months) for the Opdivo arm. In the Opdivo plus ipilimumab arm, 39% were exposed to Opdivo for ≥6 months and 24% exposed for >1 year. In the Opdivo arm, 53% were exposed for ≥6 months and 32% for >1 year.

CHECKMATE-067 excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV.

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

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

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

Table 6:     Adverse Reactions Occurring in ≥10% of Patients on the Opdivo plus Ipilimumab Arm or the Opdivo Arm and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-067)

Adverse Reaction	Percentage (%) of Patients
	Opdivo plus Ipilimumab (n=313)		Opdivo (n=313)		Ipilimumab (n=311)
	All Grades	Grades 3-4	All Grades	Grades 3-4	All Grades	Grades 3-4
Toxicity was graded per NCI CTCAE v4. a  Fatigue is a composite term which includes asthenia and fatigue. b  Rash is a composite term which includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, erythema, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, pruritic rash, and seborrheic dermatitis.
General Disorders and Administration Site Conditions
Fatiguea	59	6	53	1.9	50	3.9
Pyrexia	37	1.6	14	0	17	0.6
Skin and Subcutaneous Tissue Disorders
Rashb	53	5	40	1.6	42	3.9
Gastrointestinal Disorders
Diarrhea	52	11	31	3.8	46	8
Nausea	40	3.5	28	0.6	29	1.9
Vomiting	28	3.5	17	1.0	16	1.6
Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea	20	2.2	12	1.3	13	0.6

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

Gastrointestinal Disorders: stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders: vitiligo

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

Nervous System Disorders: neuritis, peroneal nerve palsy

Table 7:     Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Treated with Opdivo with Ipilimumab or Single-Agent Opdivo and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-067)

Laboratory Abnormality	Percentage (%) of Patientsa
	Opdivo plus Ipilimumab		Opdivo		Ipilimumab
	Any Grade	Grade 3-4	Any Grade	Grade 3-4	Any Grade	Grade 3-4
a  Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo plus ipilimumab (range: 241 to 297); Opdivo (range: 260 to 306); ipilimumab (range: 253 to 304).
Chemistry
Increased ALT	53	15	23	3.0	28	2.7
Increased AST	47	13	27	3.7	27	1.7
Hyponatremia	42	9	20	3.3	25	7
Increased lipase	41	20	29	9	23	7
Increased alkaline phosphatase	40	6	24	2.0	22	2.0
Hypocalcemia	29	1.1	13	0.7	21	0.7
Increased amylase	25	9.1	15	1.9	14	1.6
Increased creatinine	23	2.7	16	0.3	16	1.3
Hematology
Anemia	50	2.7	39	2.6	40	6
Lymphopenia	35	4.8	39	4.3	27	3.4

Metastatic Non-Small Cell Lung Cancer

The safety of Opdivo in metastatic NSCLC was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.2)]. Patients received 3 mg/kg of Opdivo administered intravenously over 60 minutes every 2 weeks or docetaxel administered intravenously at 75 mg/m2 every 3 weeks. The median duration of therapy in Opdivo-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 36% of patients received Opdivo for at least 6 months and 18% of patients received Opdivo for at least 1 year and in CHECKMATE-057, 30% of patients received Opdivo for greater than 6 months and 20% of patients received Opdivo for greater than 1 year.

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

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

Opdivo was discontinued in 11% of patients, and was delayed in 28% of patients for an adverse reaction. Serious adverse reactions occurred in 46% of patients receiving Opdivo. The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In CHECKMATE-057, in the Opdivo arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Across both trials, the most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

Table 8 summarizes selected adverse reactions occurring more frequently in at least 10% of Opdivo-treated patients.

Table 8:     Adverse Reactions Occurring in ≥10% of Opdivo-Treated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-017 and CHECKMATE-057)

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

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

Table 9:     Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Opdivo-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-017 and CHECKMATE-057)

a  Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients); TSH: Opdivo group n=314 and docetaxel group n=297. b  Not graded per NCI CTCAE v4.
Laboratory Abnormality	Percentage of Patients with Worsening Laboratory Test from Baselinea
	Opdivo		Docetaxel
	All Grades	Grades 3-4	All Grades	Grades 3-4
Chemistry
Hyponatremia	35	7	34	4.9
Increased AST	27	1.9	13	0.8
Increased alkaline phosphatase	26	0.7	18	0.8
Increased ALT	22	1.7	17	0.5
Increased creatinine	18	0	12	0.5
Increased TSHb	14	N/A	6	N/A

Renal Cell Carcinoma

The safety of Opdivo was evaluated in CHECKMATE-025, a randomized open-label trial in which 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimens received Opdivo 3 mg/kg every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.3)]. The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in Opdivo-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients.

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

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

The most common adverse reactions (reported in at least 20% of patients) were asthenic conditions, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. Table 10 summarizes adverse reactions that occurred in greater than 15% of Opdivo-treated patients.

Table 10:     Grade 1-4 Adverse Reactions in >15% of Patients Receiving Opdivo (CHECKMATE-025)

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

Other clinically important adverse reactions in CHECKMATE-025 were:

General Disorders and Administration Site Conditions: peripheral edema/edema

Gastrointestinal Disorders: abdominal pain/discomfort

Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain

Nervous System Disorders: headache/migraine, peripheral neuropathy

Investigations: weight decreased

Skin Disorders: Palmar-plantar erythrodysesthesia

The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, elevated triglycerides, and hyperkalemia. Table 11 summarizes the laboratory abnormalities that occurred in greater than 15% of Opdivo-treated patients.

Table 11:     Grade 1-4 Laboratory Values Worsening from Baseline Occurring in >15% of Patients on Opdivo (CHECKMATE-025)

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

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

Classical Hodgkin Lymphoma

The safety of Opdivo 3 mg/kg every 2 weeks was evaluated in 266 adult patients with cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials). Treatment could continue until disease progression, maximal clinical benefit, or unacceptable toxicity.

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

Opdivo was discontinued due to adverse reactions in 7% of patients. Dose delay for an adverse reaction occurred in 34% of patients. Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in at least 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last nivolumab dose, 2 from infection 8 to 9 months after completing nivolumab, and 6 from complications of allogeneic HSCT.

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

Table 12 summarizes the adverse reactions, excluding laboratory terms that occurred in at least 10% of patients in the safety population.

Table 12:     Non-Laboratory Adverse Reactions Occurring in ≥10% of Patients with cHL (CHECKMATE-205 and CHECKMATE-039)

Toxicity was graded per NCI CTCAE v4. a  Includes events occurring up to 30 days after last nivolumab dose, regardless of causality. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred up to 30 days after completing the initial nivolumab course. b  Includes asthenia. c  Includes colitis. d  Includes abdominal discomfort and upper abdominal pain. e  Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis. f  Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia. g  Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform. h  Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity. i  Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. These numbers are specific to treatment-emergent events.
Adverse Reactiona	Opdivo cHL Safety Population (n=266)
	Percentage (%)
	All Grades	Grades 3-4
General Disorders and Administration Site Conditions
Fatigueb	39	1.9
Pyrexia	29	<1
Gastrointestinal Disorders
Diarrheac	33	1.5
Nausea	20	0
Vomiting	19	<1
Abdominal paind	16	<1
Constipation	14	0.4
Infections
Upper respiratory tract infectione	44	0.8
Pneumonia/bronchopneumoniaf	13	3.8
Nasal congestion	11	0
Respiratory, Thoracic and Mediastinal Disorders
Cough/productive cough	36	0
Dyspnea/exertional dyspnea	15	1.5
Skin and Subcutaneous Tissue Disorders
Rashg	24	1.5
Pruritus	20	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painh	26	1.1
Arthralgia	16	<1
Endocrine Disorders
Hypothyroidism/thyroiditis	12	0
Nervous System Disorders
Headache	17	<1
Neuropathy peripherali	12	<1
Injury, Poisoning and Procedural Complications
Infusion-related reaction	14	<1

Additional information regarding clinically important adverse reactions:

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

Peripheral neuropathy: In CHECKMATE-205 and CHECKMATE-039, treatment-emergent peripheral neuropathy was reported in 14% (31/266) of all patients receiving Opdivo. Twenty-eight patients (11%) had new-onset peripheral neuropathy, and 3 of 40 patients had worsening of neuropathy from baseline. These adverse reactions were Grade 1 or 2, except for 1 Grade 3 event (<1%). The median time to onset was 50 (range: 1 to 309) days.

Complications of allogeneic HSCT after Opdivo:[see Warnings and Precautions (5.10)].

Table 13 summarizes laboratory abnormalities that developed or worsened in at least 10% of patients with cHL. The most common (reported in at least 20%) treatment-emergent laboratory events included cytopenias, liver function abnormalities, and elevated lipase. Other common findings (reported in at least 10%) included elevated creatinine, electrolyte abnormalities, and elevated amylase.

Table 13:     Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Opdivo-Treated Patients with cHL (CHECKMATE-205 and CHECKMATE-039)

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

Recurrent or Metastatic 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 (14.5)]. Patients received 3 mg/kg of Opdivo (n=236) administered intravenously (IV) over 60 minutes every 2 weeks or investigator’s choice of either:

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

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

CHECKMATE-141 excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma).

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

Opdivo was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Serious adverse reactions occurred in 49% of patients receiving Opdivo. The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC. The most common adverse reactions occurring in ≥10% of Opdivo-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea.

The most common laboratory abnormalities occurring in ≥10% of Opdivo-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.

Urothelial Carcinoma

The safety of Opdivo was evaluated in CHECKMATE-275, a single arm study in which 270 patients with locally advanced or metastatic urothelial carcinoma had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy received Opdivo 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a drug delay for an adverse reaction.

Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with Opdivo. Opdivo was discontinued for adverse reactions in 17% of patients. Serious adverse reactions occurred in 54% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

Twenty-five (9%) patients received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)].

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

Table 14 summarizes adverse reactions that occurred in greater than 10% of patients.

Table 14:     Adverse Reactions Occurring in ≥10% of Patients (CHECKMATE-275)

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

Table 15:     Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients (CHECKMATE-275)

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.
Test	Opdivo Urothelial Carcinomaa
	Percentage (%) of Patients
	All Grades	Grades 3-4
Hematology
Lymphopenia	42	9
Anemia	40	7
Thrombocytopenia	15	2.4
Leucopenia	11	0
Chemistry
Hyperglycemia	42	2.4
Hyponatremia	41	11
Increased creatinine	39	2.0
Increased alkaline phosphatase	33	5.5
Hypocalcemia	26	0.8
Increased AST	24	3.5
Hyperkalemia	19	1.2
Increased ALT	18	1.2
Hypomagnesemia	16	0
Increased lipase	20	7
Increased amylase	18	4.4

Immunogenicity

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

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

Of 394 patients who were treated with Opdivo with ipilimumab and evaluable for the presence of anti-nivolumab antibodies, 149 patients (37.8%) tested positive for treatment-emergent anti-nivolumab antibodies by an ECL assay and 18 patients (4.6%) had neutralizing antibodies against nivolumab. Of the 391 patients evaluable for the presence of anti-ipilimumab antibodies, 33 patients (8.4%) tested positive for treatment-emergent anti-ipilimumab antibodies by an ECL assay and one patient (0.3%) had neutralizing antibodies against ipilimumab. There was no evidence of increased incidence of infusion reactions with anti-nivolumab antibody development.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Opdivo with the incidences of antibodies to other products may be misleading.

Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

CHECKMATE-037 (NCT01721746) was a multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive either Opdivo administered intravenously at 3 mg/kg every 2 weeks or investigator’s choice of chemotherapy, either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks. Patients were required to have progression of disease on or following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of Grade 4 ipilimumab-related 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. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter.

Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received Opdivo in CHECKMATE-037 and in whom the minimum duration of follow-up was 6 months. The major efficacy outcome measures in this population were confirmed objective response rate (ORR) as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response.

Among the 120 patients treated with Opdivo, the median age was 58 years (range: 25 to 88), 65% of patients were male, 98% were white, and the ECOG performance score was 0 (58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic therapies for metastatic disease (68%).

The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of 4 complete responses and 34 partial responses in Opdivo-treated patients. Of 38 patients with responses, 33 patients (87%) had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer.

There were objective responses in patients with and without BRAF V600 mutation-positive melanoma.

Previously Untreated Metastatic Melanoma

CHECKMATE-066

CHECKMATE-066 (NCT01721772) was a multicenter, double-blind, randomized (1:1) trial conducted in patients with BRAF V600 wild-type unresectable or metastatic melanoma. Patients were randomized to receive either Opdivo 3 mg/kg by intravenous infusion every 2 weeks or dacarbazine 1000 mg/m2 by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by PD-L1 status (greater than or equal to 5% of tumor cell membrane staining by immunohistochemistry vs. less than 5% or indeterminate result) and M stage (M0/M1a/M1b versus M1c). Key eligibility criteria included histologically confirmed, unresectable or metastatic, cutaneous, mucosal, or acral melanoma; no prior therapy for metastatic disease; completion of prior adjuvant or neoadjuvant therapy at least 6 weeks prior to randomization; ECOG performance status 0 or 1; absence of autoimmune disease; and absence of active brain or leptomeningeal metastases. The trial excluded patients with ocular melanoma. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year and then every 12 weeks thereafter.

The major efficacy outcome measure was overall survival (OS). Additional outcome measures included investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per RECIST v1.1.

A total of 418 patients were randomized to Opdivo (n=210) or dacarbazine (n=208). The median age was 65 years (range: 18 to 87), 59% were men, and 99.5% were white. Disease characteristics were M1c stage disease (61%), cutaneous melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 greater than or equal to 5% tumor cell membrane expression (35%), and history of brain metastasis (4%). More patients in the Opdivo arm had an ECOG performance status of 0 (71% vs. 58%).

CHECKMATE-066 demonstrated a statistically significant improvement in OS for the Opdivo arm compared with the dacarbazine arm in an interim analysis based on 47% of the total planned events for OS. Table 16 and Figure 1 summarize the efficacy results.

Table 16:     Efficacy Results - CHECKMATE-066

a  Based on a stratified proportional hazards model. b  Based on stratified log-rank test. c  p-value is compared with the allocated alpha of 0.0021 for this interim analysis.
	Opdivo (n=210)	Dacarbazine (n=208)
Overall Survival
Deaths (%)	50 (24)	96 (46)
Median, months (95% CI)	Not Reached	10.8 (9.3, 12.1)
Hazard ratio (95% CI)a	0.42 (0.30, 0.60)
p-valueb,c	<0.0001
Progression-Free Survival
Disease progression or death (%)	108 (51)	163 (78)
Median, months (95% CI)	5.1 (3.5, 10.8)	2.2 (2.1, 2.4)
Hazard ratio (95% CI)a	0.43 (0.34, 0.56)
p-valueb,c	<0.0001
Objective Response Rate	34%	9%
(95% CI)	(28, 41)	(5, 13)
Complete response rate	4%	1%
Partial response rate	30%	8%

Figure 1:      Kaplan-Meier Curves of Overall Survival - CHECKMATE-066

At the time of analysis, 88% (63/72) of Opdivo-treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer.

CHECKMATE-067

CHECKMATE-067 (NCT01844505) was a multicenter, double-blind trial that randomized (1:1:1) patients with previously untreated, unresectable or metastatic melanoma to one of the following arms: Opdivo plus ipilimumab, Opdivo, or ipilimumab. Patients were required to have completed adjuvant or neoadjuvant treatment at least 6 weeks prior to randomization and have no prior treatment with anti-CTLA-4 antibody and no evidence of active brain metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring systemic immunosuppression.

Patients were randomized to receive:

• Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by Opdivo 3 mg/kg as a single agent every 2 weeks (Opdivo plus ipilimumab arm), • Opdivo 3 mg/kg every 2 weeks (Opdivo arm), or • Ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by placebo every 2 weeks (ipilimumab arm).

Randomization was stratified by PD-L1 expression (≥5% vs. <5% tumor cell membrane expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per the American Joint Committee on Cancer (AJCC) staging system (M0, M1a, M1b vs. M1c). Tumor assessments were conducted 12 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter.

The major efficacy outcome measures were investigator-assessed PFS per RECIST v1.1 and OS. Additional efficacy outcome measures were confirmed ORR and duration of response.

A total of 945 patients were randomized, 314 patients to the Opdivo plus ipilimumab arm, 316 to the Opdivo arm, and 315 to the ipilimumab arm. The trial population characteristics were: median age 61 years (range: 18 to 90); 65% male; 97% White; ECOG performance score 0 (73%) or 1 (27%). Disease characteristics were: AJCC Stage IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain metastases (4%); BRAF V600 mutation-positive melanoma (32%); PD-L1 ≥5% tumor cell membrane expression as determined by the clinical trials assay (46%); and prior adjuvant therapy (22%).

CHECKMATE-067 demonstrated statistically significant improvements in PFS for patients randomized to either Opdivo-containing arm as compared with the ipilimumab arm. Efficacy results are presented in Table 17 and Figure 2.

Table 17:     Efficacy Results in CHECKMATE-067

	Opdivo plus Ipilimumab (n=314)	Opdivo (n=316)	Ipilimumab (n=315)
a  Based on a stratified proportional hazards model. b  Based on stratified log-rank test. c  p-value is compared with .005 of the allocated alpha for final PFS treatment comparisons. d  Based on the stratified Cochran-Mantel-Haenszel test.
Progression-free Survival
Disease progression or death	151	174	234
Median in months (95% CI)	11.5 (8.9, 16.7)	6.9 (4.3, 9.5)	2.9 (2.8, 3.4)
Hazard ratioa (vs. ipilimumab)	0.42	0.57
(95% CI)	(0.34, 0.51)	(0.47, 0.69)
p-valueb,c	<0.0001	<0.0001
Confirmed Objective Response Rate	50%	40%	14%
(95% CI)	(44, 55)	(34, 46)	(10, 18)
p-valued	<0.0001	<0.0001
Complete response	8.9%	8.5%	1.9%
Partial response	41%	31%	12%
Duration of Response
Proportion ≥6 months in duration	76%	74%	63%
Range (months)	1.2+ to 15.8+	1.3+ to 14.6+	1.0+ to 13.8+

Figure 2:     Progression-free Survival: Unresectable or Metastatic Melanoma - CHECKMATE-067

Figures 3 and 4 present exploratory efficacy subgroup analyses of PFS based on defined PD-L1 expression levels determined in archival tumor specimens using the PD-L1 IHC 28-8 pharmDx assay. Tumor samples were available for retrospective assessment for 97% of the study population; PD-L1 expression status was ascertained for 89% of the study population while in 6% of patients, melanin precluded evaluation of PD-L1 expression status. PD-L1 expression status was unknown for 5% of the study population due to consent withdrawal or missing samples.

Figure 3:     Progression-free Survival by PD-L1 Expression (<1%) - CHECKMATE-067

Figure 4:     Progression-free Survival by PD-L1 Expression (≥1%) - CHECKMATE-067

The data presented in the figure below summarize the results of exploratory analyses comparing the two Opdivo-containing arms in subgroups defined by PD-L1 tumor expression.

Figure 5:     Forest Plot: PFS Based on PD-L1 Expression Comparing Opdivo-Containing Arms - CHECKMATE-067

Metastatic Non-Small Cell Lung Cancer (NSCLC)

Second-line Treatment of Metastatic Squamous NSCLC

CHECKMATE-017 (NCT01642004) was a randomized (1:1), open-label study enrolling 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Patients received Opdivo (n=135) administered intravenously at 3 mg/kg every 2 weeks or docetaxel (n=137) administered intravenously at 75 mg/m2 every 3 weeks. Randomization was stratified by prior paclitaxel vs. other prior treatment and region (US/Canada vs. Europe vs. Rest of World). This study included patients regardless of their PD-L1 status. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrollment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS.

In CHECKMATE-017, the median age was 63 years (range: 39 to 85) with 44% ≥65 years of age and 11% ≥75 years of age. The majority of patients were white (93%) and male (76%); the majority of patients were enrolled in Europe (57%) with the remainder in US/Canada (32%) and the rest of the world (11%). Baseline ECOG performance status was 0 (24%) or 1 (76%) and 92% were former/current smokers. Baseline disease characteristics of the population as reported by investigators were Stage IIIb (19%), Stage IV (80%), and brain metastases (6%). All patients received prior therapy with a platinum-doublet regimen and 99% of patients had tumors of squamous-cell histology.

The trial demonstrated a statistically significant improvement in OS for patients randomized to Opdivo as compared with docetaxel at the prespecified interim analysis when 199 events were observed (86% of the planned number of events for final analysis) (Table 18 and Figure 6).

Table 18:     Efficacy Results in CHECKMATE-017

	Opdivo (n=135)	Docetaxel (n=137)
a  Based on a stratified proportional hazards model. b  Based on stratified log-rank test. c  p-value is compared with .0315 of the allocated alpha for this interim analysis. d  Based on the stratified Cochran-Mantel-Haenszel test.
Overall Survival
Deaths (%)	86 (64%)	113 (82%)
Median (months)      (95% CI)	9.2 (7.3, 13.3)	6.0 (5.1, 7.3)
Hazard ratio (95% CI)a	0.59 (0.44, 0.79)
p-valueb,c	0.0002
Objective Response Rate	27 (20%)	12 (9%)
(95% CI)	(14, 28)	(5, 15)
p-value d	0.0083
Complete response	1 (0.7%)	0
Median duration of response, months (95% CI)	NR (9.8, NR)	8.4 (3.6, 10.8)
Progression-free Survival
Disease progression or death (%)	105 (78%)	122 (89%)
Median (months)	3.5	2.8
Hazard ratio (95% CI)a	0.62 (0.47, 0.81)
p-valueb	0.0004

Figure 6:     Overall Survival - CHECKMATE-017

Archival tumor specimens were retrospectively evaluated for PD-L1 expression. Across the study population, 17% (47/272) of patients had non-quantifiable results. Among the 225 patients with quantifiable results, 47% (106/225) had PD-L1 negative squamous NSCLC, defined as <1% of tumor cells expressing PD-L1, and 53% (119/225) had PD-L1 positive squamous NSCLC, defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratios for survival were 0.58 (95% CI: 0.37, 0.92) in the PD-L1 negative subgroup and 0.69 (95% CI: 0.45, 1.05) in the PD-L1 positive NSCLC subgroup.

Second-line Treatment of Metastatic Non-Squamous NSCLC

CHECKMATE-057 (NCT01673867) was a randomized (1:1), open-label study of 582 patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted therapy in patients with known sensitizing EGFR mutation or ALK translocation was allowed. Patients received Opdivo (n=292) administered intravenously at 3 mg/kg every 2 weeks or docetaxel (n=290) administered intravenously at 75 mg/m2 every 3 weeks. Randomization was stratified by prior maintenance therapy (yes vs. no) and number of prior therapies (1 vs. 2). The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS. In addition, prespecified analyses were conducted in subgroups defined by PD-L1 expression.

In CHECKMATE-057, the median age was 62 years (range: 21 to 85) with 42% of patients ≥65 years and 7% of patients ≥75 years. The majority of patients were white (92%) and male (55%); the majority of patients were enrolled in Europe (46%) followed by the US/Canada (37%) and the rest of the world (17%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79% were former/current smokers, 3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2.4%), and bronchoalveolar (0.9%).

CHECKMATE-057 demonstrated a statistically significant improvement in OS for patients randomized to Opdivo as compared with docetaxel at the prespecified interim analysis when 413 events were observed (93% of the planned number of events for final analysis) (Table 19 and Figure 7).

Table 19:     Efficacy Results in CHECKMATE-057

	Opdivo (n=292)	Docetaxel (n=290)
a  Based on a stratified proportional hazards model. b  Based on stratified log-rank test. c  p-value is compared with .0408 of the allocated alpha for this interim analysis. d  Based on the stratified Cochran-Mantel-Haenszel test.
Overall Survival
Deaths (%)	190 (65%)	223 (77%)
Median (months)      (95% CI)	12.2 (9.7, 15.0)	9.4 (8.0, 10.7)
Hazard ratio (95% CI)a	0.73 (0.60, 0.89)
p-valueb,c	0.0015
Objective Response Rate	56 (19%)	36 (12%)
(95% CI)	(15, 24)	(9, 17)
p-valued	0.02
Complete response	4 (1.4%)	1 (0.3%)
Median duration of response (months)      (95% CI)	17 (8.4, NR)	6 (4.4, 7.0)
Progression-free Survival
Disease progression or death (%)	234 (80%)	245 (84%)
Median (months)	2.3	4.2
Hazard ratio (95% CI)a	0.92 (0.77, 1.11)
p-valueb	0.39

Figure 7:     Overall Survival - CHECKMATE-057

Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial. Across the study population, 22% (127/582) of patients had non-quantifiable results. Of the remaining 455 patients, the proportion of patients in retrospectively determined subgroups based on PD-L1 testing using the PD-L1 IHC 28-8 pharmDx assay were: 46% (209/455) PD-L1 negative, defined as <1% of tumor cells expressing PD-L1 and 54% (246/455) had PD-L1 expression, defined as ≥1% of tumor cells expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% (65/246) had ≥1%, but <5% tumor cells with positive staining, 7% (16/246) had ≥5% but <10% tumor cells with positive staining, and 67% (165/246) had greater than or equal to 10% tumor cells with positive staining. Figure 8 summarizes the results of prespecified analyses of survival in subgroups determined by percentage of tumor cells expressing PD-L1. Figure 9 summarizes the results of prespecified analyses of progression-free survival in subgroups determined by percentage of tumor cells expressing PD-L1.

Figure 8:     Forest Plot: OS Based on PD-L1 Expression - CHECKMATE-057

Figure 9:     Forest Plot: PFS Based on PD-L1 Expression - CHECKMATE-057

Renal Cell Carcinoma

CHECKMATE-025 (NCT01668784) was a randomized (1:1), open-label study in patients with advanced RCC who had experienced disease progression during or after one or two prior anti-angiogenic therapy regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥70% and patients were included regardless of their PD-L1 status. CHECKMATE-025 excluded patients with any history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the number of prior anti-angiogenic therapies.

Patients were randomized to Opdivo (n=410) administered intravenously at 3 mg/kg every 2 weeks or everolimus (n=411) administered orally 10 mg daily. The median age was 62 years (range: 18 to 88) with 40% ≥65 years of age and 9% ≥75 years of age. The majority of patients were male (75%) and white (88%) and 34% and 66% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. The majority of patients (77%) were treated with one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor.

The first tumor assessments were conducted 8 weeks after randomization and continued every 8 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later.

The major efficacy outcome measure was overall survival (OS). The trial demonstrated a statistically significant improvement in OS for patients randomized to Opdivo as compared with everolimus at the prespecified interim analysis when 398 events were observed (70% of the planned number of events for final analysis) (Table 20 and Figure 10). OS benefit was observed regardless of PD-L1 expression level.

Other endpoints include confirmed objective response rates, which are also presented in Table 20.

Table 20:     Efficacy Results - CHECKMATE-025

	Opdivo (n=410)	Everolimus (n=411)
a  Based on a stratified proportional hazards model. b  Based on a stratified log-rank test. c  p-value is compared with .0148 of the allocated alpha for this interim analysis.
Overall Survival
Deaths (%)	183 (45)	215 (52)
Median survival in months (95% CI)	25.0 (21.7, NE)	19.6 (17.6, 23.1)
Hazard ratio (95% CI)a	0.73 (0.60, 0.89)
p-valueb,c	0.0018
Confirmed Objective Response Rate (95% CI)	21.5% (17.6, 25.8)	3.9% (2.2, 6.2)
Median duration of response in months (95% CI)	23.0 (12.0, NE)	13.7 (8.3, 21.9)
Median time to onset of confirmed response in months (min, max)	3.0 (1.4, 13.0)	3.7 (1.5, 11.2)

Figure 10:     Overall Survival - CHECKMATE-025

Classical Hodgkin Lymphoma

Two studies evaluated the efficacy of Opdivo as a single agent in adult patients with cHL after failure of autologous HSCT.

CHECKMATE-205 (NCT02181738) was a single-arm, open-label, multicenter, multicohort study in cHL. CHECKMATE-039 (NCT01592370) was an open-label, multicenter, dose escalation study that included cHL. Both studies included patients regardless of their tumor PD-L1 status and excluded patients with ECOG performance status of 2 or greater, autoimmune disease, symptomatic interstitial lung disease, hepatic transaminases more than 3 times ULN, creatinine clearance less than 40 mL/min, prior allogeneic HSCT, or chest irradiation within 24 weeks. In addition, both studies required an adjusted diffusion capacity of the lungs for carbon monoxide (DLCO) of over 60% in patients with prior pulmonary toxicity.

Patients received 3 mg/kg of Opdivo administered intravenously over 60 minutes every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. A cycle consisted of one dose. Dose reduction was not permitted.

Efficacy was evaluated by objective response rate (ORR) as determined by an independent radiographic review committee (IRRC). Additional outcome measures included duration of response (DOR).

Efficacy was evaluated in 95 patients in CHECKMATE-205 and CHECKMATE-039 combined who had failure of autologous HSCT and post-transplantation brentuximab vedotin. The median age was 37 years (range: 18 to 72). The majority were male (64%) and white (87%). Patients had received a median of 5 prior systemic regimens (range: 2 to 15). They received a median of 27 doses of Opdivo (range: 3 to 48), with a median duration of therapy of 14 months (range: 1 to 23 months). Results are shown in Table 21.

Table 21:     Efficacy in cHL after Autologous HSCT and Post-transplantation Brentuximab Vedotin

a  Per 2007 revised International Working Group criteria. b  Kaplan-Meier estimate. Among responders, the median follow-up for DOR, measured from the date of first response, was 9.9 months. c  A + sign indicates a censored value.
	CHECKMATE-205 and CHECKMATE-039 (n=95)
Objective Response Rate, n (%)a       (95% CI)	63 (66%) (56, 76)
Complete Remission Rate       (95% CI)	6 (6%) (2, 13)
Partial Remission Rate       (95% CI)	57 (60%) (49, 70)
Duration of Response (months)    Medianb       (95% CI)    Rangec	13.1 (9.5, NE) 0+, 23.1+
Time to Response (months)    Median    Range	2.0 0.7, 11.1

Efficacy was also evaluated in 258 patients in CHECKMATE-205 and CHECKMATE-039 combined who had relapsed or progressive cHL after autologous HSCT. The analysis included the group described above. The median age was 34 years (range: 18 to 72). The majority were male (59%) and white (86%). Patients had a median of 4 prior systemic regimens (range: 2 to 15), with 85% having 3 or more prior systemic regimens and 76% having prior brentuximab vedotin. Of the 195 patients having prior brentuximab vedotin, 17% received it only before autologous HSCT, 78% received it only after HSCT, and 5% received it both before and after HSCT. Patients received a median of 21 doses of Opdivo (range: 1 to 48), with a median duration of therapy of 10 months (range: 0 to 23 months). Results are shown in Table 22.

Table 22:     Efficacy in cHL after Autologous HSCT

a  Kaplan-Meier estimate. Among responders, the median follow-up for DOR, measured from the date of first response, was 6.7 months. b  The estimated median duration of PR was 13.1 months (95% CI, 9.5, NE). The median duration of CR was not reached.
	CHECKMATE-205 and CHECKMATE-039 (n=258)
Objective Response Rate, n (%)       (95% CI)	179 (69%) (63, 75)
Complete Remission Rate       (95% CI)	37 (14%) (10, 19)
Partial Remission Rate       (95% CI)	142 (55%) (49, 61)
Duration of Response (months)    Mediana,b       (95% CI)    Range	NE (12.0, NE) 0+, 23.1+
Time to Response (months)    Median    Range	2.0 0.7, 11.1

Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

CHECKMATE-141 (NCT02105636) was a randomized (2:1), active-controlled, open-label study enrolling patients with metastatic or recurrent SCCHN who had experienced disease progression during or within 6 months of receiving platinum-based therapy administered in either the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. The trial excluded patients with autoimmune disease, medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma), or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. Patients were randomized to receive Opdivo administered intravenously (IV) at 3 mg/kg every 2 weeks or investigator’s choice of:

• cetuximab 400 mg/m2 loading dose IV followed by 250 mg/m2 weekly, • methotrexate 40 to 60 mg/m2 IV weekly, or • docetaxel 30 to 40 mg/m2 IV weekly.

Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR.

In CHECKMATE-141, total of 361 patients were randomized; 240 patients to Opdivo and 121 patients to investigator’s choice (45% received docetaxel, 43% received methotrexate, and 12% received cetuximab). The median age was 60 years (range: 28 to 83) with 31% ≥65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83% male. Baseline ECOG performance status was 0 (20%) or 1 (78%), 76% were former/current smokers, 90% had Stage IV disease, 45% of patients received only one prior line of systemic therapy, the remaining 55% received two or more prior lines of systemic therapy, and 25% had HPVp16-positive tumors, 24% had HPV p16-negative tumors, and 51% had unknown status.

The trial demonstrated a statistically significant improvement in OS for patients randomized to Opdivo as compared with investigator’s choice at a pre-specified interim analysis (78% of the planned number of events for final analysis). The survival results are displayed in Table 23 and Figure 11. There were no statistically significant differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR (13.3% [95% CI: 9.3, 18.3] vs. 5.8% [95% CI: 2.4, 11.6] for nivolumab and investigator’s choice, respectively).

Table 23:     Overall Survival in CHECKMATE-141

	Opdivo (n=240)	Investigator’s Choice (n=121)
a  Based on stratified proportional hazards model. b  Based on stratified log-rank test. c  p-value is compared with 0.0227 of the allocated alpha for this interim analysis.
Overall Survival
Deaths (%)	133 (55%)	85 (70%)
Median (months)      (95% CI)	7.5 (5.5, 9.1)	5.1 (4.0, 6.0)
Hazard ratio (95% CI)a	0.70 (0.53, 0.92)
p-valueb,c	0.0101

Figure 11:     Overall Survival - CHECKMATE-141

Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1 IHC 28-8 pharmDx assay. Across the study population, 28% (101/361) of patients had non-quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1 negative SCCHN, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PD-L1 positive SCCHN, defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratio for survival was 0.89 (95% CI: 0.54, 1.45) with median survivals of 5.7 and 5.8 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 negative subgroup. The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median survivals of 8.7 and 4.6 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 positive SCCHN subgroup.

Urothelial Carcinoma

In CHECKMATE-275 (NCT02387996), 270 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen were treated with Opdivo. Patients were excluded for active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, and ECOG performance status >1. Patients received an intravenous infusion of 3 mg/kg of Opdivo every 2 weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 8 weeks for the first 48 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed objective response rate (ORR) as assessed by independent radiographic review committee (IRRC) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DOR).

The median age was 66 years (range: 38 to 90), 78% were male, 86% of patients were white. Twenty-seven percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy. Twenty-nine percent of patients had received ≥2 prior systemic regimens in the metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting. Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline. Patients were included regardless of their PD-L1 status.

Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 270 patients, 46% were defined as having PD-L1 expression of ≥1% (defined as ≥1% of tumor cells expressing PD-L1). The remaining 54% of patients, were classified as having PD-L1 expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed ORR in all patients and the two PD-L1 subgroups are summarized in Table 24. Median time to response was 1.9 months (range: 1.6 to 7.2). In 77 patients who received prior systemic therapy only in the neoadjuvant or adjuvant setting, the ORR was 23.4% (95% CI: 14.5%, 34.4%).

Table 24:     Efficacy Results in CHECKMATE-275

a  Estimated from the Kaplan-Meier Curve
	All Patients	PD-L1 <1%	PD-L1 ≥1%
	N=270	N=146	N=124
Confirmed Objective Response Rate, n (%)       (95% CI)	53 (19.6%) (15.1, 24.9)	22 (15.1%) (9.7, 21.9)	31 (25.0%) (17.7, 33.6)
Complete Response Rate	7 (2.6%)	1 (0.7%)	6 (4.8%)
Partial Response Rate	46 (17.0%)	21 (14.4%)	25 (20.2%)
Median Duration of Responsea (months) (range)	10.3 (1.9+, 12.0+)	7.6 (3.7, 12.0+)	NE (1.9+, 12.0+)

Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer

CHECKMATE-142 (NCT02060188) was a multicenter, open-label, single arm study conducted in patients with locally determined dMMR or MSI-H metastatic CRC who had disease progression during, after, or were intolerant to, prior treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG 0 or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. All patients received Opdivo 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or radiographic progression. Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Efficacy outcome measures included objective response rate (ORR) as assessed by independent radiographic review committee (IRRC) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DOR).

A total of 74 patients were enrolled. The median age was 53 years (range: 26 to 79) with 23% ≥65 years of age and 5% ≥75 years of age, 59% were male and 88% were white. Baseline ECOG performance status was 0 (43%), 1 (55%), or 3 (1.4%) and 36% were reported to have Lynch Syndrome. Across the 74 patients, 72% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 15%, 30%, 30%, and 24% received 1, 2, 3, or ≥4 prior lines of therapy, respectively, and 42% of patients had received an anti-EGFR antibody.

Efficacy results are shown in Table 25.

Table 25:     Efficacy Results - CHECKMATE-142

NR=Not Reached
	All Patients (n=74)	Prior Treatment with Fluoropyrimidine, Oxaliplatin, and Irinotecan (n=53)
IRC-Confirmed Objective Response Rate, n (%)	24 (32%)	15 (28%)
(95% CI)	(22, 44)	(17, 42)
Complete response (%)	2 (2.7%)	1 (1.9%)
Partial response (%)	22 (30%)	14 (26%)
Duration of Response
Median in months (range)	NR (1.4+, 26.5+)	NR (2.8+, 22.1+)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of Opdivo, including:

• Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.2)]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.3)]. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.4)]. • Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions (5.5)]. • Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions (5.6)]. • Encephalitis: Advise patients to contact their healthcare provider immediately for neurological signs or symptoms of encephalitis [see Warnings and Precautions (5.7)]. • Infusion Reactions: Advise patients of the potential risk of infusion reaction [see Warnings and Precautions (5.9)]. • Complications of allogeneic HSCT after Opdivo: Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.10)]. • Females of Reproductive Potential: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Opdivo and for at least 5 months following the last dose of Opdivo [see Use in Specific Populations (8.3)]. • Lactation: Advise women not to breastfeed while taking Opdivo [see Use in Specific Populations (8.2)].

Manufactured by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
U.S. License No. 1713

FDA Approval: 9/6/2017

BLA 125554/S-040

See How Supplied section for a complete list of available packages of Opdivo.

NDC 0003-3772-11
Rx only

Opdivo®
(nivolumab)
injection

40 mg/4 mL
(10 mg/mL)

For intravenous Infusion Only
Single-dose vial; Discard unused portion.
Please provide enclosed Medication Guide to the patient.

Bristol-Myers Squibb

Opdivo (nivolumab) is a cancer medicine that works with your immune system to interfere with the growth and spread of cancer cells in the body.

Opdivo is used to treat certain types of cancer, including melanoma (skin cancer), non-small cell lung cancer, bladder cancer, kidney cancer, squamous cell cancer of the head and neck, colorectal cancer, classical Hodgkin's Lymphoma, and urothelial carcinoma. Opdivo can be given alone or in combination with other cancer medicines. It is often used after other medicines have been tried without success.

Opdivo is sometimes used if the cancer has spread to other parts of the body. For some types of cancer, this medicine is given when the cancer cannot be treated with surgery. For Hodgkin lymphoma, Opdivo is used if the condition has relapsed or progressed after stem cell transplant and treatment with brentixumab vedotin (Adcetris).

In people with non-small cell lung cancer, Opdivo may increase the chance of a longer survival time.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.