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英文药名：OPDIVO（Nivolumab concentrate solution infusion） 中文药名：纳武单抗浓缩液/注射溶液 生产厂家：百时美施贵宝和小野制药
a Recommendation for the use of hormone replacement therapy is provided in section 4.4. Patients treated with OPDIVO must be given the patient alert card and be informed about the risks of OPDIVO (see also package leaflet). OPDIVO should also be permanently discontinued for Grade 2 or 3 immune-related adverse reactions that persist despite treatment modifications (see section 4.4) or for inability to reduce corticosteroid dose to 10 mg prednisone or equivalent per day. Special populations Paediatric population The safety and efficacy of OPDIVO in children below 18 years of age have not been established. No data are available. Elderly No dose adjustment is required for elderly patients (≥ 65 years) (see sections 5.1 and 5.2). Non-Small Cell Lung Cancer Data from patients 75 years of age or older are too limited to draw conclusions on this population. Renal impairment Based on the population pharmacokinetic (PK) results, no dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairment are too limited to draw conclusions on this population. Hepatic impairment Based on the population PK results, no dose adjustment is required in patients with mild hepatic impairment (see section 5.2). Data from patients with moderate or severe hepatic impairment are too limited to draw conclusions on these populations. OPDIVO must be administered with caution in patients with moderate (total bilirubin > 1.5 × to 3 × the upper limit of normal [ULN] and any AST) or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment. Method of administration OPDIVO is for intravenous use only. It is to be administered as an intravenous infusion over a period of 60 minutes. The infusion must be administered through a sterile, non-pyrogenic, low protein binding in-line filter with a pore size of 0.2-1.2 μm. OPDIVO must not be administered as an intravenous push or bolus injection. The total dose of OPDIVO required can be infused directly as a 10 mg/mL solution or can be diluted to as low as 1 mg/mL with sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection. For instructions on the handling of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Nivolumab is associated with immune-related adverse reactions. Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with nivolumab may occur at any time during or after discontinuation of nivolumab therapy. For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab should be withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. Rapid tapering may lead to worsening of the adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use. Nivolumab should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy. Prophylactic antibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressive therapy. Nivolumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life threatening immune-related adverse reaction. Use of nivolumab in melanoma patients with rapidly progressing disease Physicians should consider the delayed onset of nivolumab effect before initiating treatment in patients with rapidly progressing disease (see section 5.1). Immune-related pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with nivolumab treatment (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g., focal ground glass opacities, patchy filtrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out. For Grade 3 or 4 pneumonitis, nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents. For Grade 2 (symptomatic) pneumonitis, nivolumab should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents and nivolumab must be permanently discontinued. Immune-related colitis Severe diarrhoea or colitis has been observed with nivolumab treatment (see section 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Infectious and disease-related aetiologies should be ruled out. For Grade 4 diarrhoea or colitis, nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. For Grade 3 diarrhoea or colitis, nivolumab should be withheld and corticosteroids initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, nivolumab must be permanently discontinued. For Grade 2 diarrhoea or colitis, nivolumab should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab must be permanently discontinued. Immune-related hepatitis Severe hepatitis has been observed with nivolumab treatment (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis such as transaminase and total bilirubin elevations. Infectious and disease-related aetiologies should be ruled out. For Grade 3 or 4 transaminase or total bilirubin elevation, nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. For Grade 2 transaminase or total bilirubin elevation, nivolumab should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab must be permanently discontinued. Immune-related nephritis or renal dysfunction Severe nephritis or renal dysfunction has been observed with nivolumab treatment (see section 4.8). Patients should be monitored for signs and symptoms of nephritis and renal dysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled out. For Grade 4 serum creatinine elevation, nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. For Grade 2 or 3 serum creatinine elevation, nivolumab should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and nivolumab must be permanently discontinued. Immune-related endocrinopathies Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, diabetes mellitus, and diabetic ketoacidosis have been observed with nivolumab treatment (see section 4.8). Patients should be monitored for clinical signs and symptoms of endocrinopathies and for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation). Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related. For symptomatic hypothyroidism, nivolumab should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, nivolumab should be withheld and methimazole should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, nivolumab may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. For symptomatic adrenal insufficiency, nivolumab should be withheld, and physiologic corticosteroid replacement should be initiated as needed. Monitoring of adrenal function and hormone levels should continue to ensure appropriate corticosteroid replacement is utilised. For symptomatic hypophysitis, nivolumab should be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the pituitary gland is suspected. Upon improvement, nivolumab may be resumed after corticosteroid taper, if needed. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised. For symptomatic diabetes, nivolumab should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Immune-related rash Severe rash has been observed with nivolumab treatment that may be immune-related (see section 4.8). Nivolumab should be withheld for Grade 3 rash and discontinued for Grade 4 rash. Severe rash should be managed with high-dose corticosteroid at a dose of 1 to 2 mg/kg/day prednisone equivalents. Rare cases of toxic epidermal necrolysis (TEN) some of them with fatal outcome have been observed. If symptoms or signs of Stevens-Johnson Syndrome (SJS) or TEN appear, nivolumab treatment should be discontinued and the patient referred to a specialised unit for assessment and treatment. If the patient has developed SJS or TEN with the use of nivolumab, permanent discontinuation of nivolumab is recommended. Caution should be used when considering the use of nivolumab in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents. Other immune-related adverse reactions The following immune-related adverse reactions were reported in less than 1% of patients treated with nivolumab in clinical trials across doses and tumour types: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), Guillain-Barré syndrome, hypopituitarism, and myasthenic syndrome. For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab should be withheld and corticosteroids administered. Upon improvement, nivolumab may be resumed after corticosteroid taper. Nivolumab must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction. Infusion reactions Severe infusion reactions have been reported in clinical trials (see section 4.8). In case of a severe infusion reaction, nivolumab infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may receive nivolumab with close monitoring. Special populations Melanoma Patients with a baseline performance score ≥ 2, active brain metastases, ocular melanoma, autoimmune disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the pivotal clinical trials. In addition, CA209037 excluded patients who have had a Grade 4 adverse reaction that was related to anti-CTLA-4 therapy (see section 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential risk-benefit on an individual basis. Experience with nivolumab in previously untreated BRAF mutation-positive melanoma is limited. Non-Small Cell Lung Cancer Patients with a baseline performance score ≥ 2, active brain metastases or autoimmune disease, symptomatic interstitial lung disease, and patients who had been receiving systemic immunosuppressants prior to study entry were excluded from the clinical trials of NSCLC (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in these populations after careful consideration of the potential risk-benefit on an individual basis. Patients on controlled sodium diet Each mL of this medicinal product contains 0.1 mmol (or 2.5 mg) sodium. To be taken into consideration when treating patients on a controlled sodium diet. Patient Alert Card All prescribers of OPDIVO must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of OPDIVO therapy with the patient. The patient will be provided with the Patient Alert Card with each prescription. 4.5 Interaction with other medicinal products and other forms of interaction Nivolumab is a human monoclonal antibody, as such pharmacokinetic interaction studies have not been conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of nivolumab. Other forms of interaction Systemic immunosuppression The use of systemic corticosteroids and other immunosuppressants at baseline, before starting nivolumab, should be avoided because of their potential interference with the pharmacodynamic activity. However, systemic corticosteroids and other immunosuppressants can be used after starting nivolumab to treat immune-related adverse reactions. The preliminary results show that systemic immunosuppression after starting nivolumab treatment does not appear to preclude the response on nivolumab. 4.6 Fertility, pregnancy and lactation Pregnancy There are no data on the use of nivolumab in pregnant women. Studies in animals have shown embryofoetal toxicity (see section 5.3). Human IgG4 is known to cross the placental barrier and nivolumab is an IgG4; therefore, nivolumab has the potential to be transmitted from the mother to the developing foetus. Nivolumab is not recommended during pregnancy and in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk. Effective contraception should be used for at least 5 months following the last dose of OPDIVO. Breast-feeding It is unknown whether nivolumab is secreted in human milk. Because many medicinal products, including antibodies, can be secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue from nivolumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Studies to evaluate the effect of nivolumab on fertility have not been performed. Thus, the effect of nivolumab on male and female fertility is unknown. 4.7 Effects on ability to drive and use machines Based on its pharmacodynamic properties, nivolumab is unlikely to affect the ability to drive and use machines. Because of potential adverse reactions such as fatigue (see section 4.8), patients should be advised to use caution when driving or operating machinery until they are certain that nivolumab does not adversely affect them. 4.8 Undesirable effects Summary of the safety profile Nivolumab is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of nivolumab (see “Description of selected adverse reactions” below). In the pooled dataset of two phase 3 studies in melanoma (CA209066 and CA209037), the most frequent adverse reactions (≥ 10%) were fatigue (33%), rash (20%), pruritus (18%), diarrhoea (16%), and nausea (14%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). In the pooled dataset of two studies in squamous NSCLC (CA209017 and CA209063), the most frequent adverse reactions (≥ 10% of patients) were fatigue (33%), decreased appetite (15%), and nausea (12%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). Tabulated summary of adverse reactions Adverse reactions are listed according to their highest frequency reported either in the pooled dataset (n = 474) of melanoma studies (CA209037 and CA209066) or in the pooled dataset (n=248) of squamous NSCLC studies (CA209017 and CA209063) in Table 2. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Table 2: Adverse reactions in patients with advanced melanoma and with squamous NSCLC treated with nivolumab 3 mg/kg
b Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, dermatitis, dermatitis acneiform, dermatitis allergic, and dermatitis exfoliative. c Reported in studies outside the pooled dataset. The frequency is based on the program-wide exposure. d Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, spinal pain. e Frequencies reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements. See “Description of selected adverse reactions; laboratory abnormalities” below. Description of selected adverse reactions Data for the following immune-related adverse reactions are based on patients who received nivolumab 3 mg/kg in the two melanoma phase 3 studies ( see section 5.1) and in the two NSCLC studies (see section 5.1). The management guidelines for these adverse reactions are described in section 4.4. Immune-related pneumonitis In the melanoma studies, the incidence of pneumonitis, including interstitial lung disease, was 2.3% (11/474). All of these cases were Grade 1 or 2 in severity. Grade 2 cases were reported in 1.7% (8/474) of patients. Median time to onset was 2.1 months (range: 0.8-5.1). Eight patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) at a median initial dose of 1.5 mg/kg (range: 0.7-4.8) for a median duration of 0.6 month (range: 0.1-1.0). Resolution occurred in 8 patients (73%) with a median time to resolution of 1.4 months (range: 0.2-2.8). In squamous NSCLC studies, the incidence of pneumonitis, including interstitial lung disease, was 5.2% (13/248). Grade 2 and Grade 3 cases were reported in 2.8% (7/248) and 1.6% (4/248) of patients, respectively. No Grade 4 or 5 cases reported in these studies. In the phase 1 study MDX1106-03, pneumonitis, including a Grade 4 case in 1 patient, was reported in 3/37 patients (8.1%) with NSCLC receiving nivolumab 3 mg/kg. Median time to onset was 11.6 weeks (range: 2.6-85.1). Eleven patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) at a median initial dose of 1.1 mg/kg (range: 0.5-4.0) for a median total duration of 4.3 weeks (range: 0.6-13.1). Eight patients, including the 4 patients with a Grade 3 case, required permanent discontinuation of nivolumab due to pneumonitis. Resolution occurred in all 13 patients with a median time to resolution of 3.9 weeks (range: 0.6-13.4). Immune-related colitis In the melanoma studies, the incidence of diarrhoea or colitis was 16.5% (78/474). Grade 2 and Grade 3 cases were reported in 3.2% (15/474) and 1.3% (6/474) of patients, respectively. No Grade 4 or 5 cases were reported in these studies. Median time to onset was 1.9 months (range: 0.0-13.3). Seven patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) at a median initial dose of 1.0 mg/kg (range: 0.6-4.7) for a median duration of 1.1 months (range: 0.1-2.4). Two patients (0.4%) with Grade 3 colitis required permanent discontinuation of nivolumab. Resolution occurred in 68 patients (88%) with a median time to resolution of 0.3 month (range: 0.0-12.5+); + denotes a censored observation. In the squamous NSCLC studies, the incidence of diarrhoea or colitis was 9.3% (23/248). Grade 2 and Grade 3 cases were reported in 2% (5/248) and 1.6% (4/248) of patients, respectively. No Grade 4 or 5 cases were reported in these studies. Median time to onset was 5.6 weeks (range: 0.1-91.0). Three patients, including 2 patients with a Grade 3 case, received high-dose corticosteroids (at least 40 mg prednisone equivalents) at a median initial dose of 0.6 mg/kg (range: 0.4-1.3) for a median duration of 2.0 weeks (range: 1.4-14.1). One patient required permanent discontinuation of nivolumab due to Grade 3 diarrhoea. Resolution occurred in 19 patients (83%) with a median time to resolution of 2.0 weeks (range: 0.1-31.0). Immune-related hepatitis In the melanoma studies, the incidence of liver function test abnormalities was 6.8% (32/474). Grade 2, Grade 3, and Grade 4 cases were reported in 0.8% (4/474), 1.5% (7/474), and 0.4% (2/474) of patients, respectively. No Grade 5 cases were reported in these studies. Median time to onset was 2.8 months (range: 0.5-14.0). Four patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) at a median initial dose of 1.6 mg/kg (range: 0.4-4.7) for a median duration of 1.2 months (range: 0.9-1.7). Six patients (1.3%), 4 with Grade 3 and 2 with Grade 4 liver function test abnormalities, required permanent discontinuation of nivolumab. Resolution occurred in 26 patients (81%) with a median time to resolution of 0.7 month (range: 0.2-9.6+). In the squamous NSCLC studies, the incidence of liver function test abnormalities was 1.2% (3/248). Grade 2 cases were reported in 0.4% (1/248) of patients. No Grade 3-5 cases were reported in these studies. Median time to onset was 25.1 weeks (range: 4.1-31.1). None of these patients received high-dose corticosteroids. One patient required permanent discontinuation of nivolumab due to Grade 2 increases in transaminases. Resolution occurred in 2 patients (67%) with a median time to resolution of 4.1 weeks (range: 2.9-22.3+); + denotes a censored observation. Immune-related nephritis and renal dysfunction In melanoma studies, the incidence of nephritis or renal dysfunction was 1.9% (9/474). Grade 2 and Grade 3 cases were reported in 0.2% (1/474) and 0.6% (3/474) of patients, respectively. No Grade 4 or 5 nephritis or renal dysfunction was reported in these studies. Median time to onset was 3.5 months (range: 0.9-6.4). Four patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) at a median initial dose of 1.3 mg/kg (range: 0.7-2.1) for a median duration of 0.5 month (range: 0.2-1.0). Resolution occurred in 7 patients (78%) with a median time to resolution of 1.25 months (range: 0.5- 4.7+). In the squamous NSCLC studies, the incidence of nephritis or renal dysfunction was 3.2% (8/248). Grade 2 and Grade 3 cases were reported in 1.2% (3/248) and 0.4% (1/248) of patients, respectively. No Grade 4 or 5 nephritis or renal dysfunction was reported in these studies. Median time to onset was 10.5 weeks (range: 2.1-27.0). Two patients, including the one patient with a Grade 3 case (tubulointerstitial nephritis), received high-dose corticosteroids (at least 40 mg prednisone equivalents) at a median initial dose of 0.8 mg/kg (range: 0.5-1.2) for a median duration of 5.3 weeks (range: 0.9-9.7). Resolution occurred in 5 patients (71%), including the Grade 3 case, with a median time to resolution of 5.9 weeks (range: 0.7- 37.6+); + denotes a censored observation. Immune-related endocrinopathies In the melanoma studies, the incidence of thyroid disorders, including hypothyroidism or hyperthyroidism, was 7.6% (36/474). Grade 2 and Grade 3 thyroid disorders were reported in 4.2% (20/474) and 0.2% (1/474) of patients respectively. Hypophysitis (Grade 3), adrenal insufficiency (Grade 2), diabetes mellitus (Grade 2), and diabetic ketoacidosis (Grade 3) were each reported in 1 patient (0.2% each). Median time to onset of these endocrinopathies was 2.4 months (range: 0.8-10.8). Two patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) at an initial dose of 0.7 mg/kg and 1.3 mg/kg for 0.4 month and 0.7 month, respectively. Resolution occurred in 18 patients (45%) with a median time to resolution of 6.4 months (0.2-15.4+). In the squamous NSCLC studies, the incidence of thyroid disorders, including hypothyroidism or thyroiditis, was 4.4% (11/248). Grade 2 cases were reported in 3.6% (9/248) of patients. No Grade 3-5 thyroid disorders were reported. The incidence of adrenal insufficiency was 0.4% (1/248; Grade 3). There were no reports of hypophysitis, diabetes mellitus, or diabetic ketoacidosis in these studies. Median time to onset of these endocrinopathies was 17.8 weeks (range: 6.1-33.1). Three patients, including the one patient with Grade 3 adrenal insufficiency, received high-dose corticosteroids (at least 40 mg prednisone equivalents) at a median initial dose of 1.1 mg/kg (range: 0.5-1.3) for 2.7 weeks (range: 0.6-4.6). The Grade 3 case required permanent discontinuation of nivolumab. Resolution occurred in 6 patients (50%) with a median time to resolution of 20.6 weeks (0.4-47.6+); + denotes a censored observation. Immune-related rash In the melanoma studies, the incidence of rash was 36.1% (171/474). Grade 2 and Grade 3 cases were reported in 6.1% (29/474) and 0.8% (4/474) of patients respectively. No Grade 4 or 5 cases were reported in these studies. Median time to onset was 1.4 months (range: 0.0-13.1). Two patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) at an initial dose of 0.7 mg/kg and 0.9 mg/kg for 0.5 month and 0.1 month, respectively. Resolution occurred in 87 patients (51%) with a median time to resolution of 4.6 months (0.0-19.1+). In the squamous NSCLC studies, the incidence of rash was 12.1% (30/248). Grade 2 and Grade 3 cases were reported in 1.6% (4/248) and 0.8% (2/248) of patients, respectively. No Grade 4 or 5 rash was reported in these studies. Median time to onset was 8.1 weeks (range: 0.3-51.9). None of these patients received high-dose corticosteroids. Two patients (1 with Grade 2 rash and 1 with Grade 3 rash) required permanent discontinuation of nivolumab. Resolution occurred in 24 patients (83%), including the 2 patients with a Grade 3 case, with a median time to resolution of 5.7 weeks (range: 0.1- 46.9+); + denotes a censored observation. Infusion reactions In the melanoma studies, the incidence of hypersensitivity/infusion reactions was 5.3% (25/474), including a Grade 3 case in 1 patient (0.2%). In the squamous NSCLC studies, the incidence of hypersensitivity/infusion reactions was 1.6% (4/248). Grade 3 anaphylactic reaction and Grade 4 hypersensitivity were each reported in 1 patient; both of these cases led to discontinuation and resolved with treatment. Laboratory abnormalities In the melanoma studies, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 4.6% for anaemia (all Grade 3), 0.2% for thrombocytopenia, 7% for lymphopenia, 0.9% for neutropenia, 2.4% for increased alkaline phosphatase, 3.3% for increased AST, 2.4% for increased ALT, 1.5% for increased total bilirubin, and 0.9% for increased creatinine. In the squamous NSCLC studies, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 13.2% for decreased lymphocytes, 9% for hyponatraemia, 2.9% for hypercalcaemia and hyperkalaemia, 2.5% for decreased haemoglobin (all Grade 3), 2.0% for hypokalaemia, 1.6% for decreased neutrophil count, 1.3% for hypomagnesaemia, 1.2% for hypocalcaemia, 0.8% for increased total bilirubin, and 0.4% for increased AST, decreased platelet, hypermagnesaemia, and hypernatraemia. There was no worsening to Grade 3 or 4 in increased ALT, increased alkaline phosphatase, and increased creatinine. In the study CA209017, hypercalcaemia was more frequently reported in the nivolumab group (31/130, 24%) than in the docetaxel group (9/124, 7%). The exact cause is not known. Although hyperparathyroidism was not reported in CA209017, immune-related hyperparathyroidism might be considered especially if associated with hypophosphataemia (reported in 6 hypercalcemic patients in this study). Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to nivolumab. Of the 497 patients who were treated with nivolumab 3 mg/kg every 2 weeks and evaluable for the presence of anti-product-antibodies, 51 (10.3%) patients tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Only 4 (0.8%) patients were persistent positive. Neutralising antibodies were detected in only 5 (1.0% of the total) of the positive anti-product-antibody patients. There was no evidence of altered pharmacokinetic or toxicity profile associated with anti-product-antibody development. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose No cases of overdose have been reported in clinical trials. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC17. Mechanism of action Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands. In syngeneic mouse models, blocking PD-1 activity resulted in decreased tumour growth. Clinical efficacy and safety Melanoma Randomised phase 3 study vs. dacarbazine (CA209066) The safety and efficacy of nivolumab 3 mg/kg for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209066). The study included adult patients (18 years or older) with confirmed, treatment-naive, Stage III or IV BRAF wild-type melanoma and an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1. Patients with active autoimmune disease, ocular melanoma, or active brain or leptomeningeal metastases were excluded from the study. A total of 418 patients were randomised to receive either nivolumab (n = 210) administered intravenously over 60 minutes at 3 mg/kg every 2 weeks or dacarbazine (n = 208) at 1000 mg/m2 every 3 weeks. Randomisation was stratified by PD-L1 status and M stage (M0/M1a/M1b versus M1c). Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Treatment after disease progression was permitted for patients who had a clinical benefit and did not have substantial adverse effects with the study drug, as determined by the investigator. Tumour assessments, according to the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks for the first year and then every 12 weeks thereafter. The primary efficacy outcome measure was overall survival (OS). Key secondary efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR). Baseline characteristics were balanced between the two groups. The median age was 65 years (range: 18-87), 59% were men, and 99.5% were white. Most patients had ECOG performance score of 0 (64%) or 1 (34%). Sixty-one percent of patients had M1c stage disease at study entry. Seventy-four percent of patients had cutaneous melanoma, and 11% had mucosal melanoma; 35% of patients had PD-L1 positive melanoma (≥5% tumour cell membrane expression). Sixteen percent of patients had received prior adjuvant therapy; the most common adjuvant treatment was interferon (9%). Four percent of patients had a history of brain metastasis, and 37% of patients had a baseline LDH level greater than ULN at study entry. The Kaplan-Meier curves for OS are shown in Figure 1. Figure 1: Kaplan-Meier curves of OS (CA209066)
Randomised phase 3 study vs. chemotherapy (CA209037) The safety and efficacy of nivolumab 3 mg/kg for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, open-label study (CA209037). The study included adult patients who had progressed on or after ipilimumab and if BRAF V600 mutation positive had also progressed on or after BRAF kinase inhibitor therapy. Patients with active autoimmune disease, ocular melanoma or a known history of prior ipilimumab-related high-grade (Grade 4 per CTCAE v4.0) adverse reactions, except for resolved nausea, fatigue, infusion reactions, or endocrinopathies, were excluded from the study. A total of 405 patients were randomised to receive either nivolumab (n = 272) administered intravenously over 60 minutes at 3 mg/kg every 2 weeks or chemotherapy (n = 133) which consisted of the investigator's choice of either dacarbazine (1000 mg/m2 every 3 weeks) or carboplatin (AUC 6 every 3 weeks) and paclitaxel (175 mg/m2 every 3 weeks). Randomisation was stratified by BRAF and PD-L1 status and best response to prior ipilimumab. The co-primary efficacy outcome measures were confirmed ORR in the first 120 subjects treated with nivolumab, as measured by independent radiology review committee (IRRC) using RECIST 1.1, and comparison of OS of nivolumab to chemotherapy. Additional outcome measures included duration and timing of response. The median age was 60 years (range: 23-88). Sixty-four percent of patients were men and 98% were white. ECOG performance scores were 0 for 61% of patients and 1 for 39% of patients. The majority (75%) of patients had M1c stage disease at study entry. Seventy-three percent of patients had cutaneous melanoma and 10% had mucosal melanoma. The number of prior systemic regimen received was 1 for 27% of patients, 2 for 51% of patients, and > 2 for 21% of patients. Twenty-two percent of patients had tumours that tested BRAF mutation positive and 50% of patients had tumours that were considered PD-L1 positive. Sixty-four percent of patients had no prior clinical benefit (CR/PR or SD) on ipilimumab. Baseline characteristics were balanced between groups except for the proportions of patients who had a history of brain metastasis (19% and 13% in the nivolumab group and chemotherapy group, respectively) and patients with LDH greater than ULN at baseline (51% and 35%, respectively). At the time of this final ORR analysis, results from 120 nivolumab-treated patients and 47 chemotherapy-treated patients who had a minimum of 6 months of follow-up were analyzed. Efficacy results are presented in Table 4. Table 4: Best overall response, time and duration of response (CA209037)
The OS data were not mature at the time of the PFS analysis. There was no statistically significant difference between nivolumab and chemotherapy in the preliminary OS analysis that was not adjusted for the potentially confounding effects of subsequent therapy. It is of note that 42 (31.6%) patients in the chemotherapy arm subsequently received an anti-PD1 treatment. Data available indicate that the onset of nivolumab effect is delayed such that benefit of nivolumab above chemotherapy may take 2-3 months. Investigator assessed, confirmed ORRs in all treated patients were 25.7% [95% CI: 20.6, 31.4] in the nivolumab group (n=268) vs. 10.8% [95% CI: 5.5, 18.5]) in the chemotherapy group, (n=102), with an ORR difference of 15.0% (95% CI: 6.0, 22.2). Investigator assessed, confirmed ORRs in BRAF mutation-positive patients (n=79) were 19.3% [95% CI: 10.0, 31.9] vs. 13.6% [95% CI: 2.9, 34.9]), respectively, and in BRAF wild-type patients (n=291) were 27.5% [95% CI: 21.6, 34.0] vs. 10.0% [95% CI: 4.4, 18.8]), respectively. PFS numerically favoured the nivolumab group vs the chemotherapy group in all randomised patients, BRAF mutation positive patients, and BRAF wild-type patients (HRs 0.74 [95% CI: 0.57, 0.97], 0.98 [95% CI: 0.56, 1.70], and 0.63 [95% CI: 0.47, 0.85], respectively). Safety and efficacy in elderly patients No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and younger patients (< 65 years). Open-label phase 1 dose-escalation study (MDX1106-03) The safety and tolerability of nivolumab were investigated in a phase 1, open-label dose-escalation study in various tumour types, including malignant melanoma. Of the 306 previously treated patients enrolled in the study, 107 had melanoma and received nivolumab at a dose of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg for a maximum of 2 years. In this patient population, objective response was reported in 33 patients (31%) with a median duration of response of 22.9 months (95% CI: 17.0, NR). The median PFS was 3.7 months (95% CI: 1.9, 9.3). The median OS was 17.3 months (95% CI: 12.5, 36.7), and the estimated OS rates were 63% (95% CI: 53, 71) at 1 year, 48% (95% CI: 38, 57) at 2 years, and 41% (95% CI: 31, 51) at 3 years. Non-Small Cell Lung Cancer Randomised phase 3 study vs. docetaxel (CA209017) The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced or metastatic squamous NSCLC were evaluated in a phase 3, randomised, open-label study (CA209017). The study included patients (18 years or older) who have experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Patients were enrolled regardless of their PD-L1 status. Patients with active autoimmune disease, symptomatic interstitial lung disease, or untreated brain metastasis were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents. A total of 272 patients were randomised to receive either nivolumab 3 mg/kg (N = 135) administered intravenously over 60 minutes every 2 weeks or docetaxel (n = 137) 75 mg/m2 every 3 weeks. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments, according to the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks thereafter. The primary efficacy outcome measure was overall survival (OS). Key secondary efficacy outcome measures were investigator-assessed objective response rate (ORR) and progression-free survival (PFS). In addition, symptom improvement and overall health status were assessed using the Lung Cancer Symptom Score (LCSS) average symptom burden index and the EQ-5D Visual Analogue Scale (EQ-VAS), respectively. Baseline characteristics were generally balanced between the two groups. The median age was 63 years (range: 39-85) with 44% ≥65 years of age and 11% ≥75 years of age. The majority of patients were white (93%) and male (76%). Thirty-one percent had progressive disease reported as the best response to their most recent prior regimen and 45% received nivolumab within 3 months of completing their most recent prior regimen. Baseline ECOG performance status score was 0 (24%) or 1 (76%). The Kaplan-Meier curves for OS are shown in Figure 2. Figure 2: Kaplan-Meier curves of OS (CA209017)
The observed OS benefit was consistently demonstrated across subgroups of patients. Survival benefit was observed regardless of whether patients had tumours that were designated PD-L1 negative or PD-L1 positive (tumour membrane expression cut off of 1%, 5% or 10%). However, the role of this biomarker (PD-L1 expression) has not been fully elucidated.
Single-arm phase 2 study (CA209063) Study CA209063 was a single-arm, open-label study conducted in 117 patients with locally advanced or metastatic squamous NSCLC after two or more lines of therapy; otherwise similar inclusion criteria as study CA209017 were applied. Nivolumab 3 mg/kg showed an overall response rate of 14.5% (95% CI: 8.7,22.2%), a median OS of 8.21 months (95% CI: 6.05,10.9), and a median PFS of 1.87 months (95% CI 1.77,3.15). The PFS was measured by RECIST version 1.1. The estimated 1-year survival rate was 41%. Safety and efficacy in elderly patients No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and younger patients (< 65 years). Data from patients 75 years of age or older are too limited to draw conclusions on this population. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with nivolumab in all subsets of the paediatric population in the treatment of malignant solid tumours (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetics (PK) of nivolumab is linear in the dose range of 0.1 to 10 mg/kg. The geometric mean clearance (CL), terminal half-life, and average exposure at steady state at 3 mg/kg every 2 weeks of nivolumab were 9.5 mL/h, 26.7 days, and 75.3 μg/mL, respectively, based on a population PK analysis. Nivolumab CL increased with increasing body weight. Body weight normalised dosing produced approximately uniform steady-state trough concentration over a wide range of body weights (34-162 kg). The metabolic pathway of nivolumab has not been characterised. Nivolumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Special populations A population PK analysis suggested no difference in CL of nivolumab based on age, gender, race, tumour type, tumour size, and hepatic impairment. Although ECOG status, baseline glomerular filtration rate (GFR), albumin, body weight, and mild hepatic impairment had an effect on nivolumab CL, the effect was not clinically meaningful. Renal impairment The effect of renal impairment on the CL of nivolumab was evaluated in patients with mild (GFR < 90 and ≥ 60 mL/min/1.73 m2; n = 379), moderate (GFR < 60 and ≥ 30 mL/min/1.73 m2; n = 179), or severe (GFR < 30 and ≥ 15 mL/min/1.73 m2; n = 2) renal impairment compared to patients with normal renal function (GFR ≥ 90 mL/min/1.73 m2; n = 342) in population PK analyses. No clinically important differences in the CL of nivolumab were found between patients with mild or moderate renal impairment and patients with normal renal function. Data from patients with severe renal impairment are too limited to draw conclusions on this population (see section 4.2). Hepatic impairment The effect of hepatic impairment on the CL of nivolumab was evaluated in patients with mild hepatic impairment (total bilirubin 1.0 × to 1.5 × ULN or AST > ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; n = 92) compared to patients with normal hepatic function (total bilirubin and AST ≤ ULN; n = 804) in the population PK analyses. No clinically important differences in the CL of nivolumab were found between patients with mild hepatic impairment and normal hepatic function. Nivolumab has not been studied in patients with moderate (total bilirubin > 1.5 × to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin > 3 × ULN and any AST) (see section 4.2). 5.3 Preclinical safety data Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to increase foetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis in the first trimester through delivery, at exposure levels either 8 or 35 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). There was a dose-dependent increase in foetal losses and increased neonatal mortality beginning in the third trimester. The remaining offspring of nivolumab-treated females survived to scheduled termination, with no treatment-related clinical signs, alterations to normal development, organ-weight effects, or gross and microscopic pathology changes. Results for growth indices, as well as teratogenic, neurobehavioral, immunological, and clinical pathology parameters throughout the 6-month postnatal period were comparable to the control group. However, based on its mechanism of action, foetal exposure to nivolumab may increase the risk of developing immune-related disorders or altering the normal immune response and immune-related disorders have been reported in PD-1 knockout mice. Fertility studies have not been performed with nivolumab. 6. Pharmaceutical particulars 6.1 List of excipients Sodium citrate dihydrate Sodium chloride Mannitol (E421) Pentetic acid (diethylenetriaminepentaacetic acid) Polysorbate 80 Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. OPDIVO should not be infused concomitantly in the same intravenous line with other medicinal products. 6.3 Shelf life Unopened vial 2 years. After opening From a microbiological point of view, once opened, the medicinal product should be infused or diluted and infused immediately. After preparation of infusion From a microbiological point of view, the product should be used immediately. If not used immediately, chemical and physical in-use stability of OPDIVO has been demonstrated for 24 hours at 2°C to 8°C protected from light and a maximum of 4 hours at 20°C-25°C and room light (this 4-hour period of the total 24 hours should be inclusive of the product administration period). 6.4 Special precautions for storage Store in a refrigerator (2°C-8°C). Do not freeze. Store in the original package in order to protect from light. For storage conditions after preparation of the infusion, see section 6.3. 6.5 Nature and contents of container 4 mL of concentrate in a 10 mL vial (Type I glass) with a stopper (coated butyl rubber) and a dark blue flip-off seal (aluminium). Pack size of 1 vial. 10 mL of concentrate in a 10 mL vial (Type I glass) with a stopper (coated butyl rubber) and a grey flip-off seal (aluminium). Pack size of 1 vial. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Preparation should be performed by trained personnel in accordance with good practices rules, especially with respect to asepsis. Preparation and administration Calculating the dose The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the total dose to be given. More than one vial of OPDIVO concentrate may be needed to give the total dose for the patient. • The total nivolumab dose in mg = the patient's weight in kg × the prescribed dose in mg/kg. • The volume of OPDIVO concentrate to prepare the dose (mL) = the total dose in mg, divided by 10 (the OPDIVO concentrate strength is 10 mg/mL). Preparing the infusion Take care to ensure aseptic handling when you prepare the infusion. The infusion should be prepared in a laminar flow hood or safety cabinet using standard precautions for the safe handling of intravenous agents. OPDIVO can be used for intravenous administration either: • without dilution, after transfer to an infusion container using an appropriate sterile syringe; or • after diluting to concentrations as low as 1 mg/mL. The final infusion concentration should range between 1 and 10 mg/mL. OPDIVO concentrate may be diluted with either: • sodium chloride 9 mg/mL (0.9%) solution for injection; or • 50 mg/mL (5%) glucose solution for injection. STEP 1 • Inspect the OPDIVO concentrate for particulate matter or discoloration. Do not shake the vial. OPDIVO concentrate is a clear to opalescent, colourless to pale yellow liquid that may contain few light particles. • Withdraw the required volume of OPDIVO concentrate using an appropriate sterile syringe. STEP 2 • Transfer the concentrate into a sterile, evacuated glass bottle or intravenous container (PVC or polyolefin). • If applicable, dilute with the required volume of sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection. Gently mix the infusion by manual rotation. Do not shake. Administration OPDIVO infusion must not be administered as an intravenous push or bolus injection. Administer the OPDIVO infusion intravenously over a period of 60 minutes. OPDIVO infusion should not be infused at the same time in the same intravenous line with other agents. Use a separate infusion line for the infusion. Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 μm to 1.2 μm). OPDIVO infusion is compatible with PVC and polyolefin containers, glass bottles, PVC infusion sets and in-line filters with polyethersulfone membranes with pore sizes of 0.2 µm to 1.2 µm. After administration of the nivolumab dose, flush the line with sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection. Disposal Do not store any unused portion of the infusion solution for reuse. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Bristol-Myers Squibb Pharma EEIG Uxbridge Business Park Sanderson Road Uxbridge UB8 1DH United Kingdom 8. Marketing authorisation number(s) EU/1/15/1014/001-002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 19 June 2015 10. Date of revision of the text 17 December 2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 鳞状肺癌重大突破！百时美PD-1免疫疗法Opdivo再获欧盟批准 2015年7月20日，PD-1/PD-L1免疫治疗领域的王者——百时美施贵宝（BMS）近日在欧洲监管方面再传特大喜讯，该公司PD-1免疫疗法Opdivo（nivolumab）喜获欧盟批准，用于既往已治疗过的局部晚期或转移性鳞状（SQ）非小细胞肺癌（NSCLC）患者。此次批准，标志着Opdivo成为过去10多年来，鳞状非小细胞肺癌（SQ-NSCLC）领域的首个重大治疗进展，该药同时也成为首个也是唯一一个在既往已治疗转移性SQ-NSCLC群体中展现出总生存（OS）利益的PD-1免疫疗法。 Opdivo的批准，是基于2项研究（Checkmate-017，-063）的积极顶线数据。Checkmate-017是一项里程碑III期研究，在含铂化疗方案治疗期间或治疗后病情恶化的晚期鳞状非小细胞肺癌（SQ-NSCLC）患者中开展，将Opdivo（3mg/kg体重，每2周一次静脉注射）与标准护理多西他赛（75mg/㎡，每3周一次静脉注射）进行了对比。 数据显示，Opdivo在横跨所有终点均表现出相对于多西他赛化疗的显著优越性；总生存（OS）方面，Opdivo使一年生存率几乎提高一倍（42% vs 24%），死亡风险显著降低41%，中位总生存期提高3.2个月（9.2个月 vs 6.0个月）。此外，在无进展生存期（PFS）和总缓解率（ORR）方面，与多西他赛相比，Opdivo均表现出临床意义的统计学显著改善，而且治疗受益独立于PD-L1表达状态。Checkmate-063是一项II期研究，数据显示，Opdivo治疗组预计的一年生存率为41%，中位总生存期（OS）为8.2个月。研究中，Opdivo安全性与以往临床一致，相比多西他赛更有利。 在欧洲，肺癌的发病率和死亡率都在上升，目前约占所有癌症死亡病例的20%。非小细胞肺癌（NSCLC）是一种最常见的肺癌，约占肺癌病例的85%。鳞状非小细胞肺癌（SQ-NSCLC）占所有肺癌病例的25-30%。经化疗治疗后病情复发或恶化的NSCLC患者，临床治疗选择十分有限，而且预后极差，在全球范围内的5年生存率仅为2%左右。 当前，PD-1/PD-L1免疫竞赛异常激烈，市场峰值高达350亿美元，该领域的佼佼者包括默沙东、百时美施贵宝、罗氏、阿斯利康。此次竞赛中，百时美遥遥领先，其PD-1免疫疗法Opdivo在全球三大主要市场（美日欧）均已收获批文：日本（黑色素瘤）、美国（黑色素瘤，非小细胞肺癌）、欧洲（黑色素瘤，非小细胞肺癌）。默沙东则紧跟其后，其PD-1免疫疗法Keytruda在美国已收获黑色素瘤适应症，有望10月收获非小细胞肺癌适应症；欧洲方面，Keytruda很可能7月收获黑色素瘤适应症。而罗氏atezolizumab和阿斯利康MEDI4736目前尚未收获任何适应症。医药市场调研机构EvaluatePharma预测，Opdivo将成为PD-1/PD-L1领域最成功的免疫疗法，2020年销售额将达到88亿美元，而Keytruda也将达到55亿美元，罗氏atezolizumab峰值仅为20亿美元。 PD-1/PD-L1免疫疗法是当前备受瞩目的新一类抗癌免疫疗法，旨在利用人体自身的免疫系统抵御癌症，通过阻断PD-1/PD-L1信号通路使癌细胞死亡，具有治疗多种类型肿瘤的潜力。目前，各大巨头正在火速推进各自的临床项目，调查单药疗法和组合疗法用于多种癌症的治疗，以彻底发掘该类药物的最大临床潜力。
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