Opdivo

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
OPDIVO 10 mg/mL concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL of concentrate for solution for infusion contains 10 mg of nivolumab. 
One vial of 4 mL contains 40 mg of nivolumab. 
One vial of 10 mL contains 100 mg of nivolumab. 
One vial of 24 mL contains 240 mg of nivolumab. 
 
Nivolumab is produced in Chinese hamster ovary cells by recombinant DNA technology. 
 
Excipient with known effect 
Each mL of concentrate contains 0.1 mmol (or 2.5 mg) sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion (sterile concentrate). 
 
Clear to opalescent, colourless to pale yellow liquid that may contain few light particles. The solution 
has a pH of approximately 6.0 and an osmolality of approximately 340 mOsm/kg. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Melanoma 
 
OPDIVO as monotherapy or in combination with ipilimumab is indicated for the treatment of 
advanced (unresectable or metastatic) melanoma in adults. 
 
Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) and overall 
survival (OS) for the combination of nivolumab with ipilimumab is established only in patients with 
low tumour PD-L1 expression (see sections 4.4 and 5.1). 
 
Adjuvant treatment of melanoma 
 
OPDIVO as monotherapy is indicated for the adjuvant treatment of adults with melanoma with 
involvement of lymph nodes or metastatic disease who have undergone complete resection (see 
section 5.1). 
 
Non-small cell lung cancer (NSCLC) 
 
OPDIVO in combination with ipilimumab and 2 cycles of platinum-based chemotherapy is indicated 
for the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have no 
sensitising EGFR mutation or ALK translocation. 
 
OPDIVO as monotherapy is indicated for the treatment of locally advanced or metastatic non-small 
cell lung cancer after prior chemotherapy in adults. 
 



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Renal cell carcinoma (RCC) 
 
OPDIVO as monotherapy is indicated for the treatment of advanced renal cell carcinoma after prior 
therapy in adults. 
 
OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients with 
intermediate/poor-risk advanced renal cell carcinoma (see section 5.1). 
 
Classical Hodgkin lymphoma (cHL) 
 
OPDIVO as monotherapy is indicated for the treatment of adult patients with relapsed or refractory 
classical Hodgkin lymphoma after autologous stem cell transplant (ASCT) and treatment with 
brentuximab vedotin.  
 
Squamous cell cancer of the head and neck (SCCHN) 
 
OPDIVO as monotherapy is indicated for the treatment of recurrent or metastatic squamous cell 
cancer of the head and neck in adults progressing on or after platinum-based therapy (see section 5.1). 
 
Urothelial carcinoma 
 
OPDIVO as monotherapy is indicated for the treatment of locally advanced unresectable or metastatic 
urothelial carcinoma in adults after failure of prior platinum-containing therapy. 
 
4.2 Posology and method of administration 
 
Treatment must be initiated and supervised by physicians experienced in the treatment of cancer. 
 
Posology 
 
OPDIVO as monotherapy 
The recommended dose of OPDIVO is either nivolumab 240 mg every 2 weeks or 480 mg 
every 4 weeks (see section 5.1) depending on the indication, as presented in Table 1. 
 
Table 1: Recommended dose and infusion time for intravenous administration of 

nivolumab monotherapy 

Indication* Recommended dose and infusion time 

Melanoma (advanced or 
adjuvant treatment) 

240 mg every 2 weeks over 30 minutes or 
480 mg every 4 weeks over 60 minutes 

Renal cell carcinoma 240 mg every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes 

Non-small cell lung cancer 240 mg every 2 weeks over 30 minutes 

Classical Hodgkin lymphoma 240 mg every 2 weeks over 30 minutes 

Squamous cell cancer of the 
head and neck 240 mg every 2 weeks over 30 minutes 

Urothelial carcinoma 240 mg every 2 weeks over 30 minutes 

*As per monotherapy indication in section 4.1. 
 
If melanoma or RCC patients need to be switched from the 240 mg every 2 weeks schedule to the 
480 mg every 4 weeks schedule, the first 480 mg dose should be administered two weeks after the last 



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240 mg dose. Conversely, if patients need to be switched from the 480 mg every 4 weeks schedule to 
the 240 mg every 2 weeks schedule, the first 240 mg dose should be administered four weeks after the 
last 480 mg dose. 
 
OPDIVO in combination with ipilimumab 
 
Melanoma 
The recommended dose is 1 mg/kg nivolumab in combination with 3 mg/kg ipilimumab administered 
intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which 
nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg 
every 4 weeks, as presented in Table 2. For the monotherapy phase, the first dose of nivolumab should 
be administered; 
 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 

2 weeks; or 
 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 

4 weeks. 
 
Table 2: Recommended doses and infusion times for intravenous administration of 

nivolumab in combination with ipilimumab for melanoma  

 
Combination phase, 

every 3 weeks for 
4 dosing cycles

Monotherapy phase 

Nivolumab 1 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes 

Ipilimumab 3 mg/kg over 90 minutes - 

 
Renal cell carcinoma 
The recommended dose is 3 mg/kg nivolumab in combination with 1 mg/kg ipilimumab administered 
intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which 
nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg 
every 4 weeks, as presented in Table 3. For the monotherapy phase, the first dose of nivolumab should 
be administered; 
 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 

2 weeks; or 
 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 

4 weeks. 
 
Table 3: Recommended doses and infusion times for intravenous administration of 

nivolumab in combination with ipilimumab for RCC 

 
Combination phase, 

every 3 weeks for 
4 dosing cycles 

Monotherapy phase 

Nivolumab 3 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes 

Ipilimumab 1 mg/kg over 30 minutes - 

 
OPDIVO in combination with ipilimumab and chemotherapy 
 
Non-small cell lung cancer 
The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes every 
3 weeks in combination with 1 mg/kg ipilimumab administered intravenously over 30 minutes every 
6 weeks, and platinum-based chemotherapy administered every 3 weeks. After completion of 2 cycles 



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of chemotherapy, treatment is continued with 360 mg nivolumab administered intravenously every 
3 weeks in combination with 1 mg/kg ipilimumab every 6 weeks. Treatment is recommended until 
disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.  
 
Duration of treatment 
Treatment with OPDIVO, either as a monotherapy or in combination with ipilimumab, should be 
continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient 
(and up to maximum duration of therapy if specified for an indication). 
 
For adjuvant therapy, the maximum treatment duration with OPDIVO is 12 months. 
 
Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first 
few months followed by tumour shrinkage) have been observed. It is recommended to continue 
treatment with nivolumab or nivolumab in combination with ipilimumab for clinically stable patients 
with initial evidence of disease progression until disease progression is confirmed. 
 
Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required 
based on individual safety and tolerability. Guidelines for permanent discontinuation or withholding of 
doses are described in Table 4. Detailed guidelines for the management of immune-related adverse 
reactions are described in section 4.4. 
 
Table 4: Recommended treatment modifications for OPDIVO or OPDIVO in 

combination with ipilimumab
Immune-related 
adverse reaction  

Severity Treatment modification 

Immune-related 
pneumonitis 

Grade 2 pneumonitis Withhold dose(s) until symptoms 
resolve, radiographic abnormalities 
improve, and management with 
corticosteroids is complete 
 

Grade 3 or 4 pneumonitis Permanently discontinue treatment 

Immune-related colitis 

Grade 2 diarrhoea or colitis Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids, if needed, is complete 
 

Grade 3 diarrhoea or colitis  
 - OPDIVO monotherapy 

 
Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids is complete 
 

 - OPDIVO+ipilimumaba Permanently discontinue treatment 

Grade 4 diarrhoea or colitis Permanently discontinue treatment 

Immune-related 
hepatitis 

Grade 2 elevation in aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), or total 
bilirubin  

Withhold dose(s) until laboratory 
values return to baseline and 
management with corticosteroids, if 
needed, is complete 
 

Grade 3 or 4 elevation in AST, ALT, or 
total bilirubin  

Permanently discontinue treatment 

Immune-related 
nephritis and renal 
dysfunction 

Grade 2 or 3 creatinine elevation  Withhold dose(s) until creatinine 
returns to baseline and management 
with corticosteroids is complete 

Grade 4 creatinine elevation Permanently discontinue treatment 



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Table 4: Recommended treatment modifications for OPDIVO or OPDIVO in 
combination with ipilimumab 

Immune-related 
adverse reaction  

Severity Treatment modification 

Immune-related 
endocrinopathies 

Symptomatic Grade 2 or 3 
hypothyroidism, hyperthyroidism, 
hypophysitis, 
Grade 2 adrenal insufficiency 
Grade 3 diabetes 

Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids (if needed for symptoms 
of acute inflammation) is complete. 
Treatment should be continued in the 
presence of hormone replacement 
therapyb as long as no symptoms are 
present 

Grade 4 hypothyroidism  
Grade 4 hyperthyroidism  
Grade 4 hypophysitis 
Grade 3 or 4 adrenal insufficiency 
Grade 4 diabetes 

Permanently discontinue treatment 

Immune-related skin 
adverse reactions 

Grade 3 rash Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids is complete 
 

Grade 4 rash Permanently discontinue treatment 

Stevens-Johnson syndrome (SJS) or 
toxic epidermal necrolysis (TEN) 

Permanently discontinue treatment (see 
section 4.4) 

Immune-related 
myocarditis 

Grade 2 myocarditis Withhold dose(s) until symptoms 
resolve and management with 
corticosteroids is completec 
 

Grade 3 or 4 myocarditis Permanently discontinue treatment 

Other immune-related 
adverse reactions 

Grade 3 (first occurrence) Withhold dose(s) 

Grade 4 or recurrent Grade 3 ; persistent 
Grade 2 or 3 despite treatment 
modification; inability to reduce 
corticosteroid dose to 10 mg prednisone 
or equivalent per day 

Permanently discontinue treatment 

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 4.0 (NCI-CTCAE v4). 
a  During administration of the second phase of treatment (nivolumab monotherapy) following combination 

treatment, permanently discontinue treatment if Grade 3 diarrhoea or colitis occurs. 
b Recommendation for the use of hormone replacement therapy is provided in section 4.4. 
c The safety of re-initiating nivolumab or nivolumab in combination with ipilimumab therapy in patients 

previously experiencing immune-related myocarditis is not known. 
 
 
OPDIVO or OPDIVO in combination with ipilimumab should be permanently discontinued for: 
• Grade 4 or recurrent Grade 3 adverse reactions; 
• Persistent Grade 2 or 3 adverse reactions despite management. 
 
Patients treated with OPDIVO must be given the patient alert card and be informed about the risks of 
OPDIVO (see also package leaflet). 
 
When OPDIVO is administered in combination with ipilimumab, if either agent is withheld, the other 
agent should also be withheld. If dosing is resumed after a delay, either the combination treatment or 
OPDIVO monotherapy could be resumed based on the evaluation of the individual patient. 
 



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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 section 5.2). 
Data from SCCHN, adjuvant melanoma and first-line RCC patients 75 years of age or older are too 
limited to draw conclusions on this population (see sections 4.8 and 5.1). 
 
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 30 or 60 minutes depending on the dose (see Tables 1, 2 and 3). 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 
with sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for 
injection (see section 6.6). 
 
When administered in combination with ipilimumab or in combination with ipilimumab and 
chemotherapy, OPDIVO should be given first followed by ipilimumab and then by chemotherapy on 
the same day. Use separate infusion bags and filters for each infusion. 
 
For instructions on the preparation and 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 
 
Traceability  
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
Immune-related adverse reactions 
When nivolumab is administered in combination, refer to the Summary of Product Characteristics of 
the other combination therapy components prior to initiation of treatment. Immune-related adverse 
reactions have occurred at higher frequencies when nivolumab was administered in combination with 
ipilimumab compared with nivolumab as monotherapy. Most immune-related adverse reactions 



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improved or resolved with appropriate management, including initiation of corticosteroids and 
treatment modifications (see section 4.2). 
 
Cardiac and pulmonary adverse reactions including pulmonary embolism have also been reported with 
combination therapy. Patients should be monitored for cardiac and pulmonary adverse reactions 
continuously, as well as for clinical signs, symptoms, and laboratory abnormalities indicative of 
electrolyte disturbances and dehydration prior to and periodically during treatment. Nivolumab in 
combination with ipilimumab should be discontinued for life-threatening or recurrent severe cardiac 
and pulmonary adverse reactions (see section 4.2). 
 
Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse 
reaction with nivolumab or nivolumab in combination with ipilimumab may occur at any time during 
or after discontinuation of 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 or 
nivolumab in combination with ipilimumab 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 or recurrence of 
the adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is 
worsening or no improvement despite corticosteroid use. 
 
Nivolumab or nivolumab in combination with ipilimumab 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 or nivolumab in combination with ipilimumab must be permanently discontinued for any 
severe immune-related adverse reaction that recurs and for any life-threatening immune-related 
adverse reaction. 
 
Immune-related pneumonitis 
Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed with 
nivolumab monotherapy or nivolumab in combination with ipilimumab (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 or nivolumab in combination with ipilimumab 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 or nivolumab in combination with ipilimumab 
should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone 
equivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab 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 or nivolumab in combination with ipilimumab must be permanently 
discontinued. 
 
Immune-related colitis 
Severe diarrhoea or colitis has been observed with nivolumab monotherapy or nivolumab in 
combination with ipilimumab (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. Cytomegalovirus 
(CMV) infection/reactivation has been reported in patients with corticosteroid-refractory 
immune-related colitis. Infectious and other aetiologies of diarrhoea should be ruled out, therefore 
appropriate laboratory tests and additional examinations must be performed. If diagnosis of 



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corticosteroid-refractory immune-related colitis is confirmed addition of an alternative 
immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, 
should be considered. 
 
For Grade 4 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab must be 
permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day 
methylprednisolone equivalents.  
 
Nivolumab monotherapy should be withheld for Grade 3 diarrhoea or colitis, and corticosteroids 
initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement, 
nivolumab monotherapy may be resumed after corticosteroid taper. If worsening or no improvement 
occurs despite initiation of corticosteroids, nivolumab monotherapy must be permanently 
discontinued. Grade 3 diarrhoea or colitis observed with nivolumab in combination with ipilimumab 
requires permanent discontinuation of treatment and initiation of corticosteroids at a dose of 
1 to 2 mg/kg/day methylprednisolone equivalents. 
 
For Grade 2 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab 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 or nivolumab 
in combination with ipilimumab 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 or nivolumab in combination with 
ipilimumab must be permanently discontinued. 
 
Immune-related hepatitis 
Severe hepatitis has been observed with nivolumab monotherapy or nivolumab in combination with 
ipilimumab (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 or nivolumab in combination 
with ipilimumab 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 or nivolumab in combination with 
ipilimumab 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 or nivolumab in combination with ipilimumab 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 or nivolumab in combination with ipilimumab must be permanently 
discontinued. 
 
Immune-related nephritis and renal dysfunction 
Severe nephritis and renal dysfunction have been observed with monotherapy treatment or nivolumab 
in combination with ipilimumab (see section 4.8). Patients should be monitored for signs and 
symptoms of nephritis or 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 or nivolumab in combination with ipilimumab 
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 or nivolumab in combination with ipilimumab 
should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day 
methylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination with 
ipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despite 



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initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day 
methylprednisolone equivalents, and nivolumab or nivolumab in combination with ipilimumab must 
be permanently discontinued. 
 
Immune-related endocrinopathies 
Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including 
secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus, 
and diabetic ketoacidosis have been observed with nivolumab monotherapy or nivolumab in 
combination with ipilimumab (see section 4.8). 
 
Patients should be monitored for clinical signs and symptoms of endocrinopathies and for 
hyperglycaemia and 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 aetiology has been identified, signs or symptoms of endocrinopathies should be considered 
immune-related. 
 
For symptomatic hypothyroidism, nivolumab or nivolumab in combination with ipilimumab should be 
withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic 
hyperthyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld and 
antithyroid medication 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 or nivolumab in combination with ipilimumab may be 
resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure 
appropriate hormone replacement is utilised. Nivolumab or nivolumab in combination with 
ipilimumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism. 
 
For symptomatic Grade 2 adrenal insufficiency, nivolumab or nivolumab in combination with 
ipilimumab should be withheld, and physiologic corticosteroid replacement should be initiated as 
needed. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued 
for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Monitoring of adrenal 
function and hormone levels should continue to ensure appropriate corticosteroid replacement is 
utilised. 
 
For symptomatic Grade 2 or 3 hypophysitis, nivolumab or nivolumab in combination with ipilimumab 
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 or nivolumab in combination with 
ipilimumab may be resumed after corticosteroid taper, if needed. Nivolumab or nivolumab in 
combination with ipilimumab must be permanently discontinued for life-threatening (Grade 4) 
hypophysitis. Monitoring of pituitary function and hormone levels should continue to ensure 
appropriate hormone replacement is utilised. 
 
For symptomatic diabetes, nivolumab or nivolumab in combination with ipilimumab should be 
withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should 
continue to ensure appropriate insulin replacement is utilised. Nivolumab or nivolumab in 
combination with ipilimumab must be permanently discontinued for life-threatening diabetes. 
 
Immune-related skin adverse reactions 
Severe rash has been observed with nivolumab in combination with ipilimumab and, less commonly, 
with nivolumab as monotherapy (see section 4.8). Nivolumab or nivolumab in combination with 
ipilimumab 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 methylprednisolone 
equivalents. 
 



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Rare cases of SJS and TEN some of them with fatal outcome have been observed. If symptoms or 
signs of SJS or TEN appear, treatment with nivolumab or nivolumab in combination with ipilimumab 
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 or nivolumab in combination with 
ipilimumab, permanent discontinuation of treatment is recommended (see section 4.2). 
 
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 monotherapy or nivolumab in combination with ipilimumab in clinical trials across doses 
and tumour types: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and 
abducens nerve paresis), Guillain-Barré syndrome, myasthenia gravis, myasthenic syndrome, aseptic 
meningitis, encephalitis, gastritis, sarcoidosis, duodenitis, myositis, myocarditis, and rhabdomyolysis. 
Cases of Vogt-Koyanagi-Harada syndrome and hypoparathyroidism have been reported 
post-marketing (see section 4.8). 
 
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 or 
nivolumab in combination with ipilimumab should be withheld and corticosteroids administered. 
Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed after 
corticosteroid taper. Nivolumab or nivolumab in combination with ipilimumab must be permanently 
discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening 
immune-related adverse reaction. 
 
Cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal outcome, have 
been reported with nivolumab or nivolumab in combination with ipilimumab. If a patient develops 
signs and symptoms of myotoxicity, close monitoring should be implemented, and the patient referred 
to a specialist for assessment and treatment without delay. Based on the severity of myotoxicity, 
nivolumab or nivolumab in combination with ipilimumab should be withheld or discontinued (see 
section 4.2), and appropriate treatment instituted.  
The diagnosis of myocarditis requires a high index of suspicion. Patients with cardiac or cardio-
pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, prompt 
initiation of a high dose of steroids (prednisone 1 to 2 mg/kg/day or methylprednisolone 
1 to 2 mg/kg/day) and prompt cardiology consultation with diagnostic workup according to current 
clinical guidelines should be initiated. Once a diagnosis of myocarditis is established, nivolumab or 
nivolumab in combination with ipilimumab should be withheld or permanently discontinued (see 
section 4.2). 
 
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with 
PD-1 inhibitors. Treatment with nivolumab may increase the risk of rejection in solid organ transplant 
recipients. The benefit of treatment with nivolumab versus the risk of possible organ rejection should 
be considered in these patients.  
 
Haemophagocytic lymphohistiocytosis (HLH) has been observed with nivolumab as monotherapy and 
nivolumab in combination with ipilimumab. Caution should be taken when nivolumab is administered 
as monotherapy or in combination with ipilimumab. If HLH is confirmed, administration of 
nivolumab or nivolumab in combination with ipilimumab should be discontinued and treatment for 
HLH initiated. 
 
Infusion reactions 
Severe infusion reactions have been reported in clinical trials of nivolumab or nivolumab in 
combination with ipilimumab (see section 4.8). In case of a severe or life-threatening infusion 
reaction, the nivolumab or nivolumab in combination with ipilimumab infusion must be discontinued 
and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may 



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receive nivolumab or nivolumab in combination with ipilimumab with close monitoring and use of 
premedication according to local treatment guidelines for prophylaxis of infusion reactions. 
 
Disease-specific precautions 
 
Advanced melanoma 
Patients with a baseline performance score ≥ 2, active brain metastases or leptomeningeal metastases, 
autoimmune disease, and patients who had been receiving systemic immunosuppressants prior to 
study entry were excluded from the pivotal clinical trials of nivolumab or nivolumab in combination 
with ipilimumab (see sections 4.5 and 5.1). Patients with ocular/uveal melanoma were excluded from 
pivotal clinical trials of melanoma. 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). Patients with baseline 
performance score of 2, treated leptomeningeal metastases, ocular/uveal melanoma, autoimmune 
disease and patients who have had a Grade 3-4 adverse reaction that was related to prior anti-CTLA-4 
therapy were included in study CA209172 (see section 5.1). In the absence of data for patients who 
had been receiving systemic immunosuppressants prior to study entry, and for patients with active 
brain or leptomeningeal metastases, nivolumab should be used with caution in these populations after 
careful consideration of the potential benefit/risk on an individual basis. 
 
Relative to nivolumab monotherapy, an increase in PFS for the combination of nivolumab with 
ipilimumab is established only in patients with low tumour PD-L1 expression. The improvement in 
OS was similar between nivolumab in combination with ipilimumab and nivolumab monotherapy in 
patients with high tumour PD-L1 expression (PD-L1 ≥ 1%). Before initiating treatment with the 
combination, physicians are advised to carefully evaluate the individual patient and tumour 
characteristics, taking into consideration the observed benefits and the toxicity of the combination 
relative to nivolumab monotherapy (see sections 4.8 and 5.1). 
 
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). 
 
Adjuvant treatment of melanoma 
There are no data on adjuvant treatment in patients with melanoma with the following risk factors (see 
sections 4.5 and 5.1): 
• patients with prior autoimmune disease, and any condition requiring systemic treatment with 

either corticosteroids (≥ 10 mg daily prednisone or equivalent) or other immunosuppressive 
medications, 

• patients with prior therapy for melanoma (except patients with surgery, adjuvant radiotherapy after 
neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon 
completed ≥ 6 months prior to randomisation), 

• patients treated with prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti 
CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting 
T cell co-stimulation or checkpoint pathways), 

• subjects under the age of 18 years. 
In the absence of data, nivolumab should be used with caution in these populations after careful 
consideration of the potential benefit/risk on an individual basis. 
 
Non-small cell lung cancer 
First-line treatment of NSCLC 
Patients with active autoimmune disease, symptomatic interstitial lung disease, medical conditions 
requiring systemic immunosuppression, active (untreated) brain metastasis, who received prior 
systemic treatment for advanced disease, or who had sensitising EGFR mutations or ALK 
translocations were excluded from the pivotal trial in first-line treatment of NSCLC (see sections 4.5 
and 5.1). Limited data are available in elderly patients (≥ 75 years) (see section 5.1). In these patients, 
nivolumab in combination with ipilimumab and chemotherapy should be used with caution after 
careful consideration of the potential benefit/risk on an individual basis. 
 



13 

Treatment of NSCLC after prior chemotherapy 
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 pivotal clinical trials of NSCLC (see 
sections 4.5 and 5.1). Patients with baseline performance score of 2 were included in study CA209171 
(see section 5.1). In the absence of data for patients with autoimmune disease, symptomatic interstitial 
lung disease, active brain metastases and patients who had been receiving systemic 
immunosuppressants prior to study entry, nivolumab should be used with caution in these populations 
after careful consideration of the potential benefit/risk on an individual basis. 
Physicians should consider the delayed onset of nivolumab effect before initiating treatment in 
patients with poorer prognostic features and/or aggressive disease. In non-squamous NSCLC, a higher 
number of deaths within 3 months was observed in nivolumab compared to docetaxel. Factors 
associated with early deaths were poorer prognostic factors and/or more aggressive disease combined 
with low or no tumour PD-L1 expression (see section 5.1). 
 
Renal cell carcinoma 
Patients with any history of or concurrent brain metastases, active autoimmune disease, or medical 
conditions requiring systemic immunosuppression were excluded from the clinical trials of nivolumab 
or nivolumab in combination with ipilimumab (see sections 4.5 and 5.1). In the absence of data, 
nivolumab or nivolumab in combination with ipilimumab should be used with caution in these 
populations after careful consideration of the potential benefit/risk on an individual basis. 
 
Classical Hodgkin lymphoma 
Patients with active autoimmune disease and symptomatic interstitial lung disease were excluded from 
clinical trials of cHL (see section 5.1). In the absence of data, nivolumab should be used with caution 
in these populations after careful consideration of the potential benefit/risk on an individual basis. 
 
Complications of allogeneic haematopoietic stem cell transplant (HSCT) in classical Hodgkin 
lymphoma 
Preliminary results from the follow-up of patients with cHL undergoing allogeneic HSCT after 
previous exposure to nivolumab showed a higher than expected number of cases of acute 
graft-versus-host disease (GVHD) and transplant related mortality (TRM). Until further data become 
available, careful consideration to the potential benefits of HSCT and the possible increased risk of 
transplant related complications should be made case-by-case (see section 4.8). 
 
In patients treated with nivolumab after allogeneic HSCT, rapid-onset and severe GVHD, some with 
fatal outcome, have been reported in the post-marketing setting. Treatment with nivolumab may 
increase the risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainly 
in those with prior history of GVHD. The benefit of treatment with nivolumab versus the possible risk 
should be considered in these patients (see section 4.8). 
 
Head and neck cancer 
Patients with a baseline performance score ≥ 2, active brain or leptomeningeal metastases, active 
autoimmune disease, medical conditions requiring systemic immunosuppression, or carcinoma of the 
nasopharynx or salivary gland as the primary tumour sites were excluded from the SCCHN clinical 
trial (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 benefit/risk on an individual basis. 
 
Physicians should consider the delayed onset of nivolumab effect before initiating treatment in 
patients with poorer prognostic features and/or aggressive disease. In head and neck cancer, a higher 
number of deaths within 3 months was observed in nivolumab compared to docetaxel. Factors 
associated with early deaths were ECOG performance status, fast progressive disease on prior 
platinum therapy and high tumour burden. 
 
Urothelial carcinoma 
Patients with a baseline performance score ≥2, active brain metastases or leptomeningeal metastases, 
active autoimmune disease, or medical conditions requiring systemic immunosuppression were 



14 

excluded from the clinical trials of urothelial carcinoma (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 benefit/risk on an individual basis. 
 
Patients on controlled sodium diet 
Each mL of this medicinal product contains 0.1 mmol (or 2.5 mg) sodium. This medicinal product 
contains 10 mg sodium per 4 ml vial, 25 mg sodium per 10 ml vial or 60 mg sodium per 24 ml vial, 
which is equivalent to 0.5%, 1.25% or 3% respectively, of the WHO recommended maximum daily 
intake of 2 g sodium for an adult. 
 
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 from 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 nivolumab. 
 
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 
 
Nivolumab or nivolumab in combination with ipilimumab may have a minor influence on the ability 
to drive and use machines. Because of potential adverse reactions such as fatigue (see section 4.8), 



15 

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 
 
Nivolumab as monotherapy (see section 4.2) 
 
Summary of the safety profile 
In the pooled dataset of nivolumab 3 mg/kg as monotherapy across tumour types (n = 2578) with 
minimum follow-up ranging from 2.3 to 28 months, the most frequent adverse reactions (≥ 10%) were 
fatigue (30%), rash (17%), pruritus (13%), diarrhoea (13%), and nausea (12%). The majority of 
adverse reactions were mild to moderate (Grade 1 or 2). With a minimum of 63 months follow-up in 
NSCLC, no new safety signals were identified. 
 
Adjuvant treatment of melanoma  
In the dataset of nivolumab 3 mg/kg as monotherapy for the adjuvant treatment of melanoma 
(n = 452), the most frequent adverse reactions (≥ 10%) were fatigue (46%), rash (29%), diarrhoea 
(24%), pruritus (23%), nausea (15%), arthralgia (13%), musculoskeletal pain (11%), and 
hypothyroidism (11%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). 
 
Tabulated summary of adverse reactions 
Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy 
(n = 2578) are presented in Table 5. 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); not known 
(cannot be estimated from available post-marketing data). Within each frequency grouping, adverse 
reactions are presented in the order of decreasing seriousness. 
 



16 

Table 5: Adverse reactions with nivolumab monotherapy 
 Nivolumab monotherapy 

Infections and infestations 
Common upper respiratory tract infection 
Uncommon pneumoniaa, bronchitis 
Not known aseptic meningitish 
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
Rare histiocytic necrotising lymphadenitis (Kikuchi lymphadenitis) 
Blood and lymphatic system disorders 
Very common neutropaeniaa,b 
Uncommon eosinophilia 
Not known haemophagocytic lymphohistiocytosis 
Immune system disorders 
Common infusion related reactionc, hypersensitivityc 
Rare anaphylactic reactionc 
Not known solid organ transplant rejectionh, sarcoidosish 
Endocrine disorders 
Common hypothyroidism, hyperthyroidism
Uncommon adrenal insufficiency, hypopituitarism, hypophysitis, thyroiditis, diabetes mellitus 
Rare diabetic ketoacidosis 
Not known hypoparathyroidismh 
Metabolism and nutrition disorders 
Common decreased appetite 
Uncommon dehydration, metabolic acidosis 
Not known  tumour lysis syndromei  
Nervous system disorders 
Common peripheral neuropathy, headache, dizziness 
Uncommon polyneuropathy, autoimmune neuropathy (including facial and abducens nerve 

paresis) 
Rare Guillain-Barré syndrome, demyelination, myasthenic syndrome, encephalitisa,c 
Eye disorders 
Uncommon uveitis, blurred vision, dry eye 
Not known Vogt-Koyanagi-Harada syndromeh 
Cardiac disorders 
Uncommon tachycardia, pericardial disordersj
Rare arrhythmia (including ventricular arrhythmia)d, atrial fibrillation, myocarditisa,f 
Vascular disorders 
Common hypertension 
Uncommon vasculitis 
Respiratory, thoracic and mediastinal disorders 
Common pneumonitisa,c, dyspnoeaa, cough  
Uncommon pleural effusion 
Rare lung infiltration 
Gastrointestinal disorders 
Very common diarrhoea, nausea  
Common colitisa, stomatitis, vomiting, abdominal pain, constipation, dry mouth 
Uncommon pancreatitis, gastritis 
Rare duodenal ulcer 
Hepatobiliary disorders 
Uncommon hepatitisc 



17 

Rare cholestasis 
Skin and subcutaneous tissue disorders  
Very common rashe, pruritus 
Common vitiligo, dry skin, erythema, alopecia 
Uncommon erythema multiforme, psoriasis, rosacea, urticaria 
Rare toxic epidermal necrolysisa,f, Stevens-Johnson syndromea,f 
Musculoskeletal and connective tissue disorders 
Common musculoskeletal paing, arthralgia 
Uncommon polymyalgia rheumatica, arthritis 
Rare Sjogren’s syndrome, myopathy, myositis (including polymyositis)a,f, 

rhabdomyolysisa,f 
Renal and urinary disorders 
Uncommon tubulointerstitial nephritis, renal failure (including acute kidney injury)a,c 
General disorders and administration site conditions 
Very common fatigue 
Common pyrexia, oedema (including peripheral oedema) 
Uncommon pain, chest pain 
Investigationsb 
Very common increased AST, increased ALT, increased alkaline phosphatase, increased lipase, 

increased amylase, hypocalcaemia, increased creatinine, hyperglycaemiac, 
lymphopaenia, leucopoenia, thrombocytopaenia, anaemiak, hypercalcaemia, 
hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia 

Common increased total bilirubin, hypoglycaemia, hypermagnesaemia, hypernatraemia, 
weight decreased

a Fatal cases have been reported in completed or ongoing clinical studies. 
b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from 

baseline in laboratory measurements. See “Description of selected adverse reactions; laboratory 
abnormalities” below. 

c Life-threatening cases have been reported in completed or ongoing clinical studies. 
d The frequency of adverse reactions in the cardiac disorders system organ class regardless of causality was 

higher in the nivolumab group than in the chemotherapy group in post-CTLA4/BRAF inhibitor metastatic 
melanoma population. Incidence rates per 100 person-years of exposure were 9.3 vs. 0; serious cardiac 
events were reported by 4.9% patients in the nivolumab group vs. 0 in the investigator´s choice group. 
The frequency of cardiac adverse reactions was lower in the nivolumab group than in the dacarbazine 
group in the metastatic melanoma without prior treatment population. All were considered not related to 
nivolumab by investigators except arrhythmia (atrial fibrillation, tachycardia and ventricular arrhythmia). 

e Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash 
follicular, rash macular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash 
vesicular, rash generalised, exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, 
dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption and 
pemphigoid. 

f Reported also in studies outside the pooled dataset. The frequency is based on the program-wide 
exposure. 

g Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest 
pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. 

h Post-marketing event (also see section 4.4). 
i Reported in clinical studies and in the post-marketing setting.  
j Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac 

tamponade, and Dressler’s syndrome. 
k Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune 

anaemia. 
 
The overall safety profile of nivolumab 3 mg/kg for the adjuvant treatment of melanoma (n = 452) was 
consistent with that established across tumour types for nivolumab monotherapy. 
 



18 

Nivolumab in combination with ipilimumab (see section 4.2) 
 
Summary of the safety profile 
When nivolumab is administered in combination with ipilimumab, refer to the Summary of Product 
Characteristics for ipilimumab prior to initiation of treatment. For additional information on the safety 
profile of ipilimumab monotherapy, please refer to the ipilimumab SmPC. 
 
Melanoma 
In the pooled dataset of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma 
(n = 448) with minimum follow-up ranging from 6 to 28 months, the most frequent adverse 
reactions (≥ 10%) were rash (52%), fatigue (46%), diarrhoea (43%), pruritus (36%), nausea (26%), 
pyrexia (19%), decreased appetite (16%), hypothyroidism (16%), colitis (15%), vomiting (14%), 
arthralgia (13%), abdominal pain (13%), headache (11%), and dyspnoea (10%). The majority of 
adverse reactions were mild to moderate (Grade 1 or 2). 
 
Among the patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in 
CA209067, 154/313 (49%) had the first onset of Grade 3 or 4 adverse reactions during the initial 
combination phase. Among the 147 patients in this group who continued treatment in the single-agent 
phase, 47 (32%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase. 
With a minimum of 60 months follow-up from study CA209067, no new safety signals were 
identified. 
 
RCC 
In the dataset of nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC (n = 547), with 
a minimum follow-up of 17.5 months, the most frequent adverse reactions (≥ 10%) were 
fatigue (48%), rash (34%), pruritus (28%), diarrhoea (27%), nausea (20%), hypothyroidism (16%), 
musculoskeletal pain (15%), arthralgia (14%), decreased appetite (14%), pyrexia (14%), 
vomiting (11%), hyperthyroidism (11%). The majority of adverse reactions were mild to moderate 
(Grade 1 or 2). 
 
Among the patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in 
CA209214, 169/547 (31%) had the first onset of Grade 3 or 4 adverse reactions during the initial 
combination phase. Among the 382 patients in this group who continued treatment in the single-agent 
phase, 144 (38%) experienced at least one Grade 3 or 4 adverse reaction during the single-agent phase. 
 
Tabulated summary of adverse reactions 
Adverse reactions reported in the pooled dataset for patients treated with nivolumab 1 mg/kg in 
combination with ipilimumab 3 mg/kg (n = 448) and for patients treated with nivolumab 3 mg/kg in 
combination with ipilimumab 1 mg/kg (n = 547) are presented in Table 6. 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), not known (cannot be estimated from available post-marketing data). Within each 
frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 
 



19 

Table 6: Adverse reactions with nivolumab in combination with ipilimumab 
 Nivolumab 1 mg/kg in combination 

with ipilimumab 3 mg/kg* 
Nivolumab 3 mg/kg in combination 
with ipilimumab 1 mg/kg** 

Infections and infestations 
Common pneumonia, upper respiratory tract 

infection 
pneumonia, upper respiratory tract 
infection, conjunctivitis 

Uncommon bronchitis bronchitis, aseptic meningitis 
Not known aseptic meningitish  
Blood and lymphatic system disorders 
Common eosinophilia  
Uncommon  eosinophilia 
Not known haemophagocytic lymphohistiocytosis haemophagocytic lymphohistiocytosis 
Immune system disorders 
Common infusion related reaction, 

hypersensitivity 
infusion-related reaction, 
hypersensitivity 

Uncommon sarcoidosis  
Not known solid organ transplant rejectionh  
Endocrine disorders 
Very common hypothyroidism hypothyroidism, hyperthyroidism 
Common adrenal insufficiency, hypopituitarism, 

hypophysitis, hyperthyroidism, 
thyroiditis 

adrenal insufficiencyc, hypophysitisc, 
thyroiditis, diabetes mellitusc 

Uncommon diabetic ketoacidosisc, diabetes 
mellitusc 

diabetic ketoacidosisc, hypopituitarism 

Not known hypoparathyroidismh hypoparathyroidismh 
Metabolism and nutrition disorders 
Very common decreased appetite decreased appetite 
Common dehydration dehydration 
Uncommon  metabolic acidosis 
Not known  tumour lysis syndromei   
Nervous system disorders 
Very common headache  
Common peripheral neuropathy, dizziness headache, peripheral neuropathy, 

dizziness 
Uncommon Guillain-Barré syndrome, 

polyneuropathy, neuritis, peroneal nerve 
palsy, autoimmune neuropathy 
(including facial and abducens nerve 
paresis), encephalitisc

polyneuropathy, autoimmune 
neuropathy (including facial and 
abducens nerve paresis), myasthenia 
gravisc 

Eye disorders 
Common uveitis, blurred vision blurred vision 
Uncommon  uveitis 
Not known Vogt-Koyanagi-Harada syndromeh  
Cardiac disorders 
Common tachycardia tachycardia 
Uncommon arrhythmia (including ventricular 

arrhythmia)a,d, atrial fibrillation, 
myocarditisa,f 

arrhythmia (including ventricular 
arrhythmia), myocarditisc 

Not known pericardial disordersj  
Vascular disorders 
Common hypertension hypertension 
Respiratory, thoracic and mediastinal disorders 
Very common dyspnoea  



20 

Common pneumonitisa,c, pulmonary embolisma, 
cough 

pneumonitis, dyspnoea, pleural 
effusion, cough 

Uncommon pleural effusion  
Gastrointestinal disorders 
Very common colitisa, diarrhoea, vomiting, nausea, 

abdominal pain 
diarrhoea, vomiting, nausea 

Common stomatitis, pancreatitis, constipation, 
dry mouth 

colitis, stomatitis, pancreatitis, 
abdominal pain, constipation, dry 
mouth

Uncommon intestinal perforationa, gastritis, 
duodenitis 

gastritis 

Hepatobiliary disorders 
Common hepatitisc hepatitisc 
Skin and subcutaneous tissue disorders  
Very common rashe, pruritus rashe, pruritus 
Common vitiligo, dry skin, erythema, alopecia, 

urticaria 
dry skin, erythema, urticaria 

Uncommon psoriasis Stevens-Johnson syndrome, vitiligo, 
erythema multiforme, alopecia, 
psoriasis 

Rare toxic epidermal necrolysisa,f, 
Stevens-Johnson syndromef

 

Musculoskeletal and connective tissue disorders 
Very common arthralgia musculoskeletal paing, arthralgia 
Common musculoskeletal paing arthritis, muscle spasms, muscular 

weakness 
Uncommon spondyloarthropathy, Sjogren’s 

syndrome, arthritis, myopathy, 
myositis (including polymyositis)a,e, 
rhabdomyolysisa,f 

polymyalgia rheumatica, myositis 
(including polymyositis), 
rhabdomyolysis 

Renal and urinary disorders 
Common renal failure (including acute kidney 

injury)a,c 
renal failure (including acute kidney 
injury)c 

Uncommon tubulointerstitial nephritis tubulointerstitial nephritis 
General disorders and administration site conditions 
Very common fatigue, pyrexia fatigue, pyrexia 
Common oedema (including peripheral oedema), 

pain 
oedema (including peripheral oedema), 
pain, chest pain, chills 

Uncommon chest pain  
Investigationsb 
Very common increased AST, increased ALT, 

increased total bilirubin, increased 
alkaline phosphatase, increased lipase, 
increased amylase, increased 
creatinine, hyperglycaemiac, 
hypoglycaemia, lymphopaenia, 
leucopoenia, neutropaenia, 
thrombocytopaenia, anaemiak, 
hypocalcaemia, hyperkalaemia, 
hypokalaemia, hypomagnesaemia, 
hyponatraemia 

increased AST, increased ALT, 
increased total bilirubin, increased 
alkaline phosphatase, increased lipase, 
increased amylase, increased 
creatinine, hyperglycaemiac, 
hypoglycaemia, lymphopaenia, 
leucopoenia, neutropaeniac, 
thrombocytopaenia, anaemiak, 
hypercalcaemia, hypocalcaemia, 
hyperkalaemia, hypokalaemia, 
hypomagnesaemia, hyponatraemia

Common hypercalcaemia, hypermagnesaemia, 
hypernatraemia, weight decreased 

hypermagnesaemia, hypernatraemia, 
weight decreased 

*  nivolumab in combination with ipilimumab for the first 4 doses then followed by nivolumab monotherapy 
in melanoma. 



21 

** nivolumab in combination with ipilimumab for the first 4 doses then followed by nivolumab monotherapy 
in RCC. 

a Fatal cases have been reported in completed or ongoing clinical studies. 
b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from 

baseline in laboratory measurements. See “Description of selected adverse reactions; laboratory 
abnormalities” below. 

c Life-threatening cases have been reported in completed or ongoing clinical studies. 
d The frequency of adverse reactions in the cardiac disorders system organ class regardless of causality was 

higher in the nivolumab group than in the chemotherapy group in post-CTLA4/BRAF inhibitor metastatic 
melanoma population. Incidence rates per 100 person-years of exposure were 9.3 vs. 0; serious cardiac 
events were reported by 4.9% patients in the nivolumab group vs. 0 in the investigator´s choice group. 
The frequency of cardiac adverse reactions was lower in the nivolumab group than in the dacarbazine 
group in the metastatic melanoma without prior treatment population. All were considered not related to 
nivolumab by investigators except arrhythmia (atrial fibrillation, tachycardia and ventricular arrhythmia). 

e Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash 
follicular, rash macular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash 
vesicular, rash generalised, exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, 
dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption and 
pemphigoid. 

f Reported also in studies outside the pooled dataset. The frequency is based on the program-wide 
exposure. 

g Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest 
pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. 

h Post-marketing event (also see section 4.4) 
i Reported in clinical studies and in the post-marketing setting.  
j Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac 

tamponade, and Dressler’s syndrome. 
k Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune 

anaemia. 
 
Nivolumab in combination with ipilimumab and chemotherapy (see section 4.2) 
 
Summary of the safety profile 
When nivolumab is administered in combination, refer to the Summary of Product Characteristics for 
the respective combination therapy components prior to initiation of treatment. 
 
In the dataset of nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 
6 weeks and 2 cycles of chemotherapy in NSCLC (n = 358), with a minimum follow-up of 
6.5 months, the most frequent adverse reactions were fatigue (36%), nausea (26%), rash (25%), 
diarrhoea (20%), pruritus (18%), decreased appetite (16%), hypothyroidism (15%), and vomiting 
(13%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). Median duration of 
therapy was 6.1 months (95% CI 4.93, 7.06) for nivolumab in combination with ipilimumab and 
chemotherapy and 2.4 months (95% CI 2.30, 2.83) for chemotherapy.  
 
Tabulated summary of adverse reactions 
Adverse reactions reported in the dataset for patients treated with nivolumab 360 mg every 3 weeks in 
combination with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of chemotherapy in NSCLC 
(n = 358) are presented in Table 7. 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. 
 



22 

Table 7: Adverse reactions with nivolumab in combination with ipilimumab and 
chemotherapy 
Infections and infestations 
Common conjunctivitis, pneumonia, respiratory tract infection 
Blood and lymphatic system disorders 
Common febrile neutropaenia 
Uncommon eosinophilia 
Immune system disorders 
Common infusion-related reaction, hypersensitivity 
Endocrine disorders 
Very common hypothyroidism 
Common hyperthyroidism, adrenal insufficiency, hypophysitis, thyroiditis 
Uncommon hypopituitarism, hypoparathyroidism 
Metabolism and nutrition disorders 
Very common decreased appetite 
Common dehydration, hypoalbunaemia, hypophosphataemia 
Nervous system disorders 
Common peripheral neuropathy, dizziness 
Uncommon polyneuropathy, autoimmune neuropathy (including facial and abducens 

nerve paresis), encephalitis
Eye disorders 
Common dry eye 
Uncommon blurred vision, episcleritis 
Cardiac disorders 
Uncommon tachycardia, atrial fibrillation, bradycardia 
Vascular disorders 
Uncommon hypertension 
Respiratory, thoracic and mediastinal disorders 
Common pneumonitis, dyspnoea, cough 
Uncommon pleural effusion 
Gastrointestinal disorders 
Very common nausea, diarrhoea, vomiting 
Common constipation, stomatitis, abdominal pain, colitis, dry mouth, pancreatitis 
Hepatobiliary disorders 
Common hepatitis 
Skin and subcutaneous tissue disorders 
Very common rasha, pruritus 
Common alopecia, dry skin, erythema, urticaria 
Uncommon psoriasis, Stevens-Johnson syndrome, vitligo 
Musculoskeletal and connective tissue disorders 
Common musculoskeletal painb, arthralgia, arthritis 
Uncommon muscular weakness, muscle spasms, polymyalgia rheumatica 
Renal and urinary disorders 
Common renal failure (including acute kidney injury) 
Uncommon nephritis 
General disorders and administration site conditions 
Very common fatigue 
Common pyrexia, oedema (including peripheral oedema) 
Uncommon chills, chest pain 
Investigations 



23 

Very common anaemiac,d, thrombocytopaeniac, leucopoeniac, lymphopaeniac, 
neutropaeniac, increased alkaline phophatasesc, increased transaminasesc, 
increased creatininec, increased amylasec, increased lipasec, 
hypokalaemiac, hypomagnesaemiac, hyponatraemiac 

Common increased total bilirubinc, increased thyroid stimulating hormone 
Uncommon increased gamma-glutamyltransferase 

a Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash 
macular, rash morbilliform, rash papular, rash generalised, dermatitis, dermatitis acneiform, dermatitis 
allergic, dermatitis atopic, dermatitis bullous, and drug eruption. 

b Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest 
pain, myalgia, neck pain, pain in extremity, and spinal pain. 

c Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from 
baseline in laboratory measurements. 

d Anaemia is a composite term which includes iron deficiency anaemia and haemoglobin decreased. 
 
Description of selected adverse reactions 
Nivolumab or nivolumab in combination is associated with immune-related adverse reactions. With 
appropriate medical therapy, immune-related adverse reactions resolved in most cases. Permanent 
discontinuation of treatment was required in a greater proportion of patients receiving nivolumab in 
combination with ipilimumab than in those receiving nivolumab monotherapy. Table 8 presents the 
percentage for immune-related adverse reactions who were permanently discontinued from treatment 
by dosing regimen. Additionally, for patients who experienced an event, Table 8 presents the 
percentage of patients who required high-dose corticosteroids (at least 40 mg daily prednisone 
equivalents) by dosing regimen. The management guidelines for these adverse reactions are described 
in section 4.4. 
 

Table 8: Immune-related adverse reactions leading to permanent discontinuation or 
requiring high-dose corticosteroids by dosing regimen

 Nivolumab 
3 mg/kg 

monotherapy 
 

% 

Nivolumab 
1 mg/kg in 

combination 
with 

ipilimumab 
3 mg/kg in 
melanoma 

% 

Nivolumab 
3 mg/kg in 

combination 
with 

ipilimumab 
1 mg/kg in 

RCC 
% 

Nivolumab 
360 mg in 

combination 
with 

ipilimumab 
1 mg/kg and 

chemotherapy 
in NSCLC 

% 
Immune-related adverse 
reaction leading to 
permanent 
discontinuation  

    

Pneumonitis 1.2 2.0 2.2 2.2 
Colitis 0.8 16 4.0 4.2 
Hepatitis 1.0 9 4.4 3.4 
Nephritis and renal 
dysfunction 

0.3 1.1 1.3 1.4 

Endocrinopathies 0.1 2.7 2.9 2.0 
Skin 0.3 0.9 1.5 1.1 
Hypersensitivity/Infusion 
reaction 

0.2 0 0 0.6 

Immune-related adverse 
reaction requiring 
high-dose 
corticosteroidsa,b  

    

Pneumonitis 69 63 59 68 
Colitis 15 46 26 20 
Hepatitis 21 46 35 29 



24 

Table 8: Immune-related adverse reactions leading to permanent discontinuation or 
requiring high-dose corticosteroids by dosing regimen 

Nephritis and renal 
dysfunction 

27 17 27 24 

Endocrinopathies 7 27 25 8 
Skin 4 7 7 10 
Hypersensitivity/Infusion 
reaction 

20 6 9 29 

 
a at least 40 mg daily prednisone equivalents 
b frequency is based on the number of patients who experienced the immune-related adverse 

reaction 
 
Immune-related pneumonitis 
In patients treated with nivolumab monotherapy, the incidence of pneumonitis, including interstitial 
lung disease and lung infiltration, was 3.4% (87/2578). The majority of cases were Grade 1 or 2 in 
severity reported in 0.8% (21/2578) and 1.7% (44/2578) of patients respectively. Grade 3 and 4 cases 
were reported in 0.7% (19/2578) and <0.1% (1/2578) of patients respectively. Grade 5 cases were 
reported in < 0.1% (2/2578) of patients in these studies. Median time to onset was 3.6 months 
(range: 0.2-19.6). Resolution occurred in 63 patients (72.4%) with a median time to resolution of 
6.1 weeks (range: 0.1+-96.7+); + denotes a censored observation. 
 
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the 
incidence of pneumonitis including interstitial lung disease, was 7.8% (35/448). Grade 2, Grade 3, and 
Grade 4 cases were reported in 4.7% (21/448), 1.1% (5/448), and 0.2% (1/448) of patients, 
respectively. One of the Grade 3 pneumonitis cases worsened over 11 days with a fatal outcome. 
Median time to onset was 2.6 months (range: 0.7-12.6). Resolution occurred in 33 patients (94.3%) 
with a median time to resolution of 6.1 weeks (range: 0.3-35.1). 
 
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the 
incidence of pneumonitis including interstitial lung disease was 6.2% (34/547). Grade 2 and Grade 3 
cases were reported in 3.1% (17/547) and 1.1% (6/547), of patients, respectively. No 
Grade 4 or 5 cases were reported in this study. Median time to onset was 2.6 months 
(range: 0.25-20.6). Resolution occurred in 31 patients (91.2%) with a median time to resolution of 
6.1 weeks (range: 0.7-85.9+). 
 
In patients treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg 
every 6 weeks and chemotherapy in NSCLC, the incidence of pneumonitis including interstitial lung 
disease was 5.3% (19/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 1.1% 
(4/358), and 0.6% (2/358) of patients, respectively. Median time to onset was 18.1 weeks (range: 0.6-
52.4). Resolution occurred in 14 patients (74%) with a median time to resolution of 4.3 weeks (range: 
0.7-27.9+). 
 
Immune-related colitis 
In patients treated with nivolumab monotherapy, the incidence of diarrhoea, colitis, or frequent bowel 
movements was 13.1% (339/2578). The majority of cases were Grade 1 or 2 in severity reported in 
8.5% (220/2578) and 3.0% (78/2578) of patients respectively. Grade 3 cases were reported 
in 1.6% (41/2578) of patients. No Grade 4 or 5 cases were reported in these studies. Median time to 
onset was 1.8 months (range: 0.0-26.6). Resolution occurred in 296 patients (88.1%) with a median 
time to resolution of 2.1 weeks (range: 0.1-124.4+). 
 
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the 
incidence of diarrhoea or colitis was 46.7% (209/448). Grade 2, Grade 3, and Grade 4 cases were 
reported in 13.6% (61/448), 15.8% (71/448), and 0.4% (2/448) of patients, respectively. No 
Grade 5 cases were reported. Median time to onset was 1.2 months (range: 0.0-22.6). Resolution 
occurred in 186 patients (89.4%) with a median time to resolution of 3.0 weeks (range: 0.1-159.4+). 
 



25 

In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the 
incidence of diarrhoea or colitis was 28.2% (154/547). Grade 2 and Grade 3 cases were reported 
in 10.4% (57/547) and 4.9% (27/547) of patients, respectively. No Grade 4 or 5 cases were reported. 
Median time to onset was 1.2 months (range: 0.0-24.7). Resolution occurred in 140 patients (91.5%) 
with a median time to resolution of 2.4 weeks (range: 0.1-103.1+). 
 
In patients treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg 
every 6 weeks and chemotherapy in NSCLC, the incidence of diarrhoea or colitis was 22.3% (80/358). 
Grade 2, Grade 3, Grade 4, and Grade 5 cases were reported in 7% (25/358), 5% (18/358), 0.3% 
(1/358), and 0.3% (1/358) of patients, respectively. Median time to onset was 5.1 weeks (range: 0.1-
53.6). Resolution occurred in 70 patients (87.5%) with a median time to resolution of 1.4 weeks 
(range: 0.1-76.9+). 
 
Immune-related hepatitis 
In patients treated with nivolumab monotherapy, the incidence of liver function test abnormalities was 
6.7% (173/2578). The majority of cases were Grade 1 or 2 in severity reported in 3.5% (91/2578) and 
1.2% (32/2578) of patients respectively. Grade 3 and 4 cases were reported in 1.6% (41/2578) and 
0.3% (9/2578) of patients, respectively. No Grade 5 cases were reported in these studies. Median time 
to onset was 2.1 months (range: 0.0-27.6). Resolution occurred in 132 patients (76.7%) with a median 
time to resolution of 5.9 weeks (range: 0.1-82.6+). 
 
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the 
incidence of liver function test abnormalities was 29.5% (132/448). Grade 2, Grade 3, and Grade 4 
cases were reported in 6.7% (30/448), 15.4% (69/448), and 1.8% (8/448) of patients, respectively. No 
Grade 5 cases were reported. Median time to onset was 1.5 months (range: 0.0-30.1). Resolution 
occurred in 124 patients (93.9%) with a median time to resolution of 5.1 weeks (range: 0.1-106.9). 
 
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the 
incidence of liver function test abnormalities was 18.5% (101/547). Grade 2, Grade 3, and Grade 4 
cases were reported in 4.8% (26/547), 6.6% (36/547), and 1.6% (9/547) of patients, respectively. No 
Grade 5 cases were reported. Median time to onset was 2.0 months (range: 0.4-26.8). Resolution 
occurred in 86 patients (85.1%) with a median time to resolution of 6.1 weeks (range: 0.1+-82.9+). 
 
In patients treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg 
every 6 weeks and chemotherapy in NSCLC, the incidence of liver function test abnormalities was 
13.4% (48/358). Grade 2, Grade 3, and Grade 4 cases were reported in 3.1% (11/358), 3.4% (12/358), 
and 1.1% (4/358) of patients, respectively. Median time to onset was 10.6 weeks (range: 1.1-68.3). 
Resolution occurred in 37 patients (80.4%) with a median time to resolution of 5 weeks (range: 0.3+-
45.0+). 
 
Immune-related nephritis and renal dysfunction 
In patients treated with nivolumab monotherapy, the incidence of nephritis or renal dysfunction was 
2.8% (71/2578). The majority of cases were Grade 1 or 2 in severity reported in 1.6% (41/2578) and 
0.7% (18/2578) of patients respectively. Grade 3 and 4 cases were reported in 0.4% (11/2578) and 
<0.1% (1/2578) of patients, respectively. No Grade 5 nephritis or renal dysfunction was reported in 
these studies. Median time to onset was 2.3 months (range: 0.0-18.2). Resolution occurred in 
42 patients (61.8%) with a median time to resolution of 12.1 weeks (range: 0.3-79.1+). 
 
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the 
incidence of nephritis or renal dysfunction was 5.1% (23/448). Grade 2, Grade 3, and Grade 4 cases 
were reported in 1.6% (7/448), 0.9% (4/448), and 0.7% (3/448) of patients, respectively. No Grade 5 
cases were reported. Median time to onset was 2.6 months (range: 0.5-21.8). Resolution occurred in 
21 patients (91.3%) with a median time to resolution of 2.1 weeks (range: 0.1-125.1+). 
 
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the 
incidence of nephritis or renal dysfunction was 8.8% (48/547). Grade 2, Grade 3, and Grade 4 cases 
were reported in 4.4% (24/547), 0.7% (4/547), and 0.5% (3/547) of patients, respectively. No Grade 5 



26 

cases were reported. Median time to onset was 2.1 months (range: 0.0-16.1). Resolution occurred in 
37 patients (77.1%) with a median time to resolution of 13.2 weeks (range: 0.1+-106.0+). 
 
In patients treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg 
every 6 weeks and chemotherapy in NSCLC, the incidence of nephritis or renal dysfunction was 
7% (25/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 1.7% (6/358), and 
0.6 (2/358) of patients, respectively. Median time to onset was 10.6 weeks (range: 0.1-51.3). 
Resolution occurred in 14 patients (56%) with a median time to resolution of 6.3 weeks (range: 0.1+-
82.9+). 
 
Immune-related endocrinopathies 
In patients treated with nivolumab monotherapy, the incidence of thyroid disorders, including 
hypothyroidism or hyperthyroidism, was 9.6% (248/2578). The majority of cases were Grade 1 or 2 in 
severity reported in 4.2% (107/2578) and 5.4% (139/2578) of patients, respectively. Grade 3 thyroid 
disorders were reported in < 0.1% (2/2578) of patients. Hypophysitis (1 Grade 1, 2 Grade 2, 
5 Grade 3, and 1 Grade 4), hypopituitarism (4 Grade 2 and 1 Grade 3), adrenal insufficiency 
(including secondary adrenocortical insufficiency) (1 Grade 1, 9 Grade 2, and 5 Grade 3), diabetes 
mellitus (including Type 1 diabetes mellitus) (3 Grade 2 and 1 Grade 3), and diabetic ketoacidosis 
(2 Grade 3) were reported. No Grade 5 cases were reported in these studies. Median time to onset of 
these endocrinopathies was 2.8 months (range: 0.3-29.1). Resolution occurred in 117 patients (42.9%). 
Time to resolution ranged from 0.4 to 144.1+ weeks. 
 
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the 
incidence of thyroid disorders was 25.2% (113/448). Grade 2 and Grade 3 thyroid disorders were 
reported in 14.5% (65/448) and 1.3% (6/448) of patients, respectively. 
Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 5.8% (26/448) 
and 2.0% (9/448) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.4% 
(2/448) and 0.7% (3/448) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenal 
insufficiency (including secondary adrenocortical insufficiency) occurred in 1.6% (7/448), 1.3% 
(6/448) and 0.2% (1/448) of patients, respectively. Grade 1, Grade 2, Grade 3, and Grade 4 diabetes 
mellitus and Grade 4 diabetic ketoacidosis were each reported in 0.2% (1/448) of patients. No Grade 5 
endocrinopathy was reported. Median time to onset of these endocrinopathies was 1.9 months 
(range: 0.0-28.1). Resolution occurred in 64 patients (45.4%). Time to resolution ranged 
from 0.4 to 155.4+ weeks. 
 
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the 
incidence of thyroid disorders was 27.2% (149/547). Grade 2 and Grade 3 thyroid disorders were 
reported in 15.7% (86/547) and 1.3% (7/547) of patients, respectively. Hypophysitis occurred in 4.0% 
(22/547) of patients. Grade 2, Grade 3, and Grade 4 cases were reported in 0.5% (3/547), 2.4% 
(13/547), and 0.4% (2/547) of patients, respectively. Grade 2 hypopituitarism occurred in 0.4% 
(2/547) of patients. Grade 2, Grade 3, and Grade 4 adrenal insufficiency (including secondary 
adrenocortical insufficiency) occurred in 2.9% (16/547), 2.2% (12/547) and 0.4% (2/547) of patients, 
respectively. Diabetes mellitus including Type 1 diabetes mellitus (3 Grade 2, 2 Grade 3, and 
3 Grade 4), and diabetic ketoacidosis (1 Grade 4) were reported. No Grade 5 endocrinopathy was 
reported. Median time to onset of these endocrinopathies was 1.9 months (range: 0.0-22.3). Resolution 
occurred in 76 patients (42.7%). Time to resolution ranged from 0.4 to 130.3+ weeks. 
 
In patients treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg 
every 6 weeks and chemotherapy in NSCLC, the incidence of thyroid disorders was 24% (86/358). 
Grade 2 and Grade 3 thyroid disorders were reported in 12.3% (44/358) and 0.3% (1/358) of patients, 
respectively. Hypophysitis occurred in 1.4% (5/358) of patients. Grade 2 and Grade 3 cases were 
reported in 0.6% (2/358) and 0.8% (3/358) of patients, respectively. Grade 2 hypopituitarism occurred 
in 0.3% (1/358) of patients. Grade 2 and Grade 3 adrenal insufficiency occurred in 1.7% (6/358) and 
1.4% (5/358) of patients, respectively. Diabetes mellitus including Type 1 diabetes mellitus was not 
reported. Median time to onset of these endocrinopathies was 12.1 weeks (range: 1.9-58.3). Resolution 
occurred in 30 patients (35.3%). Time to resolution ranged from 1.4 to 72.4+ weeks. 
 



27 

Immune-related skin adverse reactions 
In patients treated with nivolumab monotherapy, the incidence of rash was 26.4% (680/2578). The 
majority of cases were Grade 1 in severity reported in 20.1% (518/2578) of patients. Grade 2 and 
Grade 3 cases were reported in 5.1% (131/2578) and 1.2% (31/2578) of patients respectively. No 
Grade 4 or 5 cases were reported in these studies. Median time to onset was 1.4 months 
(range: 0.0-27.9). Resolution occurred in 428 patients (63.8%) with a median time to resolution of 
17.1 weeks (0.1-150.0+). 
 
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the 
incidence of rash was 65.0% (291/448). Grade 2 and Grade 3 cases were reported in 20.3% (91/448) 
and 7.6% (34/448) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to 
onset was 0.5 months (range: 0.0-19.4). Resolution occurred in 191 patients (65.9%) with a median 
time to resolution of 11.4 weeks (range: 0.1-150.1+). 
 
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the 
incidence of rash was 48.8% (267/547). Grade 2 and Grade 3 cases were reported in 13.7% (75/547) 
and 3.7% (20/547) of patients, respectively. No Grade 4 or 5 cases were reported. Median time to 
onset was 0.9 months (range: 0.0-17.9). Resolution occurred in 192 patients (72.2%) with a median 
time to resolution of 11.6 weeks (range: 0.1-126.7+). 
 
In patients treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg 
every 6 weeks and chemotherapy in NSCLC, the incidence of rash was 37.7% (135/358). Grade 2, 
Grade 3, and Grade 4 cases were reported in 11.5% (41/358), 4.2% (14/358), and 0.3% (1/358) of 
patients, respectively. Median time to onset was 3.3 weeks (range: 0.1-83.1). Resolution occurred in 
96 patients (71.6%) with a median time to resolution of 9.4 weeks (range: 0.1+-84.1+). 
 
Rare cases of SJS and TEN some of them with fatal outcome have been observed (see 
sections 4.2 and 4.4). 
 
Infusion reactions 
In patients treated with nivolumab monotherapy, the incidence of hypersensitivity/infusion reactions 
was 4.7% (121/2578), including 6 Grade 3 and 2 Grade 4 cases. 
 
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, the incidence of 
hypersensitivity/infusion reactions was 3.8% (17/448); all were Grade 1 or 2 in severity. Grade 2 cases 
were reported in 2.2% (10/448) of patients. No Grade 3-5 cases were reported. 
 
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg//kg, the incidence of 
hypersensitivity/infusion reactions was 4.0% (22/547); all were Grade 1 or 2 in severity. Grade 2 cases 
were reported in 2.4% (13/547) of patients. No Grade 3-5 cases were reported.  
 
In patients treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg 
every 6 weeks and chemotherapy in NSCLC, the incidence of hypersensitivity/infusion reactions was 
4.7% (17/358). Grade 2, Grade 3, and Grade 4 cases were reported in 2.2% (8/358), 0.3% (1/358), and 
0.3% (1/358) of patients, respectively. 
 
Complications of allogeneic HSCT in classical Hodgkin lymphoma  
Rapid onset of GVHD has been reported with nivolumab use before and after allogeneic HSCT (see 
section 4.4). 
In 49 evaluated patients from two cHL studies who underwent allogeneic HSCT after discontinuing 
nivolumab monotherapy, Grade 3 or 4 acute GVHD was reported in 13/49 patients (26.5%). 
Hyperacute GVHD, defined as acute GVHD occurring within 14 days after stem cell infusion, was 
reported in three patients (6%). A steroid-requiring febrile syndrome, without an identified infectious 
cause, was reported in six patients (12%) within the first 6 weeks post-transplantation, with 
three patients responding to steroids. Hepatic veno-occlusive disease occurred in one patient, who died 
of GVHD and multi-organ failure. Nine of 49 patients (18.4%) died from complications of allogeneic 



28 

HSCT after nivolumab. The 49 patients had a median follow-up from subsequent allogeneic HSCT of 
5.6 months (range: 0-19 months). 
 
Laboratory abnormalities 
In patients treated with nivolumab monotherapy, the proportion of patients who experienced a shift 
from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 5.2% for anaemia (all 
Grade 3), 1.0% for thrombocytopaenia, 1.0% for leucopoenia, 10.0% for lymphopaenia, 1.1% for 
neutropaenia, 2.1% for increased alkaline phosphatase, 2.7% for increased AST, 2.2% for increased 
ALT, 1.2% for increased total bilirubin, 0.9% for increased creatinine, 3.8% for hyperglycaemia, 1.0% 
for hypoglycaemia, 3.5% for increased amylase, 7.9% for increased lipase, 6.4% for hyponatraemia, 
1.8% for hyperkalaemia, 1.5% for hypokalaemia, 1.2% for hypercalcaemia, 0.7% for 
hypermagnesaemia, 0.5% for hypomagnesaemia, 0.7% for hypocalcaemia, and 0.1% for 
hypernatraemia. 
 
In patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg in melanoma, the 
proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory 
abnormality was as follows: 2.8% for anaemia (all Grade 3), 1.2% for thrombocytopaenia, 0.5% for 
leucopoenia, 6.7% for lymphopaenia, 0.7% for neutropaenia, 4.3% for increased alkaline phosphatase, 
12.4% for increased AST, 15.3% for increased ALT, 1.2% for increased total bilirubin, 2.4% for 
increased creatinine, 5.3% for hyperglycaemia, 8.7% for increased amylase, 19.5% for increased 
lipase, 1.2% for hypocalcaemia, 0.2% each for hypernatraemia and hypercalcaemia, 0.5% for 
hyperkalaemia, 0.3% for hypermagnesaemia, 4.8% for hypokalaemia, and 9.5% for hyponatraemia. 
 
In patients treated with nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg in RCC, the 
proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratory 
abnormality was as follows: 3.0% for anaemia (all Grade 3), 0.7% for thrombocytopaenia, 0.6% for 
leucopoenia, 5.1% for lymphopaenia, 1.1% for neutropaenia, 2.0% for increased alkaline phosphatase, 
4.8% for increased AST, 6.5% for increased ALT, 1.1% for increased total bilirubin, 2.1% for 
increased creatinine, 7.2% for hyperglycaemia, 1.8% for hypoglycaemia, 12.2% for increased 
amylase, 20.1% for increased lipase, 0.4% for hypocalcaemia, 1.3% for hypercalcaemia, 2.4% for 
hyperkalaemia, 1.1% for hypermagnesaemia, 0.4% for hypomagnesaemia 1.9% for hypokalaemia, and 
9.9% for hyponatraemia. 
 
In patients treated with nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg 
every 6 weeks and chemotherapy in NSCLC, the proportion of patients who experienced a worsening 
from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 9.2% for anaemia, 4.3% for 
thrombocytopaenia, 9.8% for leucopoenia, 5.8% for lymphopaenia, 14.7% for neutropaenia, 1.2% for 
increased alkaline phosphatase, 3.5% for increased AST, 4.3% for increased ALT, 0% for increased 
total bilirubin, 1.2% for increased creatinine, 7.1% for hyperglycaemia, 0% for hypoglycaemia, 
6.7% for increased amylase, 11.9% for increased lipase, 1.4% for hypocalcaemia, 1.2% for 
hypercalcaemia, 1.7% for hyperkalaemia, 0.3% for hypermagnesaemia, 1.2% for hypomagnesaemia 
3.5% for hypokalaemia, and 10.7% for hyponatraemia. 
 
Immunogenicity 
Of the 2022 patients who were treated with nivolumab monotherapy 3 mg/kg every 2 weeks and 
evaluable for the presence of anti-product-antibodies, 231 patients (11.4%) tested positive for 
treatment-emergent anti-product-antibodies with fifteen patients (0.7%) testing positive for 
neutralising antibodies. 
 
Of the patients who were treated with nivolumab in combination with ipilimumab and evaluable for 
the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26.0% with 
nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks and 37.8% with nivolumab 1 mg/kg and 
ipilimumab 3 mg/kg every 3 weeks. The incidence of neutralising antibodies against nivolumab was 
0.5% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks and 4.6% with nivolumab 
1 mg/kg and ipilimumab 3 mg/kg every 3 weeks. Of patients evaluable for the presence of 
anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies ranged from 6.3 to 8.4% and 
neutralising antibodies against ipilimumab ranged from 0 to 0.3%. 



29 

 
Of the patients who were treated with nivolumab in combination with ipilimumab and chemotherapy 
and evaluable for the presence of anti-nivolumab antibodies or neutralising antibodies against 
nivolumab, the incidence of anti-nivolumab antibodies was 33.8% and the incidence of neutralising 
antibodies was 2.6%. Of the patients who were treated with nivolumab in combination with 
ipilimumab and chemotherapy and evaluable for the presence of anti-ipilimumab antibodies or 
neutralising antibodies against ipilimumab, the incidence of anti-ipilimumab antibodies was 7.5%, and 
the neutralising antibodies was 1.6%. 
 
Although the clearance of nivolumab was increased by 20% when anti-nivolumab-antibodies were 
present, there was no evidence of loss of efficacy or altered toxicity profile in the presence of 
nivolumab antibodies based on the pharmacokinetic and exposure-response analyses for both 
monotherapy and combination. 
 
Elderly 
No overall differences in safety were reported between elderly (≥ 65 years) and younger patients 
(< 65 years). Data from SCCHN and adjuvant melanoma patients 75 years of age or older are too 
limited to draw conclusions on this population (see section 5.1). Data from cHL patients 65 years of 
age or older are too limited to draw conclusions on this population (see section 5.1). 
 
Hepatic or renal impairment 
In the non-squamous NSCLC study (CA209057), the safety profile in patients with baseline renal or 
hepatic impairment was comparable to that in the overall population. These results should be 
interpreted with caution due to the small sample size within the subgroups. 
 
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 national reporting system 
listed in Appendix V. 
 
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. 
 



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Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in 
improved anti-tumour responses in metastatic melanoma. In murine syngeneic tumour models, dual 
blockade of PD-1 and CTLA-4 resulted in synergistic anti-tumour activity. 
 
Clinical efficacy and safety 
 
Based on modelling of dose/exposure efficacy and safety relationships, there are no clinically 
significant differences in efficacy and safety between a nivolumab dose of 240 mg every 2 weeks or 
3 mg/kg every 2 weeks. Additionally, based on these relationships, there were no clinically significant 
differences between a nivolumab dose of 480 mg every 4 weeks or 3 mg/kg every 2 weeks in adjuvant 
treatment of melanoma, advanced melanoma and advanced RCC. 
 
Melanoma 
 
Treatment of advanced 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 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 tumour 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 events 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 OS. Key 
secondary efficacy outcome measures were investigator-assessed 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. 
 



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Figure 1: Kaplan-Meier curves of OS (CA209066) 
 

 
Overall survival (months) 

Number of subjects at risk 
Nivolumab 

210 185 150 105 45 8 0 
Dacarbazine 

208 177 123 82 22 3 0 
 
──∆─── Nivolumab (events: 50/210), median and 95% CI: N.A. 
- - -- - - Dacarbazine (events: 96/208), median and 95% CI: 10.84 (9.33, 12.09) 
 
The observed OS benefit was consistently demonstrated across subgroups of patients including 
baseline ECOG performance status, M stage, history of brain metastases, and baseline LDH level. 
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 5% or 10%). 
 
Data available indicate that the onset of nivolumab effect is delayed such that benefit of nivolumab 
above chemotherapy may take 2-3 months. 
 
Efficacy results are shown in Table 9. 

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Table 9: Efficacy results (CA209066) 
 nivolumab 

(n = 210)
dacarbazine 

(n = 208) 
Overall survival  
 Events 50 (23.8%) 96 (46.2%) 

Hazard ratio  0.42
99.79% CI (0.25, 0.73) 

95% CI (0.30, 0.60)
p-value < 0.0001 

   
 Median (95% CI) Not reached 10.8 (9.33, 12.09) 
 Rate (95% CI)   
  At 6 months 84.1 (78.3, 88.5) 71.8 (64.9, 77.6) 
  At 12 months 72.9 (65.5, 78.9) 42.1 (33.0, 50.9) 
Progression-free survival    
 Events 108 (51.4%) 163 (78.4%) 

Hazard ratio  0.43 
95% CI (0.34, 0.56) 
p-value < 0.0001

    
 Median (95% CI) 5.1 (3.48, 10.81) 2.2 (2.10, 2.40) 
 Rate (95% CI)    
  At 6 months 48.0 (40.8, 54.9) 18.5 (13.1, 24.6) 
  At 12 months 41.8 (34.0, 49.3) NA 
   
Objective response  84 (40.0%) 29 (13.9%) 

(95% CI) (33.3, 47.0) (9.5, 19.4) 
Odds ratio (95% CI) 4.06 (2.52, 6.54) 

p-value < 0.0001
    

 Complete response (CR) 16 (7.6%) 2  (1.0%) 
 Partial response (PR) 68 (32.4%) 27  (13.0%) 
 Stable disease (SD) 35 (16.7%) 46  (22.1%) 
    
Median duration of response  
 Months (range) Not reached (0+-12.5+) 6.0 (1.1-10.0+) 
    
Median time to response    
 Months (range) 2.1 (1.2-7.6) 2.1 (1.8-3.6) 

“+” denotes a censored observation. 
 
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, active brain or leptomeningeal metastases 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 tumour PD-L1 status and best response to prior ipilimumab. 
 



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The co-primary efficacy outcome measures were confirmed ORR in the first 120 patients treated with 
nivolumab, as measured by independent radiology review committee (IRRC) using RECIST, 
version 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 analysed. 
Efficacy results are presented in Table 10. 
 
Table 10: Best overall response, time and duration of response (CA209037) 

 nivolumab 
(n = 120)

chemotherapy 
(n = 47) 

Confirmed objective response 
(IRRC) 

38 (31.7%) 5 (10.6%) 

(95% CI) (23.5, 40.8) (3.5, 23.1) 
    

 Complete response (CR) 4 (3.3%) 0  
 Partial response (PR) 34 (28.3%) 5 (10.6%) 
 Stable disease (SD) 28 (23.3%) 16 (34.0%) 
    
Median duration of response    
 Months (range) Not reached 3.6 (Not available) 
    
Median time to response    
 Months (range) 2.1 (1.6-7.4) 3.5 (2.1-6.1) 

 
Data available indicate that the onset of nivolumab effect is delayed such that benefit of nivolumab 
above chemotherapy may take 2-3 months. 
 
Updated analysis (24-month follow-up) 
Among all randomised patients, the ORR was 27.2% (95% CI: 22.0, 32.9) in the nivolumab group and 
9.8% (95% CI: 5.3, 16.1) in the chemotherapy group. Median durations of response were 31.9 months 
(range: 1.4+-31.9) and 12.8 months (range: 1.3+-13.6+), respectively. The PFS HR for nivolumab vs. 
chemotherapy was 1.03 (95% CI: 0.78, 1.36). The ORR and PFS were assessed by IRRC per RECIST 
version 1.1. 
 
There was no statistically significant difference between nivolumab and chemotherapy in the final OS 
analysis. The primary OS analysis was not adjusted to account for subsequent therapies, with 
54 (40.6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS may 
be confounded by dropout, imbalance of subsequent therapies and differences in baseline factors. 
More patients in the nivolumab arm had poor prognostic factors (elevated LDH and brain metastases) 
than in the chemotherapy arm. 
 
Efficacy by BRAF status: Objective responses to nivolumab (according to the definition of the 
co-primary endpoint) were observed in patients with or without BRAF mutation-positive melanoma. 



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The ORRs in the BRAF mutation-positive subgroup were 17% (95% CI: 8.4, 29.0) for nivolumab and 
11% (95% CI: 2.4, 29.2) for chemotherapy, and in the BRAF wild-type subgroup were 
30% (95% CI: 24.0, 36.7) and 9% (95% CI: 4.6, 16.7), respectively. 
 
The PFS HRs for nivolumab vs. chemotherapy were 1.58 (95% CI: 0.87, 2.87) for BRAF 
mutation-positive patients and 0.82 (95% CI: 0.60, 1.12) for BRAF wild-type patients. The OS HRs 
for nivolumab vs. chemotherapy were 1.32 (95% CI: 0.75, 2.32) for BRAF mutation-positive patients 
and 0.83 (95% CI: 0.62, 1.11) for BRAF wild-type patients. 
 
Efficacy by tumour PD-L1 expression: Objective responses to nivolumab were observed regardless of 
tumour PD-L1 expression. However, the role of this biomarker (tumour PD-L1 expression) has not 
been fully elucidated. 
 
In patients with tumour PD-L1 expression ≥1%, ORR was 33.5% for nivolumab 
(n = 179; 95% CI: 26.7, 40.9) and 13.5% for chemotherapy (n = 74; 95% CI: 6.7, 23.5). In patients 
with tumour PD-L1 expression <1%, ORR per IRRC was 13.0% (n = 69; 95% CI: 6.1, 23.3) and 
12.0% (n = 25; 95% CI: 2.5, 31.2), respectively. 
 
The PFS HRs for nivolumab vs. chemotherapy were 0.76 (95% CI: 0.54, 1.07) in patients with tumour 
PD-L1 expression ≥1% and 1.92 (95% CI: 1.05, 3.5) in patients with tumour PD-L1 expression <1%. 
 
The OS HRs for nivolumab vs. chemotherapy were 0.69 (95% CI: 0.49, 0.96) in patients with tumour 
PD-L1 expression ≥1% and 1.52 (95% CI: 0.89, 2.57) in patients with tumour PD-L1 expression <1%. 
 
These subgroup analyses should be interpreted with caution given the small size of the subgroups and 
lack of statistically significant difference in OS in the all randomised population. 
 
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, 37.8), and the estimated OS rates were 42% 
(95% CI: 32, 51) at 3 years, 35% (95% CI: 26, 44) at 4 years, and 34% (95% CI: 25, 43) at 5 years 
(minimum follow-up of 45 months). 
 
Single-arm phase 2 study (CA209172) 
Study CA209172 was a single-arm, open label study of nivolumab monotherapy in patients with 
stage III (unresectable) or stage IV metastatic melanoma after prior treatment containing an 
anti-CTLA-4 monoclonal antibody. Safety was the primary endpoint and efficacy was a secondary 
endpoint. Of the 1008 treated patients, 103 (10%) had ocular/uveal melanoma, 66 (7%) had an ECOG 
performance score of 2, 165 (16%) had asymptomatic treated and untreated CNS metastases, 
13 (1.3%) had treated leptomeningeal metastases, 25 (2%) had autoimmune disease, and 84 (8%) had 
Grade 3-4 immune-related AEs with prior anti-CTLA-4 therapy. No new safety signals were identified 
in all treated patients and the overall safety profile of nivolumab was similar across subgroups. 
Efficacy results based on investigator-assessed response rates at week 12 are presented in Table 11 
below. 
 



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Table 11: Response rate at week 12 - all response evaluable patients and by subgroup 
(CA209172) 

 Total Ocular/ 
Uveal 

melanoma 

ECOG PS 2 
 

CNS 
metastasis 

Autoimmune 
disease 

Grade 3-4 
irAEs with 

anti-CTLA-4 

N 
(%)a 

161/588 
(27.4) 

4/61 
(6.6) 

4/20 
(20.0) 

20/73 
(27.4) 

3/16 
(18.8) 

13/46 
(28.3) 

a Responses were assessed per RECIST 1.1 for 588/1008 (58.3%) of patients who continued treatment 
through week 12 and had a follow-up scan at week 12.  

 
Randomised phase 3 study of nivolumab in combination with ipilimumab or nivolumab as 
monotherapy vs. ipilimumab as monotherapy (CA209067) 
The safety and efficacy of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg or nivolumab 
3 mg/kg vs. ipilimumab 3 mg/kg monotherapy for the treatment of advanced (unresectable or 
metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). The 
differences between the two nivolumab-containing groups were evaluated descriptively. The study 
included adult patients with confirmed unresectable Stage III or Stage IV melanoma. Patients were to 
have ECOG performance status score of 0 or 1. Patients who had not received prior systemic 
anticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant or 
neoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patients 
with active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastases 
were excluded from the study. 
 
A total of 945 patients were randomised to receive nivolumab in combination with ipilimumab 
(n = 314), nivolumab monotherapy (n = 316), or ipilimumab monotherapy (n = 315). Patients in the 
combination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 
90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab 
3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm received 
nivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg and 
nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every 
2 weeks. Randomisation was stratified by PD-L1 expression (≥ 5% vs. < 5% tumour cell membrane 
expression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging 
system. Treatment was continued as long as clinical benefit was observed or until treatment was no 
longer tolerated. Tumour assessments were conducted 12 weeks after randomisation then every 
6 weeks for the first year, and every 12 weeks thereafter. The primary outcome measures were 
progression-free survival and OS. ORR and the duration of response were also assessed. 
 
Baseline characteristics were balanced across the three treatment groups. The median age was 61 years 
(range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance status 
score was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58% 
had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy. 
Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1 
≥ 5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and 
36% of patients had a baseline LDH level greater than ULN at study entry. Among patients with 
quantifiable tumour PD-L1 expression, the distribution of patients was balanced across the three 
treatment groups. Tumour PD-L1 expression was determined using the 
PD-L1 IHC 28-8 pharmDx assay. 
 
At primary analysis (minimum follow-up 9 months) the median PFS was 6.9 months in the nivolumab 
group as compared with 2.9 months in the ipilimumab group (HR = 0.57, 99.5% CI: 0.43, 0.76; 
p < 0.0001). The median PFS was 11.5 months in the nivolumab in combination with ipilimumab 
group, as compared with 2.9 months in the ipilimumab group (HR = 0.42, 99.5% CI: 0.31, 0.57; 
p < 0.0001). 
 



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PFS results from descriptive analysis (with minimum follow up of 60 months) are shown in Figure 2 
(all randomised population), Figure 3 (at the tumour PD-L1 5% cut off), and Figure 4 (at the tumour 
PD-L1 1% cut off).   



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Figure 2: Progression-free survival (CA209067) 

 
Progression-free survival per investigator (months) 

Number of subjects at risk 
Nivolumab + ipilimumab 

314 174 136 124 110 101 95 90 82 76 45 2 0 
Nivolumab 

316 151 120 106 97 84 78 73 68 65 40 1 0 
Ipilimumab 

315 78 46 34 31 28 21 18 17 15 11 1 0 
 
- - -*- - - -  Nivolumab+ipilimumab (events: 182/314), median and 95% CI: 11.50 (8.74, 19.32). 

PFS rate at 12 months and 95% CI: 49% (44, 55), PFS rate at 60 months and 95% CI: 36% (32, 42) 
──∆─── Nivolumab (events: 203/316), median and 95% CI: 6.93 (5.13, 10.18). 

PFS rate at 12 months and 95% CI: 42% (36, 47), PFS rate at 60 months and 95% CI: 29% (24, 35) 
- - -- - -  Ipilimumab (events: 261/315), median and 95% CI: 2.86 (2.79, 3.15). 

PFS rate at 12 months and 95% CI: 18% (14, 23), PFS rate at 60 months and 95% CI: 8% (5, 12) 
 
Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.35, 0.51) 
Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.53 (0.44, 0.64) 
Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.79 (0.64, 0.96) 
  

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Figure 3: Progression-free survival by PD-L1 expression: 5% cut off (CA209067) 
 

PD-L1 expression < 5% 

 
Progression-free survival (months) 

 
 
 
 
 
 
 
 

 
- - -*- - - - Nivolumab+ipilimumab (events: 123/210), median and 95% CI: 11.17 (7.98, 17.51) 

 ──∆───  Nivolumab (events: 136/208), median and 95% CI: 5.39 (2.96, 7.13) 
 - - -- - -  Ipilimumab (events: 171/202), median and 95% CI: 2.83 (2.76, 3.02) 
 
   Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.33, 0.53) 
   Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.54 (0.43, 0.68) 
   Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.77 (0.60, 0.98) 
 

PD-L1 expression ≥ 5% 

 
Progression-free survival (months) 

 
 
 
 
 
 
 
 

- - -*- - - - Nivolumab+ipilimumab (events: 36/68), median and 95% CI: 22.11 (9.72, N.A.) 
──∆───  Nivolumab (events: 46/80), median and 95% CI: 22.34 (9.46, 40.02) 
- - -- - -  Ipilimumab (events: 60/75), median and 95% CI: 3.94 (2.79, 4.21) 

 
   Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.37 (0.24, 0.56) 
   Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.28, 0.62) 
   Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.89 (0.57, 1.37) 
  

Number of subjects at risk 
Nivolumab + ipilimumab 
210 113 87 78 71 64 59 55 52 49 33 2 0 
Nivolumab 
208 91 73 66 60 50 48 45 40 38 23 1 0 
Ipilimumab 
202 45 26 19 18 16 14 13 12 10 6 0 0 

Number of subjects at risk
Nivolumab + ipilimumab 

68 44 35 33 28 27 26 25 22 19 7 0 0 
Nivolumab 

80 52 41 36 33 30 27 25 25 24 15 0 0 
Ipilimumab 

75 21 14 10 10 9 5 5 5 5 5 1 0 

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Figure 4: Progression-free survival by PD-L1 expression: 1% cut off (CA209067)  
 

PD-L1 expression < 1% 

 
 Progression-free survival (months) 

 
 
 
 

 
 
 
 
- - -*- - - - Nivolumab+ipilimumab (events: 73/123), median and 95% CI: 11.17 (6.93, 22.18) 
──∆───  Nivolumab (events: 82/117), median and 95% CI: 2.83 (2.76, 5.62) 
- - -- - -  Ipilimumab (events: 94/113), median and 95% CI: 2.76 (2.66, 2.86) 

 

   Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.39 (0.29, 0.54) 
   Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.59 (0.44, 0.80) 
   Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.66 (0.48, 0.91) 
 

PD-L1 expression ≥ 1% 

 
Progression-free survival (months) 

 
 
 
 
 
 
 
 
 - - -*- - -  Nivolumab+ipilimumab (events: 86/155), median and 95% CI: 16.13 (8.90, 39.06) 
 ──∆───  Nivolumab (events: 100/171), median and 95% CI: 16.20 (8.11, 27.66) 
 - - -- - -  Ipilimumab (events: 137/164), median and 95% CI: 3.48 (2.83, 4.17) 
 
   Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.41 (0.31, 0.54) 
   Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.45 (0.35, 0.58) 
   Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.91 (0.68, 1.22) 
  

Number of subjects at risk 
Nivolumab + ipilimumab 
123 65 51 46 41 38 36 33 30 28 21 1 0 

Nivolumab 
117 44 35 33 30 25 23 20 17 15 8 0 0 

Ipilimumab 
113 20 12 9 9 7 5 5 4 3 3 0 0 

Number of subjects at risk 
Nivolumab + ipilimumab 
155 92 71 65 58 53 49 47 44 40 19 1 0 

Nivolumab 
171 99 79 69 63 55 52 50 48 47 30 1 0 

Ipilimumab 
164 46 28 20 19 18 14 13 13 12 8 1 0 

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The final (primary) OS analysis occurred when all patients had a minimum follow-up of 28 months. 
At 28 months, median OS was not reached in the nivolumab group as compared with 19.98 months in 
the ipilimumab group (HR = 0.63, 98% CI: 0.48, 0.81; p-value: < 0.0001). Median OS was not 
reached in the nivolumab in combination with ipilimumab group as compared with the ipilimumab 
group (HR = 0.55, 98% CI: 0.42, 0.72; p-value: < 0.0001). 
 
OS results at an additional descriptive analysis undertaken at a minimum follow-up of 60 months 
show outcomes consistent with the original primary analysis. OS results from this follow-up analysis 
are shown in Figure 5 (all randomised), Figure 6 and 7 (at the tumour PD-L1 5% and 1% cut off). 
 
The OS analysis was not adjusted to account for subsequent therapies received. Subsequent systemic 
therapy was received by 34.7%, 48.1%, and 65.7% of patients in the combination, nivolumab 
monotherapy, and ipilimumab arms, respectively. Subsequent immunotherapy (including anti-PD1 
therapy, anti-CTLA-4 antibody, or other immunotherapy) was received by 17.5%, 33.2%, and 47.3% 
of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively. 
 
Figure 5: Overall survival (CA209067) - Minimum follow-up of 60 months 
 

  
Overall survival (months) 

 
 
 

- - -*- - - - Nivolumab+ipilimumab (events: 152/314), median and 95% CI: N.A. (38.18, N.A.) 
OS rate and 95% CI at 12 months: 73% (68, 78), 24 months: 64% (59, 69), 36 months: 58% (52, 63), and 
60 months: 52% (46, 57) 

──∆─── Nivolumab (events: 176/316), median and 95% CI: 36.93 months (28.25, 58.71)  
OS rate and 95% CI at 12 months: 74% (69, 79), 24 months: 59% (53, 64), 36 months: 52% (46, 57), and 
60 months: 44% (39, 50) 

- - -- - -  Ipilimumab (events: 230/315), median and 95% CI: 19.94 months (16.85, 24.61) 
OS rate and 95% CI at 12 months: 67% (61, 72), 24 months: 45% (39, 50), 36 months: 34% (29, 39), and 
60 months: 26% (22, 31) 

 
Nivolumab+ipilimumab vs ipilimumab - HR (95% CI): 0.63 (0.52, 0.76)  
Nivolumab vs ipilimumab - HR (95% CI): 0.52 (0.42, 0.64) 
Nivolumab+ipilimumab vs nivolumab - HR (95% CI): 0.83 (0.67, 1.03) 

  

Number of subjects at risk 
Nivolumab+ipilimumab 

314 265 227 210 199 187 179 169 163 157 150 14 0 

Nivolumab 
316 266 231 201 181 171 158 145 141 137 130 14 0 

Ipilimumab 
315 253 203 163 135 113 100 94 87 81 73 12 0 

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Figure 6: Overall survival by PD-L1 expression: 5% cut off (CA209067) - Minimum 
follow-up of 60 months 

PD-L1 expression < 5% 

 
Overall survival (months) 

 
 
 
 
 
 
 
 
 
- - -*- - - - Nivolumab+ipilimumab (events: 103/210), median and 95% CI: N.A. (32.72, N.A.) 

 ──∆───  Nivolumab (events: 117/208), median and 95% CI: 35.94 months (23.06, 59.24.) 
 - - -- - -  Ipilimumab (events: 154/202), median and 95% CI: 18.40 months (13.70, 22.51) 
   Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.50 (0.39, 0.65) 
   Nivolumab vs. ipilimumab - HR (95% CI): 0.62 (0.49, 0.79) 

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.81 (0.62, 1.06) 
 

PD-L1 expression ≥ 5% 

 
Overall survival (months) 

 
 
 
 
 
 
 

 
 
 
 
- - -*- - - - Nivolumab+ipilimumab (events: 30/68), median and 95% CI: N.A. (39.06, N.A.) 

 ──∆───  Nivolumab (events: 41/80), median and 95% CI: 61.57 months (33.64, N.A.) 
 - - -- - -  Ipilimumab (events: 50/75), median and 95% CI: 28.88 months (18.10, 44.16) 
 
   Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.58 (0.37, 0.91) 
   Nivolumab vs. ipilimumab - HR (95% CI): 0.63 (0.42, 0.96) 

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.91 (0.657, 1.46) 
  

Number of subjects at risk 
Nivolumab+ipilimumab 
210 178 146 139 130 123 116 109 106 103 101 9 0 

Nivolumab 
208 169 144 123 112 108 102 92 90 88 82 9 0 

Ipilimumab 
202 158 124 99 80 69 59 57 55 50 45 5 0 

Number of subjects at risk 
Nivolumab+ipilimumab 

68 56 52 45 45 43 43 41 40 37 33 2 0 
Nivolumab 

80 76 69 61 57 53 47 44 43 41 41 5 0 
Ipilimumab 

75 66 60 46 40 34 32 29 25 24 22 5 0 

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Figure 7: Overall survival by PD-L1 expression: 1% cut off (CA209067) - Minimum 
follow-up of 60 months 

PD-L1 expression < 1% 

 
Overall survival (months) 

Number of subjects at risk 
Nivolumab+ipilimumab 

123 102 82 79 74 70 65 63 62 61 59 6 0 
Nivolumab 

117 86 73 62 57 53 49 43 43 42 41 5 0 
Ipilimumab 

113 87 71 57 44 36 33 32 31 28 27 3 0 
 - - -*- - - - Nivolumab+ipilimumab (events: 62/123), median and 95% CI: 61.44 (26.45, N.A.) 
 ──∆───  Nivolumab (events: 74/117), median and 95% CI: 23.46 months (13.01, 36.53) 
 - - -- - -  Ipilimumab (events: 86/113), median and 95% CI: 18.56 months (13.67, 23.20) 
 
   Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.53 (0.38, 0.74) 
   Nivolumab vs. ipilimumab - HR (95% CI): 0.77 (0.56, 1.05) 
   Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.69 (0.50, 0.97) 
 

PD-L1 expression ≥ 1% 

 
Overall survival (months) 

 
 
 
 
 
 
 
 
 
 
 - - -*- - - - Nivolumab+ipilimumab (events: 71/155), median and 95% CI: N.A. (39.06, N.A.) 
 ──∆───  Nivolumab (events: 84/171), median and 95% CI: 66.99 months (39.00, N.A.) 
 - - -- - -  Ipilimumab (events: 118/164), median and 95% CI: 21.49 months (16.85, 29.08) 
 
   Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.51 (0.38, 0.69) 
   Nivolumab vs. ipilimumab - HR (95% CI): 0.53 (0.40, 0.70) 

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.97 (0.70, 1.32) 
  

Number of subjects at risk 
Nivolumab+ipilimumab 
155 132 116 105 101 96 94 87 84 79 75 5 0 

Nivolumab 
171 159 140 122 112 108 100 93 90 87 82 9 0 

Ipilimumab 
164 137 113 88 76 67 58 54 49 46 40 7 0 

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43 

Minimum follow-up for the analysis of ORR was 60 months. Responses are summarised in Table 12. 
 

Table 12: Objective response (CA209067) 

 
nivolumab + 
ipilimumab  

(n = 314)

 
nivolumab  
(n = 316)

 
ipilimumab  

(n = 315)
Objective response  183 (58%) 141 (45%) 60 (19%) 
  (95% CI) (52.6, 63.8) (39.1, 50.3) (14.9, 23.8) 

 Odds ratio (vs. ipilimumab) 6.35 3.5  

  (95% CI) (4.38, 9.22) (2.46, 5.10)  

 Complete response (CR) 69(22%) 60 (19%) 18 (6%) 

 Partial response (PR) 114 (36%) 81 (26%) 42 (13%) 

 Stable disease (SD) 38 (12%) 30 (10%) 69 (22%) 

Duration of response    

 Median (range), months 
N.A. 

(0-65.2) 
N.A.  

(0-63.3)  
14.39 

(0-61.9) 
 Proportion ≥12 months in 
duration 

67% 71% 47% 

 Proportion ≥24 months in 
duration 

57% 55% 36% 

ORR (95% CI) by tumour PD-L1 expression    

 <5% 
56% (48.7, 62.5) 

n = 210 
43% (36, 49.8) 

n = 208 
18% (12.8, 23.8) 

n = 202 

 ≥5% 
72% (59.9, 82.3) 

n = 68 
58% (45.9, 68.5) 

n = 80 
21% (12.7, 32.3) 

n = 75 

 <1% 
54% (44.4, 62.7) 

n = 123 
36% (27.2, 45.3) 

n = 117 
18% (11.2, 26.0) 

n = 113 

 ≥1% 
65% (56.4, 72) 

n = 155 
54% (46.6, 62) 

n = 171 
20% (13.7, 26.4) 

n = 164 
 
Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORR 
compared with ipilimumab alone. The observed PFS results at 18 months of follow-up and ORR and 
OS results at 28 months of follow-up were consistently demonstrated across subgroups of patients 
including baseline ECOG performance status, BRAF status, M stage, age, history of brain metastases, 
and baseline LDH level. This observation was maintained with the OS results with a minimum 
follow-up of 60 months. 
 
Among 131 patients who discontinued the combination due to adverse reaction after 28 months of 
follow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median 
OS was not reached.  
 
Both nivolumab-containing arms demonstrated greater objective response rates than ipilimumab 
regardless of PD-L1 expression levels. ORRs were higher for the combination of nivolumab and 
ipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels (Table 12) 
after 60 months of follow-up, with a best overall response of complete response correlating to an 
improved survival rate. 
 
After 60 months of follow-up, median durations of response for patients with tumour PD-L1 
expression level ≥5% were not reached (range: 18.07-N.A.) in the combination arm, not reached 
(range: 26.71-N.A.) in the nivolumab monotherapy arm and 31.28 months (range: 6.08-N.A.) in the 
ipilimumab arm. At tumour PD-L1 expression <5%, median durations of response were not reached 
(range: 40.08-N.A.) in the combination arm, were not reached (range: 50.43-N.A.) in the nivolumab 
monotherapy arm and 12.75 months (range: 5.32-53.65) in the ipilimumab monotherapy arm. 



44 

 
No clear cut off for PD-L1 expression can reliably be established when considering the relevant 
endpoints of tumour response and PFS and OS. Results from exploratory multivariate analyses 
identified patient and tumour characteristics (ECOG performance status, M stage, baseline LDH, 
BRAF mutation status, PD-L1 status, and gender) which might contribute to the survival outcome. 
 
Efficacy by BRAF status:  
After 60 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients 
randomised to nivolumab in combination with ipilimumab had a median PFS of 16.76 months 
(95% CI: 8.28, 32.0) and 11.7 months (95% CI: 7.0, 18.14), while those in the nivolumab 
monotherapy arm had a median PFS of 5.6 months (95% CI: 2.79, 9.46) and 8.18 months 
(95% CI: 5.13, 19.55), respectively. BRAF[V600] mutation-positive and BRAF wild-type patients 
randomised to ipilimumab monotherapy had a median PFS of 3.38 months (95% CI: 2.79, 5.19) and 
2.83 months (95% CI: 2.76, 3.06), respectively. 
After 60 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients 
randomised to nivolumab in combination with ipilimumab had an ORR of 67.0% (95% CI: 57.0, 75.9; 
n = 103) and 54.0% (95% CI: 47.1, 60.9; n = 211), while those in the nivolumab monotherapy arm had 
an ORR of 37.87% (95% CI: 28.2, 48.1; n = 98) and 47.7% (95% CI: 40.9, 54.6; n = 218), 
respectively. BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumab 
monotherapy had an ORR of 23.0% (95% CI: 15.2, 32.5; n = 100) and 17.2% (95% CI: 12.4, 22.9; 
n = 215). 
After 60 months of follow-up, in BRAF [V600] mutation-positive patients median OS was not reached 
in the combination arm and 45.5 months in the nivolumab monotherapy arm. Median OS for BRAF 
[V600] mutation-positive patients in the ipilimumab monotherapy arm was 24.6 months. In BRAF 
wild-type patients median OS was 39.06 months in the combination arm, 34.37 months in the 
nivolumab monotherapy arm and 18.5 months in the ipilimumab monotherapy arm. The OS HRs for 
nivolumab in combination with ipilimumab vs. nivolumab monotherapy were 0.70 
(95% CI: 0.46, 1.05) for BRAF[V600] mutation-positive patients and 0.89 (95% CI: 0.69, 1.15) for 
BRAF wild-type patients. 
 
Randomised phase 2 study of nivolumab in combination with ipilimumab and ipilimumab (CA209069) 
Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination of 
nivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable or 
metastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis in 
patients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was 
61% (95% CI: 48.9, 72.4) in the combination arm (n = 72) versus 11% (95% CI: 3.0, 25.4) for the 
ipilimumab arm (n = 37). The estimated 2 and 3 year OS rates were 68% (95% CI: 56, 78) and 61% 
(95% CI: 49, 71), respectively, for the combination (n = 73) and 53% (95% CI: 36, 68) and 44% 
(95% CI: 28, 60), respectively, for ipilimumab (n = 37). 
 
Adjuvant treatment of melanoma 
 
Randomised phase 3 study of nivolumab vs ipilimumab 10 mg/kg (CA209238) 
The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of patients with 
completely resected melanoma were evaluated in a phase 3, randomised, double-blind study 
(CA209238). The study included adult patients, who had an ECOG performance status score of 0 or 1, 
with Stage IIIB/C or Stage IV American Joint Committee on Cancer (AJCC), 7th edition, histologically 
confirmed melanoma that is completely surgically resected. Per the AJCC 8th edition, this corresponds 
to patients with lymph node involvement or metastases. Patients were enrolled regardless of their 
tumour PD-L1 status. Patients with prior autoimmune disease, and any condition requiring systemic 
treatment with either corticosteroids (≥ 10 mg daily prednisone or equivalent) or other 
immunosuppressive medications, as well as patients with prior therapy for melanoma (except patients 
with surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous 
system, and prior adjuvant interferon completed ≥6 months prior to randomisation) prior therapy with, 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA-4 antibody (including ipilimumab or 
any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways), were 
excluded from the study. 



45 

 
A total of 906 patients were randomised to receive either nivolumab 3 mg/kg (n = 453) administered 
every 2 weeks or ipilimumab 10 mg/kg (n = 453) administered every 3 weeks for 4 doses then every 
12 weeks beginning at week 24 for up to 1 year. Randomisation was stratified by tumour PD-L1 
expression (≥ 5% vs. < 5%/indeterminate), and stage of disease per the AJCC staging system. Tumour 
assessments were conducted every 12 weeks for the first 2 years then every 6 months thereafter. The 
primary endpoint was recurrence-free survival (RFS). RFS, assessed by investigator, was defined as 
the time between the date of randomisation and the date of first recurrence (local, regional, or distant 
metastasis), new primary melanoma, or death due to any cause, whichever occurred first. 
 
Baseline characteristics were generally balanced between the two groups. The median age was 
55 years (range: 18-86), 58% were men, and 95% were white. Baseline ECOG performance status 
score was 0 (90%) or 1 (10%). The majority of patients had AJCC Stage III disease (81%), and 19% 
had Stage IV disease. Forty-eight percent of patients had macroscopic lymph nodes and 32% had 
tumour ulceration. Forty-two percent of patients were BRAF V600 mutation positive while 45% were 
BRAF wild type and 13% BRAF were status unknown. For tumour PD-L1 expression, 34% of 
patients had PD-L1 expression ≥ 5% and 62% had < 5% as determined by clinical trial assay. Among 
patients with quantifiable tumour PD-L1 expression, the distribution of patients was balanced across 
the treatment groups. Tumour PD-L1 expression was determined using the 
PD-L1 IHC 28-8 pharmDx assay.  
 
Minimum follow-up was approximately 24 months. OS was not mature at the time of this analysis. 
RFS results are shown in Table 13 and Figure 8 (all randomised population). 
 
Table 13: Efficacy results (CA209238) 

 nivolumab 
(n = 453) 

ipilimumab 10 mg/kg 
(n = 453) 

Recurrence-free survival    
 Events 171 (37.7%) 221 (48.8%) 

Hazard ratioa  0.66 
95% CI (0.54, 0.81)
p-value p<0.0001 

   
 Median (95% CI) months Not Availableb 

 
24.08  

(16.56, NR) 
 

 Rate (95% CI) at 12 months 70.4 (65.9, 74.4) 60.0 (55.2, 64.5) 
 Rate (95% CI) at 18 months 65.8 (61.2, 70.0) 53.0 (48.1, 57.6) 
 Rate (95% CI) at 24 months 62.6 (57.9, 67.0) 50.2 (45.3, 54.8) 

a Derived from a stratified proportional hazards model. 
b Not available as median unstable due to low number of patients and censoring with 24 months of follow-up 
 



46 

Figure 8: Recurrence-free survival (CA209238) 

 
 

Number of subjects at risk 
Nivolumab  

453 394 353 331 311 291 280 264 205 28 7 0 
Ipilimumab  

453 363 314 270 251 230 216 204 149 23 5 0 
 

- - - ∆- - - Nivolumab   ──── Ipilimumab 

 
The trial demonstrated a statistically significant improvement in RFS for patients randomised to the 
nivolumab arm compared with the ipilimumab 10 mg/kg arm. RFS benefit was consistently 
demonstrated across subgroups, including tumour PD-L1 expression, BRAF status, and stage of 
disease. 
 
Quality of life (QoL) with nivolumab remained stable and close to baseline values during treatment, as 
assessed by valid and reliable scales like the European Organization for Research and Treatment of 
Cancer (EORTC) QLQ-C30 and the EQ-5D utility index and visual analog scale (VAS). 
 
Non-small cell lung cancer 
 
First-line treatment of NSCLC 
 
Randomised phase 3 study of nivolumab in combination with ipilimumab and 2 cycles of platinum-
based chemotherapy vs. 4 cycles of platinum-based chemotherapy (CA2099LA) 
The safety and efficacy of nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg 
every 6 weeks and 2 cycles of platinum-based chemotherapy were evaluated in a phase 3, randomised, 
open-label study (CA2099LA). The study included patients (18 years or older) with histologically 
confirmed non-squamous or squamous Stage IV or recurrent NSCLC (per the 7th International 
Association for the Study of Lung Cancer classification), ECOG performance status 0 or 1, and no 

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prior anticancer therapy (including EGFR and ALK inhibitors). Patients were enrolled regardless of 
their tumour PD-L1 status.  
 
Patients with sensitising EGFR mutations or ALK translocations, active (untreated) brain metastases, 
carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic 
immunosuppression 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. Randomisation was 
stratified by histology (squamous vs non-squamous), tumour PD-L1 expression level (≥ 1% vs < 1%), 
and gender (male vs female).  
 
A total of 719 patients were randomised to receive either nivolumab in combination with ipilimumab 
and platinum-based chemotherapy (n = 361) or platinum-based chemotherapy (n = 358). Patients in the 
nivolumab in combination with ipilimumab and platinum-based chemotherapy arm received nivolumab 
360 mg administered intravenously over 30 minutes every 3 weeks in combination with ipilimumab 
1 mg/kg administered intravenously over 30 minutes every 6 weeks and platinum-based chemotherapy 
administered every 3 weeks for 2 cycles. Patients in the chemotherapy arm received platinum-based 
chemotherapy administered every 3 weeks for 4 cycles; non-squamous patients could receive optional 
pemetrexed maintenance therapy. 
Platinum-based chemotherapy consisted of carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2; or 
cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and 
paclitaxel 200 mg/m2 for squamous NSCLC. 
 
Treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment 
could continue beyond disease progression if the patient was clinically stable and was considered to be 
deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of 
an adverse event attributed to ipilimumab were permitted to continue nivolumab monotherapy. Tumour 
assessments were performed every 6 weeks after first dose of study treatment for the first 12 months, 
then every 12 weeks until disease progression or study treatment was discontinued.  
 
CA2099LA baseline characteristics were generally balanced across all treatment groups. The median 
age was 65 years (range: 26-86) with 51% ≥ 65 years of age and 10% ≥ 75 years of age. The majority 
of patients were white (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 
1 (68%), 57% of patients with PD-L1 ≥ 1% and 37% with PD-L1 < 1%, 31% had squamous and 69% 
had non-squamous histology, 17% had brain metastases, and 86% were former/current smokers. No 
patients received prior immunotherapy. 
 
CA2099LA primary efficacy outcome measure was OS. Additional efficacy endpoints were PFS, ORR, 
and duration of response as assessed by BICR. 
 
The study demonstrated a statistically significant benefit in OS, PFS, and ORR for patients randomised 
to nivolumab in combination with ipilimumab and platinum-based chemotherapy as compared to 
platinum-based chemotherapy alone at the prespecified interim analysis when 351 events were observed 
(87% of the planned number of events for final analysis). Minimum follow-up for OS was 8.1 months. 
 
Efficacy results are shown in Figure 9 (updated OS analysis with a minimum follow-up of 12.7 months) 
and Table 14 (primary analysis with a minimum follow-up of 8.1 months). 
An updated efficacy analysis was performed when all patients had a minimum follow-up of 12.7 months 
(see Figure 9). At the time of this analysis, the hazard ratio for OS was 0.66 (95% CI: 0.55, 0.80) and 
the hazard ratio for PFS was 0.68 (95% CI: 0.57, 0.82). 
 



48 

Figure 9: Kaplan-Meier plot of OS (CA2099LA) 

 
Overall Survival (Months) 

 
Number of Subjects at Risk 
Nivolumab + ipilimumab + chemotherapy   

 361 326 292    250        227 153 86 33 10 1 0 
Chemotherapy   

 358 319 260    208        166 116 67 26 11 0 0 
 

Nivolumab + ipilimumab + chemotherapy (events: 190/361), median and 95% CI: 15.64 (13.93, 19.98) 
Chemotherapy (events: 242/358), median and 95% CI: 10.91 (9.46, 12.55) 

 
Table 14: Efficacy results (CA2099LA) 

 
nivolumab + ipilimumab + 

chemotherapy 
(n = 361) 

chemotherapy 
(n = 358) 

Overall survival 
 Events 156 (43.2%) 195 (54.5%) 

Hazard ratio  
(96.71% CI)a 

0.69  
(0.55, 0.87) 

Stratified log-rank p-valueb 0.0006 
 Median (months) 
 (95% CI) 

14.1 
(13.24, 16.16) 

10.7 
(9.46, 12.45) 

 Rate (95% CI) at 6 months 80.9 (76.4,84.6) 72.3 (67.4,76.7) 
   
Progression-free survival 
 Events 232 (64.3%) 249 (69.6%) 

Hazard ratio  
(97.48% CI)a 

0.70  
(0.57, 0.86) 

Stratified log-rank p-valuec 0.0001 

 Median (months)d

 (95% CI) 
6.83 

(5.55, 7.66) 
4.96 

(4.27, 5.55) 

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Table 14: Efficacy results (CA2099LA) 

 
nivolumab + ipilimumab + 

chemotherapy 
(n = 361) 

chemotherapy 
(n = 358) 

Rate (95% CI) at 6 months 51.7 (46.2, 56.8) 35.9 (30.5, 41.3) 
   
Overall response ratee 136 (37.7%) 90 (25.1%) 
 (95% CI) (32.7, 42.9) (20.7, 30.0) 

Stratified CMH test p-valuef 0.0003 
 Complete response (CR) 7 (1.9%) 3 (0.8%) 
 Partial response (PR) 129 (35.7%) 87 (24.3%) 
   
Duration of response 
 Median (months)  
 (95% CI)d 

10.02 
(8.21, 13.01) 

5.09 
(4.34, 7.00) 

 % with duration ≥ 6 monthsg 74 41 
a Based on a stratified Cox proportional hazard model. 
b p-value is compared with the allocated alpha of 0.0329 for this interim analysis. 
c p-value is compared with the allocated alpha of 0.0252 for this interim analysis. 
d Kaplan-Meier estimate. 
e Proportion with complete or partial response; CI based on the Clopper and Pearson Method. 
f p-value is compared with the allocated alpha of 0.025 for this interim analysis. 
g Based on Kaplan-Meier estimates of duration of response. 
CMH = Cochran-Mantel-Haenszel 
 
Subsequent systemic therapy was received by 28.8% and 41.1% of patients in the combination and 
chemotherapy arms, respectively. Subsequent immunotherapy (including anti-PD-1, anti-PD-L1, and 
anti-CTLA4) was received by 3.9% and 27.9% of patients in the combination and chemotherapy arms, 
respectively. 
 
In study CA2099LA, subgroup descriptive analysis relative to chemotherapy, OS benefit was shown 
in patients treated with nivolumab in combination with ipilimumab and chemotherapy with squamous 
histology (HR [95% CI] 0.65 [0.46, 0.93], n = 227) and in patients with non-squamous histology (HR 
[95% CI] 0.72 [0.55, 0.93], n = 492). 
 
Table 15 summarises efficacy results of OS, PFS, and ORR by tumour PD-L1 expression in pre-
specified subgroup analyses. 
 
Table 15: Efficacy results by tumour PD-L1 expression (CA2099LA) 

 

nivolumab  
+  

ipilimumab  
+ 

chemotherapy 

chemo-
therapy 

nivolumab  
+  

ipilimumab  
+ 

chemotherapy

chemo-
therapy 

nivolumab  
+  

ipilimumab  
+  

chemotherapy 

chemo-
therapy 

nivolumab  
+  

ipilimumab  
+ 

chemotherapy

chemo-
therapy 

 PD-L1 < 1% (n = 264) 
PD-L1 ≥ 1% 

(n = 406) 
PD-L1 ≥ 1% to 49% 

(n = 233) 
PD-L1 ≥ 50% 

(n = 173) 
OS hazard 

ratio 
(95% CI)a 

0.65 
(0.46, 0.92) 

0.67 
(0.51, 0.89) 

0.69 
(0.48, 0.98) 

0.64 
(0.41, 1.02) 

PFS hazard 
ratio  

(95% CI)a 

0.77 
(0.57, 1.03) 

0.67 
(0.53, 0.85) 

0.71 
(0.52, 0.97) 

0.59 
(0.40, 0.86) 

ORR % 31.1 20.9 41.9 27.6 37.8 24.5 48.7 30.9 

a Hazard ratio based on unstratified Cox proportional hazards model. 
 



50 

A total of 70 NSCLC patients aged ≥ 75 years were enrolled in study CA2099LA (37 patients in the 
nivolumab in combination with ipilimumab and chemotherapy arm and 33 patients in the chemotherapy 
arm). A HR of 1.36 (95% CI: 0.74, 2.52) in OS and a HR of 1.12 (95% CI: 0.64, 1.96) in PFS was 
observed for nivolumab in combination with ipilimumab and chemotherapy vs. chemotherapy within 
this study subgroup. ORR was 27.0% in the nivolumab in combination with ipilimumab and 
chemotherapy arm and 15.2% in the chemotherapy arm. Forty-three percent of patients aged ≥ 75 years 
discontinued treatment with nivolumab in combination with ipilimumab and chemotherapy. Efficacy 
and safety data of nivolumab in combination with ipilimumab and chemotherapy are limited in this 
patient population. 
 
In a subgroup analysis, a reduced survival benefit for nivolumab in combination with ipilimumab and 
chemotherapy compared to chemotherapy was observed in patients who were never smokers. However, 
due to the small numbers of patients, no definitive conclusions can be drawn from these data. 
 
Treatment of NSCLC after prior chemotherapy 
Squamous NSCLC 
 
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 ECOG performance status score 
of 0 or 1. Patients were enrolled regardless of their tumour PD-L1 status. Patients with active 
autoimmune disease, symptomatic interstitial lung disease, or active brain metastases 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 RECIST, version 1.1, were conducted 9 weeks after 
randomisation and continued every 6 weeks thereafter. The primary efficacy outcome measure was 
OS. Key secondary efficacy outcome measures were investigator-assessed ORR and 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 10. 
 



51 

Figure 10: Kaplan-Meier curves of OS (CA209017) 
 

 
Overall survival (months) 

Number of subjects at risk   
Nivolumab 3 mg/kg   

135 113 86 69 52 31 15 7 0 
Docetaxel   

137 103 68 45 30 14 7 2 0 
 
──∆─── Nivolumab 3 mg/kg (events: 86/135), median and 95% CI: 9.23 (7.33, 13.27) 
- - -- - - Docetaxel (events: 113/137), median and 95% CI: 6.01 (5.13, 7.33) 
 
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 (tumour PD-L1 expression) has not been fully elucidated. With a minimum of 62.6 months 
follow-up, OS benefit remains consistently demonstrated across subgroups. 
 
Study CA209017 included a limited number of patients ≥ 75 years (11 in the nivolumab group and 
18 in the docetaxel group). Nivolumab showed numerically less effect on OS (HR 1.85; 95% CI: 0.76, 
4.51), PFS (HR = 1.76; 95%-CI: 0.77, 4.05) and ORR (9.1% vs. 16.7%). Because of the small sample 
size, no definitive conclusions can be drawn from these data. 
 
Efficacy results are shown in Table 16. 
 
Table 16: Efficacy results (CA209017) 

 nivolumab 
(n = 135)

docetaxel 
(n = 137) 

Primary analysis 
Minimum follow-up: 10.6 months

Overall survival    
 Events 86 (63.7%) 113 (82.5%) 

Hazard ratio  0.59 
96.85% CI (0.43, 0.81)

p-value 0.0002 
     
 Median (95% CI) months 9.23 (7.33, 13.27) 6.01 (5.13, 7.33) 
 Rate (95% CI) at 12 months 42.1 (33.7, 50.3) 23.7 (16.9, 31.1) 
     
Confirmed objective response  27 (20.0%) 12 (8.8%) 

(95% CI) (13.6, 27.7) (4.6, 14.8) 

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Odds ratio (95% CI) 2.64 (1.27, 5.49) 
p-value 0.0083

     
 Complete response (CR) 1 (0.7%) 0   
 Partial response (PR) 26 (19.3%) 12  (8.8%) 
 Stable disease (SD) 39 (28.9%) 47  (34.3%) 
     
Median duration of response   
 Months (range) Not reached (2.9-20.5+) 8.4 (1.4+-15.2+) 
     
Median time to response   
 Months (range) 2.2 (1.6-11.8) 2.1 (1.8-9.5) 
     
Progression-free survival     
 Events 105 (77.8%) 122 (89.1%) 

Hazard ratio  0.62  
95% CI (0.47, 0.81) 
p-value < 0.0004

     
 Median (95% CI) (months) 3.48 (2.14, 4.86) 2.83 (2.10, 3.52) 
 Rate (95% CI) at 12 months 20.8 (14.0, 28.4) 6.4 (2.9, 11.8) 

Updated analysis 
Minimum follow-up: 24.2 months

Overall survivala   
 Events 110 (81.4%) 128 (93.4%) 

Hazard ratio  0.62 
95% CI (0.47, 0.80)

 Rate (95% CI) at 24 months 22.9 (16.2, 30.3) 8 (4.3, 13.3) 
   
Confirmed objective response 20.0% 8.8% 

(95% CI) (13.6, 27.7) (4.6, 14.8) 
   
Median duration of response  
 Months (range) 25.2 (2.9-30.4) 8.4 (1.4+-18.0+) 
   
Progression-free survival   
 Rate (95% CI) at 24 months 15.6 (9.7, 22.7) All patients had either progressed, 

were censored, or lost to follow-up 
Updated analysis 

Minimum follow-up: 62.6 months
Overall survivala   
 Events 118 (87.4%) 133 (97.1%) 

Hazard ratio  0.62 
(0.48, 0.79)95% CI 

 Rate (95% CI) at 60 months 12.3 (7.4, 18.5) 3.6 (1.4, 7.8) 
   
Confirmed objective response 20.0% 8.8% 

(95% CI) (13.6, 27.7) (4.6, 14.8) 
   
Median duration of response  
 Months (range) 25.2 (2.9-70.6+) 7.5 (0.0+-18.0+) 
   
Progression-free survival  
 Rate (95% CI) at 60 months 9.4 (4.8, 15.8) All patients had either progressed, 

were censored, or lost to follow-up 
a Six patients (4%) randomised to docetaxel crossed over at any time to receive nivolumab treatment. 
“+” Denotes a censored observation. 
 
The rate of disease-related symptom improvement, as measured by LCSS, was similar between the 
nivolumab group (18.5%) and the docetaxel group (21.2%). The average EQ-VAS increased over time 
for both treatment groups, indicating better overall health status for patients remaining on treatment. 
 



53 

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 ORR 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%. 
 
Single-arm phase 2 study (CA209171) 
Study CA209171 was a single-arm, open label study of nivolumab monotherapy in patients with 
previously treated advanced or metastatic squamous NSCLC. Safety was the primary endpoint and 
efficacy was a secondary endpoint. Of the 811 treated patients, 103 (13%) had an ECOG performance 
score of 2, 686 (85%) were < 75 years old and 125 (15%) were ≥ 75 years old. No new safety signals 
were identified in all treated patients and the overall safety profile of nivolumab was similar across 
subgroups. Efficacy results based on investigator-assessed ORR are presented in Table 17 below. 
 
Table 17: ORR based on response evaluable patients – total and by subgroup (CA209171) 

Results Total ECOG PS 2 < 75 years ≥ 75 years 
N responders/ N evaluablea 

(%) 
 

95% CIb 

66/671 
(9.8) 

 
(7.7, 12.3) 

1/64 
(6.1) 

 
(0.0, 8.4) 

55/568 
(9.7) 

 
(7.4, 12.4) 

11/103 
(10.7) 

 
(5.5, 18.3) 

a includes confirmed and unconfirmed responses, scans were mandatory only at week 8/9 and week 52. 
b CR+PR, confidence interval based on the Clopper and Pearson method 
 
Non-squamous NSCLC 
 
Randomised phase 3 study vs. docetaxel (CA209057) 
The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced or 
metastatic non-squamous NSCLC were evaluated in a phase 3, randomised, open-label study 
(CA209057). The study included patients (18 years or older) who have experienced disease 
progression during or after one prior platinum doublet-based chemotherapy regimen which may have 
included maintenance therapy and who had an ECOG performance status score of 0 or 1. An 
additional line of TKI therapy was allowed for patients with known EGFR mutation or ALK 
translocation. Patients were enrolled regardless of their tumour PD-L1 status. Patients with active 
autoimmune disease, symptomatic interstitial lung disease, or active brain metastases 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 582 patients were randomised to receive either nivolumab 3 mg/kg administered 
intravenously over 60 minutes every 2 weeks (n = 292) or docetaxel 75 mg/m2 every 3 weeks 
(n = 290). Treatment was continued as long as clinical benefit was observed or until treatment was no 
longer tolerated. Tumour assessments were conducted according to the RECIST version 1.1. The 
primary efficacy outcome measure was OS. Key secondary efficacy outcome measures were 
investigator-assessed ORR and PFS. Additional prespecified subgroup analyses were conducted to 
evaluate the efficacy of tumour PD-L1 expression at predefined levels of 1%, 5% and 10%. 
Assessment according to discrete PD-L1 expression intervals were not included in the prespecified 
analyses due to the small sample sizes within the intervals. 
 
Pre-study tumour tissue specimens were systematically collected prior to randomisation in order to 
conduct pre-planned analyses of efficacy according to tumour PD-L1 expression. Tumour PD-L1 
expression was determined using the PD-L1 IHC 28-8 pharmDx assay. 
 
The median age was 62 years (range: 21 to 85) with 34% ≥65 years of age and 7% ≥75 years of age. 
The majority of patients were white (92%) and male (55%). Baseline ECOG performance status was 
0 (31%) or 1 (69%). Seventy-nine percent of patients were former/current smokers. 



54 

 
The Kaplan-Meier curves for OS are shown in Figure 11. 
 
Figure 11: Kaplan-Meier curves of OS (CA209057) 

 
Overall survival (months) 

Number of subjects at risk 
Nivolumab 3 mg/kg 

292 232 194 169 146 123 62 32 9 0 
Docetaxel 

290 244 194 150 111 88 34 10 5 0 
──∆─── Nivolumab 3 mg/kg (events: 190/292), median and 95% CI: 12.19 (9.66, 14.98) 
- - -- - - Docetaxel (events: 223/290), median and 95% CI: 9.36 (8.05, 10.68) 
 
The trial demonstrated a statistically significant improvement in OS for patients randomised to 
nivolumab as compared with docetaxel at the prespecified interim analysis when 413 events were 
observed (93% of the planned number of events for final analysis). Efficacy results are shown in 
Table 18. 
 
Table 18: Efficacy results (CA209057) 
 nivolumab 

(n = 292) 
docetaxel 
(n = 290) 

Prespecified interim analysis 
Minimum follow-up: 13.2 months 

Overall survival   
 Events 190 (65.1%) 223 (76.9%) 
  Hazard ratioa 0.73 
  (95.92% CI) (0.59, 0.89) 
  p-valueb 0.0015 
   
 Median (95% CI) months 12.19 (9.66, 14.98) 9.36 (8.05, 10.68) 
 Rate (95% CI) at 12 months 50.5 (44.6, 56.1) 39.0 (33.3, 44.6) 
   
Confirmed objective response 56 (19.2%) 36 (12.4%) 
  (95% CI) (14.8, 24.2) (8.8, 16.8) 
  Odds ratio (95% CI) 1.68 (1.07, 2.64) 
  p-value 0.0246 
   
 Complete response (CR) 4 (1.4%) 1 (0.3%) 
 Partial response (PR) 52 (17.8%) 35 (12.1%) 
 Stable disease (SD) 74 (25.3%) 122 (42.1%) 
   

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Median duration of response    
 Months (range) 17.15 (1.8-22.6+) 5.55 (1.2+-15.2+) 
   
Median time to response   
 Months (range) 2.10 (1.2-8.6) 2.61 (1.4-6.3) 
   
Progression-free survival   
 Events 234 (80.1%) 245 (84.5%) 
  Hazard ratio 0.92 
  95% CI (0.77, 1.11) 
  p-value 0.3932 
   
 Median (95% CI) (months) 2.33 (2.17, 3.32) 4.21 (3.45, 4.86) 
 Rate (95% CI) at 12 months 18.5 (14.1, 23.4) 8.1 (5.1, 12.0) 

Updated analysis 
Minimum follow-up: 24.2 months 

Overall survivalc   
 Events 228 (78.1%) 247 (85.1%) 
  Hazard ratioa 0.75 
  (95% CI) (0.63, 0.91) 
 Rate (95% CI) at 24 months 28.7 (23.6, 34.0) 15.8 (11.9, 20.3) 
   
Confirmed objective response 19.2% 12.4% 
  (95% CI) (14.8, 24.2) (8.8, 16.8) 
   
Median duration of response   
 Months (range) 17.2 (1.8-33.7+) 5.6 (1.2+-16.8) 
   
Progression-free survival   
 Rate (95% CI) at 24 months 11.9 (8.3, 16.2) 1.0 (0.2, 3.3) 

Updated analysis 
Minimum follow-up: 62.7 months 

Overall survivald   
 Events 250 (85.6%) 279 (96.2%) 

Hazard ratioa 0.70 
(95% CI) (0.58, 0.83) 

 Rate (95% CI) at 60 months 14.0 (10.2, 18.3) 2.1 (0.9, 4.4) 
  
Confirmed objective response 19.5% 12.4% 

(95% CI) (15.1, 24.5) (8.8, 16.8) 
  
Median duration of response   
 Months (range) 17.2 (1.8-70.4+) 5.6 (0.0+-33.4) 
   
Progression-free survival   
 Rate (95% CI) at 60 months 7.5 (4.5, 11.4) All patients had either progressed, 

were censored, or lost to follow-up 
a Derived from a stratified proportional hazards model. 
b P-value is derived from a log-rank test stratified by prior maintenance therapy and line of therapy; the 

corresponding O’Brien-Fleming efficacy boundary significance level is 0.0408. 
c Sixteen patients (6%) randomised to docetaxel crossed over at any time to receive nivolumab treatment. 
d Seventeen patients (6%) randomised to docetaxel crossed over at any time to receive nivolumab 

treatment. 
“+” Denotes a censored observation. 
 
Quantifiable tumour PD-L1 expression was measured in 79% of patients in the nivolumab group and 
77% of patients in the docetaxel group. Tumour PD-L1 expression levels were balanced between the 
two treatment groups (nivolumab vs. docetaxel) at each of the predefined tumour PD-L1 expression 
levels of ≥ 1% (53% vs. 55%), ≥ 5% (41% vs. 38%), or ≥ 10% (37% vs. 35%). 
 



56 

Patients with tumour PD-L1 expression by all predefined expression levels in the nivolumab group 
demonstrated greater likelihood of improved survival compared to docetaxel, whereas survival was 
similar to docetaxel in patients with low or no tumour PD-L1 expression. In terms of ORR, increasing 
PD-L1 expression was associated with larger ORR. Comparable to the overall population, median 
duration of response was increased with nivolumab vs. docetaxel for patients with no PD-L1 
expression (18.3 months vs. 5.6 months) and for patients with PD-L1 expression (16.0 months vs. 
5.6 months). 
 
Table 19 summarises results of ORR and OS by tumour PD-L1 expression. 
 
Table 19: ORR and OS by tumour PD-L1 expression (CA209057) 

PD-L1 expression nivolumab docetaxel  

ORR by tumour PD-L1 expression 
Minimum follow-up: 13.2 months 

   Odds ratio (95% CI) 

< 1% 10/108 (9.3%) 
95% CI: 4.5, 16.4 

15/101 (14.9%) 
95% CI: 8.6, 23.3 

0.59 (0.22, 1.48) 

≥ 1% 38/123 (30.9%) 
95% CI: 22.9, 39.9 

15/123 (12.2%) 
95% CI: 7.0, 19.3 

3.22 (1.60, 6.71) 

≥ 1% to < 10%a 6/37 (16.2%) 
95% CI: 6.2, 32.0 

5/44 (11.4%) 
95% CI: 3.8, 24.6 

1.51 (0.35, 6.85) 

≥ 10% to < 50%a 5/20 (25.0%) 
95% CI: 8.7, 49.1 

7/33 (21.2%) 
95% CI: 9.0, 38.9 

1.24 (0.26, 5.48) 

≥ 50%a 27/66 (40.9%) 
95% CI: 29.0, 53.7 

3/46 (6.5%) 
95% CI: 1.4, 17.9 

9.92 (2.68, 54.09) 

OS by tumour PD-L1 expression 
Minimum follow-up: 13.2 months 

 Number of events (number of patients) Unstratified hazard 
ratio (95% CI) 

< 1% 77 (108) 75 (101) 0.90 (0.66, 1.24) 

≥ 1% 68 (123) 93 (123) 0.59 (0.43, 0.82) 

≥ 1% to < 10%a 27 (37) 30 (44) 1.33 (0.79, 2.24) 

≥ 10% to < 50%a 11 (20) 26 (33) 0.61 (0.30, 1.23) 

≥ 50%a 30 (66) 37 (46) 0.32 (0.20, 0.53) 
  

Updated analysis  
Minimum follow-up: 24.2 months

< 1% 91 (108) 86 (101) 0.91 (0.67, 1.22) 

≥ 1% 87 (123) 103 (123) 0.62 (0.47, 0.83) 

    

Updated analysis 
Minimum follow-up: 62.7 months 

< 1% 100 (109) 96 (101) 0.87 (0.66, 1.16) 

≥1% 96 (122) 119 (123) 0.55 (0.42, 0.73) 
a Post-hoc analysis; results should be interpreted with caution as the subgroup samples sizes are small and, at 

the time of the analysis, the PD-L1 IHC 28-8 pharmDx assay was not analytically validated at the 10% or 50% 
expression levels. 

 



57 

A higher proportion of patients experienced death within the first 3 months in the nivolumab arm 
(59/292, 20.2%) as compared to the docetaxel arm (44/290, 15.2%). Results of a post-hoc, exploratory 
multivariate analysis indicated that nivolumab-treated patients with poorer prognostic features and/or 
aggressive disease when combined with lower (e.g., < 50%) or no tumour PD-L1 expression may be at 
higher risk of death within the first 3 months. 
 
In subgroup analyses, survival benefit compared to docetaxel was not shown for patients who were 
never-smokers or whose tumours harboured EGFR activating mutations; however, due to the small 
numbers of patients, no definitive conclusions can be drawn from these data. 
 
Renal cell carcinoma  
 
Randomised phase 3 study of nivolumab as monotherapy vs. everolimus (CA209025) 
The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced RCC 
with a clear cell component was evaluated in a Phase 3, randomised, open-label study (CA209025). 
The study included patients (18 years or older) who have experienced disease progression during or 
after 1 or 2 prior anti-angiogenic therapy regimens and no more than 3 total prior systemic treatment 
regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥ 70%. This study included 
patients regardless of their tumour PD-L1 status. Patients with any history of or concurrent brain 
metastases, prior treatment with an mammalian target of rapamycin (mTOR) inhibitor, active 
autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded 
from the study. 
 
A total of 821 patients were randomised to receive either nivolumab 3 mg/kg (n = 410) administered 
intravenously over 60 minutes every 2 weeks or everolimus (n = 411) 10 mg daily, administered 
orally. Treatment was continued as long as clinical benefit was observed or until treatment was no 
longer tolerated. The first tumour assessments were conducted 8 weeks after randomisation and 
continued every 8 weeks thereafter for the first year and then every 12 weeks until progression or 
treatment discontinuation, whichever occurred later. Tumour assessments were continued after 
treatment discontinuation in patients who discontinued treatment for reasons other than progression. 
Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was 
permitted if the patient had a clinical benefit and was tolerating study drug as determined by the 
investigator. The primary efficacy outcome measure was OS. Secondary efficacy assessments 
included investigator-assessed ORR and PFS. 
 
Baseline characteristics were generally balanced between the two groups. The median age was 
62 years (range: 18-88) with 40% ≥ 65 years of age and 9% ≥ 75 years of age. The majority of patients 
were male (75%) and white (88%), all Memorial Sloan Kettering Cancer Center (MSKCC) risk groups 
were represented, and 34% and 66% of patients had a baseline KPS of 70 to 80% and 90 to 100%, 
respectively. The majority of patients (72%) were treated with one prior anti-angiogenic therapy. The 
median duration of time from initial diagnosis to randomisation was 2.6 years in both the nivolumab 
and everolimus groups. The median duration of treatment was 5.5 months (range: 0-29.6+ months) in 
nivolumab-treated patients and was 3.7 months (range: 6 days-25.7+ months) in everolimus-treated 
patients. 
Nivolumab was continued beyond progression in 44% of patients. 
 
The Kaplan-Meier curves for OS are shown in Figure 12. 
 



58 

Figure 12: Kaplan-Meier curves of OS (CA209025) 
 

 
Overall survival (months) 

Number of subjects at risk 
Nivolumab 

410 389 359 337 305 275 213 139 73 29 3 0 
Everolimus 

411 366 324 287 265 241 187 115 61 20 2 0 
Nivolumab 3 mg/kg (events: 183/410), median and 95% CI: 25.00 (21.75, N.A.) 
 Everolimus 10 mg (events: 215/411), median and 95% CI: 19.55 (17.64, 23.06) 

 
The trial demonstrated a statistically significant improvement in OS for patients randomised to 
nivolumab 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 12). OS 
benefit was observed regardless of tumour PD-L1 expression level. 
Efficacy results are shown in Table 20. 
 

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Table 20: Efficacy results (CA209025) 
 nivolumab 

(n = 410)
everolimus 
(n = 411) 

Overall survival    
 Events 183 (45%) 215 (52%) 

Hazard ratio  0.73
98.52% CI (0.57, 0.93) 

p-value 0.0018
    
 Median (95% CI) 25.0 (21.7, NE) 19.6 (17.6, 23.1) 
 Rate (95% CI)    
  At 6 months 89.2 (85.7, 91.8) 81.2 (77.0, 84.7) 
  At 12 months 76.0 (71.5, 79.9) 66.7 (61.8, 71.0) 
    
Objective response  103 (25.1%) 22 (5.4%) 

(95% CI) (21.0, 29.6) (3.4, 8.0) 
Odds ratio (95% CI) 5.98 (3.68, 9.72) 

p-value < 0.0001 
   

 Complete response (CR) 4 (1.0%) 2 (0.5%) 
 Partial response (PR) 99 (24.1%) 20 (4.9%) 
 Stable disease (SD) 141 (34.4%) 227 (55.2%) 
   
Median duration of response     
  Months (range) 11.99 (0.0-27.6+) 11.99 (0.0+-22.2+)
    
Median time to response   
 Months (range) 
 

3.5 (1.4-24.8) 3.7 (1.5-11.2) 

Progression-free survival   
 Events 318 (77.6%) 322 (78.3%) 

Hazard ratio  0.88 
95% CI (0.75, 1.03) 
p-value 0.1135 

 Median (95% CI) 4.6 (3.71, 5.39) 4.4 (3.71, 5.52) 
“+” denotes a censored observation. 
NE = non-estimable  
 
The median time to onset of objective response was 3.5 months (range: 1.4-24.8 months) after the start 
of nivolumab treatment. Fourty-nine (47.6%) responders had ongoing responses with a duration 
ranging from 0.0-27.6+ months. 
 
Overall survival could be accompanied by an improvement over time in disease related symptoms and 
non-disease specific QoL as assessed using valid and reliable scales in the Functional Assessment of 
Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and the EuroQoL 
EQ-5D. Apparently meaningful symptom improvement (MID = 2 point change in FKSI-DRS score; 
p < 0.001) and time to improvement (HR = 1.66 (1.33, 2.08), p < 0.001) were significantly better for 
patients on the nivolumab arm. While both arms of the study received active therapy, the QoL data 
should be interpreted in the context of the open-label study design and therefore cautiously taken. 
 
Phase 3b/4 safety study (CA209374) 
Additional safety and descriptive efficacy data are available from study CA209374, an open-label 
Phase 3b/4 safety study of nivolumab monotherapy (treated with 240 mg every 2 weeks) for the 
treatment of patients with advanced or metastatic RCC (n = 142), including 44 patients with non-clear 
cell histology.  
 



60 

In subjects with non-clear cell histology, at a minimum follow-up of approximately 16.7 months ORR 
and median duration of response were 13.6% and 10.2 months, respectively. Clinical activity was 
observed regardless of tumour PD-L1 expression status. 
 
Randomised phase 3 study of nivolumab in combination with ipilimumab vs. sunitinib (CA209214) 
The safety and efficacy of nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg for the 
treatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open-label study 
(CA209214). The study included patients (18 years or older) with previously untreated, advanced or 
metastatic renal cell carcinoma with a clear-cell component. The primary efficacy population included 
those intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the 
International Metastatic RCC Database Consortium (IMDC) criteria (less than one year from time of 
initial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status <80%, 
haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, platelet 
count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit 
of normal). This study included patients regardless of their tumour PD-L1 status. Patients with 
Karnofsky performance status < 70% and patients with any history of or concurrent brain metastases, 
active autoimmune disease, or medical conditions requiring systemic immunosuppression were 
excluded from the study. Patients were stratified by IMDC prognostic score and region. 
 
A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk 
RCC and received either nivolumab 3 mg/kg (n = 425) administered intravenously over 60 minutes in 
combination with ipilimumab 1 mg/kg administered intravenously over 30 minutes every 3 weeks for 
4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n = 422) 50 mg 
daily, administered orally for 4 weeks followed by 2 weeks off, every cycle. Treatment was continued 
as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour 
assessments were conducted 12 weeks after randomisation and continued every 6 weeks thereafter for 
the first year and then every 12 weeks until progression or treatment discontinuation, whichever 
occurred later. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined 
progression was permitted if the patient had a clinical benefit and was tolerating study drug as 
determined by the investigator. The primary efficacy outcome measures were OS, ORR and PFS as 
determined by a Blinded Independent Central Review (BICR) in intermediate/poor risk patients.  
 
Baseline characteristics were generally balanced between the two groups. The median age was 
61 years (range: 21-85) with 38% ≥ 65 years of age and 8% ≥ 75 years of age. The majority of patients 
were male (73%) and white (87%), and 31% and 69% of patients had a baseline KPS of 70 to 80% and 
90 to 100%, respectively. The median duration of time from initial diagnosis to randomisation was 
0.4 years in both the nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg and sunitinib 
groups. The median duration of treatment was 7.9 months (range: 1 day-21.4+ months) in nivolumab 
with ipilimumab-treated patients and was 7.8 months (range: 1 days-20.2+ months) in sunitinib-treated 
patients. Nivolumab with ipilimumab was continued beyond progression in 29% of patients. 
 
The Kaplan-Meier curves for OS (with a minimum follow-up of 24 months) in intermediate/poor risk 
patients are shown in Figure 13. 



61 

Figure 13: Kaplan-Meier curves of OS in intermediate/poor risk patients (CA209214) 
 

 
Overall survival (months) 

Number of subjects at risk 
Nivolumab + ipilimumab 
425 399 372 348 332 317 306 282 257 201 102 33 4 0 
Sunitinib   
422 387 352 316 288 253 233 216 196 147 87 36 3 0 
Nivolumab + ipilimumab (events: 166/425), median and 95.0% CI: NA (32.49, NA) 
 Sunitinib (events: 209/422), median and 95.0% CI: 26.97 (22.08, 34.83) 

 
In intermediate/poor-risk patients, OS benefit was observed in the nivolumab in combination with 
ipilimumab arm vs. sunitinib regardless of tumour PD-L1 expression. Median OS for tumour PD-L1 
expression ≥ 1% was not reached for nivolumab in combination with ipilimumab, and was 
19.61 months in the sunitinib arm (HR = 0.52; 95% CI: 0.34, 0.78). For tumour PD-L1 
expression < 1%, the median OS was 34.7 months for the nivolumab in combination with ipilimumab, 
and was 32.2 months in the sunitinib arm (HR = 0.70; 95% CI: 0.54, 0.92). 
 
CA209214 also randomised 249 favourable risk patients as per IMDC criteria to nivolumab plus 
ipilimumab (n = 125) or to sunitinib (n = 124). These patients were not evaluated as part of the 
primary efficacy population. OS in favourable risk patients receiving nivolumab plus ipilimumab 
compared to sunitinib had a hazard ratio of 1.13 (95% CI: 0.64, 1.99; p = 0.6710). 
 
There are no data on the use of nivolumab in combination with ipilimumab in patients with only a non 
clear-cell histology in first line RCC. 
 
Efficacy results for the intermediate/poor risk patients from the primary analysis (minimum follow-up 
17.5 months) are shown in Table 21. 
 

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Table 21: Efficacy results in intermediate/poor risk patients (CA209214) 
 nivolumab + ipilimumab 

(n = 425)
sunitinib 
(n = 422) 

Overall survival   
 Events 140 (33%) 188 (45%) 

Hazard ratioa  0.63
99.8% CI (0.44, 0.89) 
p-valueb, c < 0.0001

 
 Median (95% CI) NE (28.2, NE) 25.9 (22.1, NE) 
 Rate (95% CI)   
  At 6 months 89.5 (86.1, 92.1) 86.2 (82.4, 89.1)
  At 12 months 80.1 (75.9, 83.6) 72.1 (67.4, 76.2) 
Progression-free survival   
 Events 228 (53.6%) 228 (54.0%) 

Hazard ratioa 0.82 
99.1% CI (0.64, 1.05) 
p-valueb,h 0.0331

 Median (95% CI) 
 

11.6 (8.71, 15.51) 8.4 (7.03, 10.81) 

Confirmed objective response 
(BICR)  

177 (41.6%) 112 (26.5%) 

(95% CI) (36.9, 46.5) (22.4, 31.0) 
Difference in ORR (95% CI)d 16.0 (9.8, 22.2)

p-valuee,f < 0.0001 

 Complete response (CR) 40 (9.4%) 5 (1.2%) 
 Partial response (PR) 137 (32.2%) 107 (25.4%) 
 Stable disease (SD) 133 (31.3%) 188 (44.5%) 
 
Median duration of responseg    
  Months (range) NE (1.4+-25.5+) 18.17 (1.3+-23.6+) 
 
Median time to response   
 Months (range) 2.8 (0.9-11.3) 3.0 (0.6-15.0) 

a Based on a stratified proportional hazards model. 
b Based on a stratified log-rank test. 
c p-value is compared to alpha 0.002 in order to achieve statistical significance. 
d Strata adjusted difference. 
e Based on the stratified DerSimonian-Laird test. 
f p-value is compared to alpha 0.001 in order to achieve statistical significance. 
g Computed using Kaplan-Meier method. 
h p-value is compared to alpha 0.009 in order to achieve statistical significance. 
“+” denotes a censored observation. 
NE = non-estimable  
 
An updated OS analysis was performed when all patients had a minimum follow-up of 24 months (see 
figure 13). At the time of this analysis, the hazard ratio was 0.66; (99.8% CI 0.48-0.91) with 166/425 
events in the combination arm and 209/422 events in the sunitinib arm. At 18 months, the OS rate was 
74.3 (95% CI 69.8-78.2) for nivolumab in combination with ipilimumab and 59.9 (95% CI 54.9-64.5) 
for sunitinib. At 24 months, the OS rate was 66.5 (95% CI 61.8-70.9) for nivolumab in combination 
with ipilimumab and 52.9 (95% CI 47.9-57.7) for sunitinib. 
 
Patients ≥ 75 years of age represented 8% of all intermediate/poor risk patients in CA209214, and the 
combination of nivolumab and ipilimumab showed numerically less effect on OS (HR 0.97, 95% CI: 
0.48, 1.95) in this subgroup versus the overall population. Because of the small size of this subgroup, 
no definitive conclusions can be drawn from these data. 



63 

 
Classical Hodgkin lymphoma 
 
The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of relapsed or 
refractory cHL following ASCT was evaluated in two multi-centre, open-label, single-arm studies 
(CA209205 and CA209039). 
 
CA209205 is an ongoing Phase 2, open-label, multi-cohort, single-arm study of nivolumab in cHL. It 
includes 243 patients who had ASCT; Cohort A included 63 (26%) patients who were brentuximab 
vedotin naïve; Cohort B included 80 (33%) patients who had received brentuximab vedotin after 
ASCT failure; and Cohort C included 100 (41%) patients who had received brentuximab vedotin 
before and/or after ASCT out of which 33 (14%) patients received brentuximab vedotin only prior to 
ASCT. All patients received nivolumab 3 mg/kg monotherapy intravenously over 60 minutes every 
2 weeks. The first tumour assessments were conducted 9 weeks after the start of treatment and 
continued thereafter until disease progression or treatment discontinuation. The primary efficacy 
outcome measure was ORR as determined by an IRRC. Additional efficacy measures included 
duration of response, PFS and OS. 
 
CA209039 is a Phase 1b open-label, multi-centre, dose-escalation, and multidose study of nivolumab 
in relapsed/refractory hematologic malignancies, including 23 patients with cHL treated with 
nivolumab 3 mg/kg monotherapy; amongst which, 15 patients received prior brentuximab vedotin 
treatment as a salvage therapy following ASCT, similar to Cohort B of study CA209205. The first 
tumour assessments were conducted 4 weeks after the start of treatment and continued thereafter until 
disease progression or treatment discontinuation. Efficacy assessments included investigator-assessed 
ORR, retrospectively evaluated by an IRRC, and duration of response.  
 
Data from the 80 patients from CA209205 Cohort B and from the 15 patients from CA209039 who 
received prior brentuximab vedotin treatment following ASCT were integrated. Additional data from 
100 patients from CA209205 Cohort C who received brentuximab before and/or after ASCT are also 
presented. Baseline characteristics were similar across the two studies and cohorts (see Table 22 
below). 
 
Table 22: Baseline patient characteristics in CA209205 Cohort B, Cohort C and CA209039 

 CA209205 
Cohort B and 

CA209039 

CA209205 
Cohort Ba 

CA209039 CA209205 
Cohort Cb 

 (n = 95) (n = 80) (n = 15) (n = 100) 
Median age, years (range) 37.0 (18–72) 37.0 (18–72) 40.0 (24–54) 32.0 (19-69) 
Gender 61 (64%) M 

34 (36%) F
51 (64%) M 
29 (36%) F

10 (67%) M 
5 (33%) F

56 (56%) M 
44 (44%) F

ECOG status     
 0 49 (52%) 42 (52.5%) 7 (47%) 50 (50%) 
 1 46 (48%) 38 (47.5%) 8 (53%) 50 (50%) 
≥ 5 prior lines of systemic 
therapy 

49 (52%) 39 (49%) 10 (67%) 30 (30%) 

Prior radiation therapy 72 (76%) 59 (74%) 13 (87%) 69 (69%) 
Prior ASCT     
 1 87 (92%) 74 (92.5%) 13 (87%) 100 (100%) 
 ≥ 2 8 (8%) 6 (7.5%) 2 (13%) 0 (0%) 
Years from most recent 
transplant to first dose of 
study therapy, median 
(min-max) 

3.5 (0.2–19.0) 3.4 (0.2–19.0) 5.6 (0.5–15.0) 1.7 (0.2-17.0) 

a 18/80 (22.5%) of the patients in CA209205 Cohort B presented B-Symptoms at baseline. 
b 25/100 (25%) of the patients in CA209205 Cohort C presented B-Symptoms at baseline. 
 



64 

Efficacy from both studies was evaluated by the same IRRC. Results are shown in Table 23. 
 

Table 23: Efficacy results in patients with relapsed/refractory classical Hodgkin lymphoma 
 CA209205 Cohort Ba

and CA209039 
CA209205 Cohort Ba CA209039 

Number (n)/ minimum follow-up (months) (n = 95/12.0) (n = 80/12.0) (n = 15/12.0) 
Objective response, n (%); (95% CI) 63 (66%); (56, 76) 54 (68%); (56, 78) 9 (60%); (32, 84)
 Complete remission (CR), n (%); (95% CI) 6 (6%); (2, 13) 6 (8%); (3, 16) 0 (0%); (0, 22) 
 Partial remission (PR), n (%); (95% CI) 57 (60%); (49, 70) 48 (60%); (48, 71) 9 (60%); (32, 84)

Stable disease, n (%) 22 (23) 17 (21) 5 (33) 

Duration of response (months)b    
 Median (95% CI) 13.1 (9.5, NE) 13.1 (8.7, NE) 12.0 (1.8, NE) 
 Range 0.0+-23.1+ 0.0+-14.2+ 1.8-23.1+ 

Median time to response     
 Months (range) 2.0 (0.7-11.1) 2.1 (1.6-11.1) 0.8 (0.7-4.1) 

Median duration of follow-up   
 Months (range) 15.8 (1.9-27.6) 15.4 (1.9-18.5) 21.9 (11.2-27.6)

Progression-free survival       
 Rate (95% CI) at 12 months 57 (45, 68) 55 (41, 66) 69 (37, 88) 
“+” denotes a censored observation. 
a Follow-up was ongoing at the time of data submission.  
b Data unstable due to the limited duration of response for Cohort B resulting from censoring. 
NE = non-estimable  
 
Longer follow-up data from Cohort B (minimum 20.5 months) and efficacy of Cohort C from 
CA209205 are presented below in Table 24. 
 



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Table 24:  Updated efficacy results in patients with relapsed/refractory classical Hodgkin 
lymphoma from longer follow up of study CA209205 

 CA209205 Cohort Ba CA209205 Cohort Ca 

Number (n)/ minimum follow-up (months) (n = 80/20.5) (n = 100/13.7)b 
Objective response, n (%); (95% CI) 54 (68%); (56, 78) 73 (73%); (63, 81) 
 Complete remission (CR), n (%); (95% CI) 10 (13%); (6, 22) 12 (12%); (6, 20) 
 Partial remission (PR), n (%); (95% CI) 44 (55%); (44, 66) 61 (61%); (51, 71) 

Stable disease, n (%) 17 (21) 15 (15%) 

Duration of response in all responders 
(months)c 

  

 Median (95% CI) 15.9 (7.8, 20.3) 14.5 (9.5, 16.6) 
 Range 0.0+-21.0+ (0.0+, 16.8+) 

Duration of response in CR (months)    
 Median (95% CI) 20.3 (3.8, NE) 14.5 (8.2, NE) 
 Range 1.6+-21.0+ (0.0+, 16.5+) 

Duration of response in PR (months)    
 Median (95% CI) 10.6 (6.8, 18.0) 13.2 (9.4, 16.6) 
 Range 0.0+-20.7+ (0.0+, 16.8+) 

Median time to response  
 Months (range) 2.2 (1.6-9.1) 2.1 (0.8, 8.6) 

Median duration of follow-up   
 Months (range) 22.7 (1.9-27.2) 16.2 (1.4, 20.4) 

Progression-free survival   
 Rate (95% CI) at 12 months 51 (38, 62) 49 (37, 60) 
 Rate (95% CI) at 18 months 47 (35, 59) – 

Overall survival   
 Median  Not reached Not reached 
 Rate (95% CI) at 12 months 95 (87, 98) 90 (82, 94) 
 Rate (95% CI) at 18 months 91 (82, 96) – 

“+” denotes a censored observation. 
a Follow-up was ongoing at the time of data submission.  
b Patients in Cohort C (n = 33) who have received brentuximab vedotin only prior to ASCT had ORR of 

70% (95% CI: 51, 84), CR of 15% (95% CI: 5, 32), PR of 55% (95% CI: 36, 72). Median duration of 
response was 13.2 months (95% CI: 8.2, NE) 

c Determined for subjects with CR or PR 
NE = non-estimable 
 
B-symptoms were present in 22% (53/243) of the patients in CA209205 at baseline. Nivolumab 
treatment resulted in rapid resolution of B-symptoms in 88.7% (47/53) of the patients, with a median 
time to resolution of 1.9 months. 
 
In a post-hoc analysis of the 80 patients in CA209205 Cohort B, 37 had no response to prior 
brentuximab vedotin treatment. Among these 37 patients, treatment with nivolumab resulted in an 
ORR of 59.5% (22/37). The median duration of response is 18.0 months (6.6, NE) for the 
22 responders to nivolumab who had failed to achieve response with prior brentuximab vedotin 
treatment. 
 
Squamous cell cancer of the head and neck 
 
The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of metastatic or 
recurrent SCCHN were evaluated in a phase 3, randomised, open-label study (CA209141). The study 
included patients (18 years or older), with histologically confirmed recurrent or metastatic SCCHN 



66 

(oral cavity, pharynx, larynx), stage III/IV and not amenable to local therapy with curative intent 
(surgery or radiation therapy with or without chemotherapy) and who have experienced disease 
progression during or within 6 months of receiving platinum-based therapy regimen and had an ECOG 
performance status score of 0 or 1. Prior platinum-based therapy was administered in either the 
adjuvant, neo-adjuvant, primary, recurrent, or metastatic setting. Patients were enrolled regardless of 
their tumour PD-L1 or human papilloma virus (HPV) status. Patients with active autoimmune disease, 
medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the 
nasopharynx, squamous cell carcinoma of unknown primary, salivary gland or non-squamous 
histologies (e.g., mucosal melanoma), or active brain or leptomeningeal metastases 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 361 patients were randomised to receive either nivolumab 3 mg/kg (n = 240) administered 
intravenously over 60 minutes every 2 weeks or investigator’s choice of either cetuximab (n = 15), 
400 mg/m2 loading dose followed by 250 mg/m2 weekly or methotrexate (n = 52) 40 to 60 mg/m2 
weekly, or docetaxel (n = 54) 30 to 40 mg/m2 weekly. Randomisation was stratified by prior 
cetuximab treatment. Treatment was continued as long as clinical benefit was observed or until 
treatment was no longer tolerated. Tumour assessments, according to RECIST version 1.1, were 
conducted 9 weeks after randomisation and continued every 6 weeks thereafter. Treatment beyond 
initial investigator-assessed RECIST version 1.1-defined progression was permitted in patients 
receiving nivolumab, if the patient had a clinical benefit and was tolerating study drug, as determined 
by the investigator. The primary efficacy outcome measure was OS. Key secondary efficacy outcome 
measures were investigator-assessed PFS and ORR. Additional prespecified subgroup analyses were 
conducted to evaluate the efficacy by tumour PD-L1 expression at predefined levels of 1%, 5%, and 
10%. 
 
Pre-study tumour tissue specimens were systematically collected prior to randomisation in order to 
conduct pre-planned analyses of efficacy according to tumour PD-L1 expression. Tumour PD-L1 
expression was determined using the PD-L1 IHC 28-8 pharmDx assay. 
 
Baseline characteristics were generally balanced between the two groups. The median age 
was 60 years (range: 28-83) with 31% ≥ 65 years of age and 5% ≥ 75 years of age, 83% were male, 
and 83% were white. Baseline ECOG performance status score was 0 (20%) or 1 (78%), 77% were 
former/current smokers, 90% had Stage IV disease, 66% had two or more lesions, 45%, 34% and 20% 
received 1, 2, or 3 or more prior lines of systemic therapy, respectively, and 25% were HPV-16 status 
positive. 
 
With a minimum follow-up of 11.4 months, the trial demonstrated a statistically significant 
improvement in OS for patients randomised to nivolumab as compared with investigator’s choice. The 
Kaplan-Meier curves for OS are shown in Figure 14. Efficacy results are shown in Table 25. 
 



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Figure 14: Kaplan-Meier curves of OS (CA209141)  
 

 
Overall survival (months) 

Number of subjects at risk 
Nivolumab 

240 169 132 98 76 45 27 12 3 
Investigator’s choice 

121 88 51 32 22 9 4 3 0 
 

Nivolumab 3 mg/kg (events: 184/240), median and 95% CI: 7.72 (5.68, 8.77) 
Investigator’s choice (events: 105/121), median and 95% CI: 5.06 (4.04, 6.24) 

 

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Table 25: Efficacy results (CA209141) 
 nivolumab 

(n = 240)
investigator’s choice 

(n = 121) 
Overall survival  
 Events 184 (76.7%) 105 (86.8%) 
  Hazard ratioa 0.71
  (95% CI) (0.55, 0.90) 
  p-valueb 0.0048
 Median (95% CI) (months) 7.72 (5.68, 8.77) 5.06 (4.04, 6.24) 

 Rate (95% CI) at 6 months 56.5 (49.9, 62.5) 43.0 (34.0, 51.7) 

 Rate (95% CI) at 12 months 34.0 (28.0, 40.1) 19.7 (13.0, 27.3) 

 Rate (95% CI) at 18 months 21.5 (16.2, 27.4) 8.3 (3.6, 15.7) 

Progression-free survival  
 Events 204 (85.0%) 104 (86.0%) 
  Hazard ratio 0.87 
  95% CI (0.69, 1.11) 
  p-value 0.2597 

 Median (95% CI) (months) 2.04 (1.91, 2.14) 2.33 (1.97, 3.12) 

 Rate (95% CI) at 6 months 21.0 (15.9, 26.6) 11.1 (5.9, 18.3) 

 Rate (95% CI) at 12 months 9.5 (6.0, 13.9) 2.5 (0.5, 7.8) 

Confirmed objective responsec 32 (13.3%) 7 (5.8%) 
  (95% CI) (9.3, 18.3) (2.4, 11.6) 
  Odds ratio (95% CI) 2.49 (1.07, 5.82)

 Complete response (CR) 6 (2.5%) 1 (0.8%) 
 Partial response (PR) 26 (10.8%) 6 (5.0%) 
 Stable disease (SD) 55 (22.9%) 43 (35.5%) 

Median time to response   
 Months (range) 2.1 (1.8-7.4) 2.0 (1.9-4.6) 
Median duration of response   
 Months (range) 9.7 (2.8-20.3+) 4.0 (1.5+-8.5+) 

a Derived from a stratified proportional hazards model. 
b P-value is derived from a log-rank test stratified by prior cetuximab; the corresponding O’Brien-Fleming 

efficacy boundary significance level is 0.0227. 
c In the nivolumab group there were two patients with CRs and seven patients with PRs who had tumour 

PD-L1 expression < 1%. 
 
Quantifiable tumour PD-L1 expression was measured in 67% of patients in the nivolumab group and 
82% of patients in the investigator’s choice group. Tumour PD-L1 expression levels were balanced 
between the two treatment groups (nivolumab vs. investigator’s choice) at each of the predefined 
tumour PD-L1 expression levels of ≥ 1% (55% vs. 62%), ≥ 5% (34% vs. 43%), or ≥ 10% (27% vs. 
34%). 
 
Patients with tumour PD-L1 expression by all predefined expression levels in the nivolumab group 
demonstrated greater likelihood of improved survival compared to investigator’s choice. The 
magnitude of OS benefit was consistent for ≥ 1%, ≥ 5% or ≥ 10% tumour PD-L1 expression levels 
(see Table 26). 
 



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Table 26: OS by tumour PD-L1 expression (CA209141) 
PD-L1 Expression nivolumab investigator’s choice  

OS by tumour PD-L1 expression 
 Number of events (number of patients) Unstratified hazard 

ratio (95% CI) 

< 1% 56 (73) 32 (38) 0.83 (0.54, 1.29) 

≥ 1% 66 (88) 55 (61) 0.53 (0.37, 0.77) 

≥ 5%  39 (54) 40 (43) 0.51 (0.32, 0.80) 

≥ 10% 30 (43) 31 (34) 0.57 (0.34, 0.95) 
 
In an exploratory post-hoc analysis using a non-validated assay, both tumour cell PD-L1 expression 
and tumour-associated immune cell (TAIC) PD-L1 expression were analysed in relation to the 
magnitude of treatment effect of nivolumab compared to investigator’s choice. This analysis showed 
that not only tumour cell PD-L1 expression but also TAIC PD-L1 expression appeared to be 
associated with benefit from nivolumab relative to investigator’s choice (see Table 27). Due to the 
small numbers of patients in the subgroups, and exploratory nature of the analysis, no definitive 
conclusions can be drawn from these data. 
 
Table 27: Efficacy by tumour cell and TAIC PD-L1 expression (CA209141) 

 Median OSa (months) Median PFSa (months) ORR (%) 

 HRb (95% CI) HRb (95% CI) (95% CI)c 

 nivolumab investigator’s 
choice 

nivolumab investigator’s 
choice 

nivolumab investigator’s 
choice 

PD-L1 ≥ 1%, 
PD-L1+ TAIC 
abundantd 
(61 nivolumab, 
47 investigator’s choice) 

9.10 4.60 3.19 1.97 19.7 0 

0.43 (0.28, 0.67) 0.48 (0.31, 0.75) (10.6, 31.8) (0, 7.5) 

PD-L1 ≥ 1%, 
PD-L1+ TAIC rared 
(27 nivolumab, 
14 investigator’s choice) 

6.67 4.93 1.99 2.04 11.1 7.1 

0.89 (0.44, 1.80) 0.93 (0.46, 1.88) (2.4, 29.2) (0.2, 33.9) 

PD-L1 < 1%, 
PD-L1+ TAIC 
abundantd 
(43 nivolumab, 
25 investigator’s choice) 

11.73 6.51 2.10 2.73 18.6  12.0 

0.67 (0.38, 1.18) 0.96 (0.55, 1.67) (8.4, 33.4) (2.5, 31.2) 

PD-L1 < 1%, 
PD-L1+ TAIC rared 
(27 nivolumab, 
10 investigator’s choice) 

3.71 4.85 1.84 2.12 3.7 10.0 

1.09 (0.50, 2.36) 1.91 (0.84, 4.36) (< 0.1, 19.0) (0.3, 44.5) 

a OS and PFS were estimated using Kaplan-Meier method. 
b Hazard ratio in each subgroup derived from a Cox proportional hazards model with treatment as the only 

covariate. 
c Confidence interval for ORR calculated using the Clopper-Pearson method. 
d PD-L1+ TAIC in the tumour microenvironment were qualitatively assessed, and characterised as 

“numerous”, “intermediate”, and “rare” based on pathologist assessments. “Numerous” and 
“intermediate” groups were combined to define the “abundant” group. 

 
Patients with investigator-assessed primary site of oropharyngeal cancer were tested for HPV 
(determined by p16 immunohistochemistry [IHC]). OS benefit was observed regardless of HPV status 
(HPV-positive: HR = 0.63; 95% CI: 0.38, 1.04, HPV-negative: HR = 0.64; 95% CI: 0.40, 1.03, and 
HPV-unknown: HR = 0.78; 95% CI: 0.55, 1.10). 
 



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Patient-reported outcomes (PROs) were assessed using the EORTC QLQ-C30, EORTC QLQ-H&N35, 
and 3-level EQ-5D. Over 15 weeks of follow-up, patients treated with nivolumab exhibited stable 
PROs, while those assigned to investigator’s choice therapy exhibited significant declines in 
functioning (e.g., physical, role, social) and health status as well as increased symptomatology (e.g., 
fatigue, dyspnoea, appetite loss, pain, sensory problems, social contact problems). The PRO data 
should be interpreted in the context of the open-label study design and therefore taken cautiously. 
 
Urothelial carcinoma 
 
Open-label phase 2 study (CA209275) 
The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of patients with 
locally advanced or metastatic urothelial carcinoma was evaluated in a phase 2, multicentre, 
open-label, single-arm study (CA209275). 
The study included patients (18 years or older) who had disease progression during or following 
platinum-containing chemotherapy for advanced or metastatic disease or had disease progression 
within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 
Patients had an ECOG performance status score of 0 or 1 and were enrolled regardless of their tumour 
PD-L1 status. Patients with active brain metastases or leptomeningeal metastases, active autoimmune 
disease, or medical conditions requiring systemic immunosuppression were excluded from the study. 
Patients that received more than 2 prior lines of chemotherapy with liver metastases were excluded. 
 
A total of 270 patients who received nivolumab 3 mg/kg administered intravenously over 60 minutes 
every 2 weeks with a minimum follow-up of 8.3 months were evaluable for efficacy. Treatment was 
continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first 
tumour assessments were conducted 8 weeks after the start of treatment and continued every 8 weeks 
thereafter up to 48 weeks, then every 12 weeks until disease progression or treatment discontinuation, 
whichever occurred later. Tumour assessments were continued after treatment discontinuation in 
patients who discontinued treatment for reasons other than progression. Treatment beyond initial 
investigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had a 
clinical benefit, did not have rapid disease progression, and was tolerating study drug as determined by 
the investigator. The primary efficacy outcome measure was ORR as determined by BICR. Additional 
efficacy measures included duration of response, PFS and OS. 
 
The median age was 66 years (range: 38 to 90) with 55% ≥65 years of age and 14% ≥75 years of age. 
The majority of patients were white (86%) and male (78%). Baseline ECOG performance status was 
0 (54%) or 1 (46%). 
 



71 

Table 28:  Efficacy results (CA209275)a 
 nivolumab 

(n = 270) 

Confirmed objective response 54 (20.0%) 
  (95% CI) (15.4, 25.3) 
 Complete response (CR) 8 (3.0%) 
 Partial response (PR) 46 (17.0%) 
 Stable disease (SD) 60 (22.2%) 

Median duration of responseb  
 Months (range) 10.4 (1.9+-12.0+) 

Median time to response  
 Months (range) 1.9 (1.6, 7.2) 

Progression-free survival  
 Events (%) 216 (80%) 
 Median (95% CI) months 2.0 (1.9, 2.6) 
 Rate (95% CI) at 6 months 26.1 (20.9, 31.5) 

Overall survivalc  
 Events (%) 154 (57%) 
 Median (95% CI) months 8.6 (6.05, 11.27) 
 Rate (95% CI) at 12 months 41.0 (34.8, 47.1) 

Tumour PD-L1 expression level 
 < 1% ≥ 1% 

Confirmed objective response 
(95% CI) 

 16% (10.3, 22.7) 
n = 146 

25% (17.7, 33.6) 
n = 124 

Median duration of response 
Months (range) 

 10.4 (3.7, 12.0+) Not Reached (1.9+, 12.0+) 

Progression-free survival 

 Median (95% CI) months 1.9 (1.8, 2.0) 3.6 (1.9, 3.7) 

 Rate (95% CI) at 6 months 22.0 (15.6, 29.2) 30.8 (22.7, 39.3) 

Overall survival   

 Median (95% CI) months 5.9 (4.37, 8.08) 11.6 (9.10, NE) 

 Rate (95% CI) at 12 months 34.0 (26.1, 42.1) 49.2 (39.6, 58.1) 

“+” denotes a censored observation. 
a median follow-up 11.5 months. 
b Data unstable due to the limited duration of response. 
c included 4 drug-related deaths: 1 pneumonitis, 1 acute respiratory failure, 1 respiratory failure, and 

1 cardiovascular failure. 
NE: non-estimable 
 
Results from post-hoc, exploratory analyses indicate that in patients with low (e.g. <1%) to no tumour 
PD-L1 expression, other patient characteristics (e.g. liver metastases, visceral metastases, baseline 
haemoglobin <10g/dL and ECOG performance status = 1) might contribute to the clinical outcome. 
 
Open-label phase 1/2 study (CA209032) 
CA209032 was a Phase 1/2 open-label multi-cohort study which included a cohort of 78 patients 
(including 18 subjects who received planned crossover treatment with nivolumab 3 mg/kg plus 



72 

ipilimumab 1 mg/kg combination) with similar inclusion criteria to study CA209275 treated with 
nivolumab monotherapy 3 mg/kg for urothelial carcinoma. At a minimum follow-up of 9 months, 
investigator-assessed confirmed ORR was 24.4% (95% CI: 15.3, 35.4). The median duration of 
response was not reached (range: 4.4-16.6+ months). The median OS was 9.7 months (95% CI:7.26, 
16.16) and the estimated OS rates were 69.2% (CI: 57.7, 78.2) at 6 months and 45.6% (CI: 34.2, 56.3) 
at 12 months. 
 
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 SCCHN and adjuvant melanoma patients 75 years of age or older are 
too limited to draw conclusions on this population. Data from cHL patients 65 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, 
malignant neoplasms of lymphoid tissue and malignant neoplasms of the central nervous system (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Nivolumab monotherapy 
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 7.9 mL/h, 25.0 days, and 86.6 μg/mL, respectively, based on a population PK 
analysis. 
 
Nivolumab CL in cHL patients was approximately 32% lower relative to NSCLC. Nivolumab baseline 
CL in adjuvant melanoma patients was approximately 40% lower and steady state CL approximately 
20 % lower relative to advanced melanoma. With available safety data, these decreases in CL were not 
clinically meaningful. 
 
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. 
 
Nivolumab in combination with ipilimumab  
When nivolumab 1 mg/kg was administered in combination with ipilimumab 3 mg/kg, the CL of 
nivolumab was increased by 29% and the CL of ipilimumab was increased by 9%, which was not 
considered clinically relevant. When nivolumab 3 mg/kg was administered in combination with 
ipilimumab 1 mg/kg, the CL of nivolumab was increased by 1% and the CL of ipilimumab was 
decreased by 1.5%, which were not considered clinically relevant.  
 
When administered in combination with ipilimumab, the CL of nivolumab increased by 20% in the 
presence of anti-nivolumab antibodies and the CL of ipilimumab increased by 5.7% in the presence of 
anti-ipilimumab antibodies. These changes were not considered clinically relevant. 
 
Nivolumab in combination with ipilimumab and chemotherapy 
When nivolumab 360 mg every 3 weeks was administered in combination with ipilimumab 1 mg/kg 
every 6 weeks and with 2 cycles of chemotherapy, the CL of nivolumab decreased approximately 10% 
and the CL of ipilimumab increased approximately 22%, which were not considered clinically 
relevant.  
 
Special populations 
 
A population PK analysis suggested no difference in CL of nivolumab based on age, gender, race, 
solid tumour type, tumour size, and hepatic impairment. Although ECOG status, baseline glomerular 



73 

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 (E433) 
Sodium hydroxide (for pH adjustment) 
Hydrochloric acid (for pH adjustment) 
Water for injections 
 



74 

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 
3 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 
Chemical and physical in-use stability from the time of preparation has been demonstrated as follows 
(times are inclusive of the administration period): 
 

Infusion preparation 
In-use stability 

Storage at 2ºC to 8ºC 
protected from light 

Storage at room temperature 
(≤ 25°C) and room light 

Undiluted or diluted with sodium 
chloride 9 mg/mL (0.9%) solution 
for injection 

30 days 24 hours (of total 30 days storage) 

Diluted with 50 mg/mL (5%) 
glucose solution for injection 24 hours 

8 hours 
(of total 24 hours storage) 

 
From a microbiological point of view the prepared solution for infusion, regardless of the diluent, 
should be used immediately. If not used immediately, in-use storage times and conditions prior to use 
are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C or 
8 hours (of the total 24 hours of storage) at room temperature (≤ 25°C), unless infusion preparation has 
taken place in controlled and validated aseptic conditions. 
 
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. 
The unopened vial can be stored at controlled room temperature up to 25°C with room light for up to 
48 hours. 
 
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. 
24 mL of concentrate in a 25 mL vial (Type I glass) with a stopper (coated butyl rubber) and a red 
matte flip-off seal (aluminium). Pack size of 1 vial. 
 
Not all pack sizes may be marketed. 
 



75 

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 
 
More than one vial of OPDIVO concentrate may be needed to give the total dose for the patient. 
 
Nivolumab monotherapy 
The prescribed dose for the patient is 240 mg or 480 mg given regardless of body weight depending on 
indication (see section 4.2). 
 
Nivolumab in combination with ipilimumab 
The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the total 
dose to be given.  

 
 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).  
 
Nivolumab in combination with ipilimumab and chemotherapy 
The prescribed dose for the patient is 360 mg given regardless of body weight. 
 
Preparing the infusion 
Take care to ensure aseptic handling when you prepare the infusion. 
 
OPDIVO can be used for intravenous administration either: 
 without dilution, after transfer to an infusion container using an appropriate sterile syringe; or 
 after diluting according to the following instructions: 
 the final infusion concentration should range between 1 and 10 mg/mL. 
 the total volume of infusion must not exceed 160 mL. For patients weighing less than 40 kg, 

the total volume of infusion must not exceed 4 mL per kilogram of patient weight.  
 
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. Discard the vial if 
the solution is cloudy, is discoloured, or contains particulate matter other than a few 
translucent-to-white 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. For ease of preparation, the concentrate 
can also be transferred directly into a pre-filled bag containing the appropriate 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. 
 



76 

Administration 
OPDIVO infusion must not be administered as an intravenous push or bolus injection. 
Administer the OPDIVO infusion intravenously over a period of 30 or 60 minutes depending on the 
dose. 
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 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1014/001 
EU/1/15/1014/002 
EU/1/15/1014/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 June 2015 
Date of latest renewal: 23 April 2020 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  



77 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 



78 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers of the biological active substance 
 
Bristol-Myers Squibb Company 
6000 Thompson Road 
East Syracuse, New York 13057 
USA 
 
Lonza Biologics, Inc. 
101 International Drive 
Portsmouth, New Hampshire 03801 
USA 
 
Samsung Biologics Co. Ltd. 
300, Songdo Bio Way (Daero) 
Yeonsu-gu, Incheon, 21987 
Korea 
 
Swords Laboratories t/a Bristol-Myers Squibb Cruiserath Biologics 
Cruiserath Road, Mulhuddart 
Dublin 15, D15 H6EF 
Ireland 
 
Name and address of the manufacturers responsible for batch release 
 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc 
Strada Provinciale 12 Casilina, 41 
03012 ANAGNI (FR) 
Italy 
 
Swords Laboratories t/a Bristol-Myers Squibb Cruiserath Biologics 
Cruiserath Road, Mulhuddart 
Dublin 15, D15 H6EF 
Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 



79 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures  
 
The MAH shall ensure that in each Member State where OPDIVO is marketed, all healthcare 
professionals and patients/carers who are expected to prescribe and use OPDIVO have access to/are 
provided with the patient alert card.  
 

• The patient alert card shall contain the following key messages: 
 

• That OPDIVO treatment may increase the risk of:  
o Immune-related pneumonitis 
o Immune-related colitis 
o Immune-related hepatitis 
o Immune-related nephritis and renal dysfunction 
o Immune-related endocrinopathies  
o Immune-related skin adverse reactions 
o Other immune-related ARs 

 
• Signs or symptoms of the safety concern and when to seek attention from a HCP 

 
• Contact details of the OPDIVO prescriber 

 
• Obligation to conduct post-authorisation measures  
 
The MAH shall complete, within the stated timeframe, the below measures: 
 

Description Due date 
1. Post authorisation efficacy study (PAES): The MAH should submit the 
addendum to the CA209205 Final CSR reporting the OS data and data from 
the discontinuation schedule in Cohort C. 

30th June 2021 

2. The MAH should submit the final OS data for study CA209238: A 
Phase 3, randomised double-blind study of OPDIVO versus Yervoy in 
patients who have undergone complete resection of Stage IIIb/c or Stage IV 
melanoma. 

4Q2020 



80 

3. Post authorisation efficacy study (PAES): In order to further elucidate the 
contribution of ipilimumab to the efficacy and toxicity of the combination 
regimen of nivolumab and ipilimumab, the MAH should conduct and 
submit the results of a randomised, clinical study comparing the efficacy 
and safety of the combination of nivolumab and ipilimumab to nivolumab 
monotherapy in previously untreated adult patients with 
intermediate/poor-risk advanced renal cell carcinoma and with an 
appropriate spectrum of PD-L1 expression levels. This study should be 
conducted according to an agreed protocol.

30th September 2021 

  



81 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



82 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



83 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT  
 
OPDIVO 10 mg/mL concentrate for solution for infusion 
nivolumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of concentrate contains 10 mg of nivolumab. 
Each vial of 4 mL contains 40 mg of nivolumab. 
Each vial of 10 mL contains 100 mg of nivolumab. 
Each vial of 24 mL contains 240 mg of nivolumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium citrate dihydrate, sodium chloride, mannitol (E421), pentetic acid, 
polysorbate 80 (E433), sodium hydroxide, hydrochloric acid, water for injections. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion. 
 
40 mg/4 mL 
100 mg/10 mL 
240 mg/24 mL 
 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use. 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 



84 

8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1014/001 40 mg vial 
EU/1/15/1014/002 100 mg vial 
EU/1/15/1014/003 240 mg vial 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 



85 

 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



86 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
OPDIVO 10 mg/mL sterile concentrate 
nivolumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of concentrate contains 10 mg of nivolumab. 
Each vial of 24 mL contains 240 mg of nivolumab. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium citrate dihydrate, sodium chloride, mannitol (E421), pentetic acid, 
polysorbate 80 (E433), sodium hydroxide, hydrochloric acid, water for injections. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Sterile concentrate 
 
240 mg/24 mL 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
IV use 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 



87 

Do not freeze. 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1014/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
 
  



88 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
OPDIVO 10 mg/mL sterile concentrate 
nivolumab 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
For single use only. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
40 mg/4 mL 
100 mg/10 mL 
 
 
6. OTHER 
 
 
 
  



89 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



90 

Package leaflet: Information for the user 
 

OPDIVO 10 mg/mL concentrate for solution for infusion 
nivolumab 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- It is important that you keep the alert card with you during treatment. 
- If you have any further questions, ask your doctor. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in 

this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What OPDIVO is and what it is used for 
2. What you need to know before you use OPDIVO 
3. How to use OPDIVO 
4. Possible side effects 
5. How to store OPDIVO 
6. Contents of the pack and other information 
 
 
1. What OPDIVO is and what it is used for 
 
OPDIVO is a medicine used to treat: 
 advanced melanoma (a type of skin cancer) in adults 
 melanoma after complete resection in adults (treatment after surgery is called adjuvant therapy) 
 advanced non-small cell lung cancer (a type of lung cancer) in adults 
 advanced renal cell carcinoma (advanced kidney cancer) in adults 
 classical Hodgkin lymphoma that has come back after or has not responded to previous therapies, 

including an autologous stem-cell transplant (a transplant of your own blood-producing cells) in 
adults 

 advanced cancer of the head and neck in adults 
 advanced urothelial carcinoma (bladder and urinary tract cancer) in adults. 
 
It contains the active substance nivolumab, which is a monoclonal antibody, a type of protein designed 
to recognise and attach to a specific target substance in the body. 
 
Nivolumab attaches to a target protein called programmed death-1 receptor (PD-1) that can switch off 
the activity of T cells (a type of white blood cell that forms part of the immune system, the body’s 
natural defences). By attaching to PD-1, nivolumab blocks its action and prevents it from switching 
off your T cells. This helps increase their activity against the melanoma, lung, kidney, lymphoid, head 
and neck or bladder cancer cells. 
 
OPDIVO may be given in combination with other anti-cancer medicines. It is important that you also 
read the package leaflet for these other medicines. If you have any questions about these medicines, 
please ask your doctor. 
 
 
2. What you need to know before you use OPDIVO 
 
You should not be given OPDIVO 
 if you are allergic to nivolumab or any of the other ingredients of this medicine (listed in section 6 

"Contents of the pack and other information"). Talk to your doctor if you are not sure. 
 



91 

Warnings and precautions 
Talk to your doctor before using OPDIVO as it may cause: 
 Problems with your heart such as a change in the rhythm or rate of the heartbeat or an abnormal 

heart rhythm. 
 Problems with your lungs such as breathing difficulties or cough. These may be signs of 

inflammation of the lungs (pneumonitis or interstitial lung disease). 
 Diarrhoea (watery, loose or soft stools) or any symptoms of inflammation of the intestines 

(colitis), such as stomach pain and mucus or blood in stool. 
 Inflammation of the liver (hepatitis). Signs and symptoms of hepatitis may include abnormal 

liver function tests, eye or skin yellowing (jaundice), pain on the right side of your stomach area, 
or tiredness. 

 Inflammation or problems with your kidneys. Signs and symptoms may include abnormal 
kidney function tests, or decreased volume of urine. 

 Problems with your hormone producing glands (including the pituitary, the thyroid, the 
parathyroid and adrenal glands) that may affect how these glands work. Signs and symptoms that 
these glands are not working properly may include fatigue (extreme tiredness), weight change or 
headache, decreased blood levels of calcium and visual disturbances. 

 Diabetes (symptoms include excessive thirst, the passing of a greatly increased amount of urine, 
increase in appetite with a loss of weight, feeling tired, drowsy, weak, depressed, irritable and 
generally unwell) or diabetic ketoacidosis (acid in the blood produced from diabetes). 

 Inflammation of the skin that can lead to severe skin reaction (known as toxic epidermal 
necrolysis and Stevens-Johnson syndrome). Signs and symptoms of severe skin reaction may 
include rash, itching, and peeling of the skin (possibly fatal). 

 Inflammation of the muscles such as myocarditis (inflammation of the heart muscle), myositis 
(inflammation of the muscles) and rhabdomyolysis (stiffness in muscles and joints, muscle 
spasm). Signs and symptoms may include muscle pain, stiffness, weakness, chest pain, or severe 
fatigue. 

 Solid organ transplant rejection. 
 Graft-versus-host disease. 
 Haemophagocytic lymphohistiocytosis. A rare disease in which our immune system makes too 

many of otherwise normal infection fighting cells called histiocytes and lymphocytes. Symptoms 
may include enlarged liver and/or spleen, skin rash, lymph node enlargement, breathing problems, 
easy bruising, kidney abnormalities, and heart problems. 

 
Tell your doctor immediately if you have any of these signs or symptoms or if they get worse. Do 
not try to treat your symptoms with other medicines on your own. Your doctor may 
 give you other medicines in order to prevent complications and reduce your symptoms, 
 withhold the next dose of OPDIVO, 
 or stop your treatment with OPDIVO altogether. 
Please note that these signs and symptoms are sometimes delayed, and may develop weeks or months 
after your last dose. Before treatment, your doctor will check your general health. You will also have 
blood tests during your treatment. 
 
Check with your doctor or nurse before you are given OPDIVO if: 
 you have an autoimmune disease (a condition where the body attacks its own cells); 
 you have melanoma of the eye; 
 you were previously given ipilimumab, another medicine for treating melanoma, and experienced 

serious side effects because of that medicine; 
 you have been told that your cancer has spread to your brain; 
 you have any history of inflammation of the lungs; 
 you have been taken medicines to suppress your immune system. 
 
Complications of stem cell transplant that uses donor stem cells (allogeneic) after treatment with 
OPDIVO. These complications can be severe and can lead to death. Your healthcare provider will 
monitor you for signs of complications if you have an allogeneic stem cell transplant. 
 



92 

Children and adolescents 
OPDIVO should not be used in children and adolescents below 18 years of age. 
 
Other medicines and OPDIVO 
Before you are given OPDIVO, tell your doctor if you are taking any medicines that suppress your 
immune system, such as corticosteroids, since these medicines may interfere with the effect of 
OPDIVO. However, once you are treated with OPDIVO, your doctor may give you corticosteroids to 
reduce any possible side effects that you may have during your treatment and this will not impact the 
effect of the medicine. 
Tell your doctor if you are taking or have recently taken any other medicines. Do not take any other 
medicines during your treatment without talking to your doctor first. 
 
Pregnancy and breast-feeding 
Tell your doctor if you are pregnant or think you might be, if you are planning to become pregnant, 
or if you are breast-feeding. 
 
Do not use OPDIVO if you are pregnant unless your doctor specifically tells you to. The effects of 
OPDIVO in pregnant women are not known, but it is possible that the active substance, nivolumab, 
could harm an unborn baby. 
 You must use effective contraception while you are being treated with OPDIVO and for at least 

5 months following the last dose of OPDIVO, if you are a woman who could become pregnant. 
 If you become pregnant while using OPDIVO tell your doctor. 
 
It is not known whether OPDIVO gets into breast milk. A risk to the breast-fed infant cannot be 
excluded. Ask your doctor if you can breast-feed during or after treatment with OPDIVO. 
 
Driving and using machines 
OPDIVO or OPDIVO in combination with ipilimumab may have a minor influence on the ability to 
drive and use machines; however, use caution when performing these activities until you are sure that 
OPDIVO does not adversely affect you. 
 
OPDIVO contains sodium 
Tell your doctor if you are on a low-sodium (low-salt) diet before you are given OPDIVO. This 
medicine contains 2.5 mg sodium (main component of cooking/table salt) in each mL of concentrate. 
OPDIVO contains 10 mg sodium per 4 ml vial, 25 mg sodium per 10 ml vial or 60 mg sodium per 
24 ml vial, which is equivalent to 0.5%, 1.25% or 3% respectively, of the recommended maximum 
daily dietary intake of sodium for an adult. 
 
You will also find key messages from this package leaflet in the patient alert card you have been given 
by your doctor. It is important that you keep this patient alert card and show it to your partner or 
caregivers. 
 
 
3. How to use OPDIVO 
 
How much OPDIVO is given 
When OPDIVO is given on its own, the recommended dose is either 240 mg given every 2 weeks or 
480 mg given every 4 weeks depending on indication. 
 
When OPDIVO is given in combination with ipilimumab for the treatment of skin cancer, the 
recommended dose of OPDIVO is 1 mg of nivolumab per kilogram of your body weight for the first 
4 doses (combination phase). Thereafter the recommended dose of OPDIVO is 240 mg given every 
2 weeks or 480 mg given every 4 weeks (single-agent phase).  
 
When OPDIVO is given in combination with ipilimumab for the treatment of advanced kidney cancer, 
the recommended dose of OPDIVO is 3 mg of nivolumab per kilogram of your body weight for the 



93 

first 4 doses (combination phase). Thereafter, the recommended dose of OPDIVO is 240 mg given 
every 2 weeks or 480 mg given every 4 weeks (single-agent phase). 
 
When OPDIVO is given in combination with ipilimumab and chemotherapy for the treatment of 
advanced non-small cell lung cancer, the recommended dose of OPDIVO is 360 mg every 3 weeks. 
After completion of 2 cycles of chemotherapy, OPDIVO is given in combination with ipilimumab, the 
recommended dose of OPDIVO is 360 mg every 3 weeks. 
 
Depending on your dose, the appropriate amount of OPDIVO will be diluted with sodium 
chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection 
before use. More than one vial of OPDIVO may be necessary to obtain the required dose. 
 
How OPDIVO is given 
You will receive treatment with OPDIVO in a hospital or clinic, under the supervision of an 
experienced doctor. 
 
OPDIVO will be given to you as an infusion (a drip) into a vein (intravenously) over a period of 30 or 
60 minutes, every 2 weeks or 4 weeks, depending on the dose you are receiving. Your doctor will 
continue giving you OPDIVO for as long as you keep benefitting from it or until you no longer 
tolerate the treatment. 
 
When OPDIVO is given in combination with ipilimumab, you will be given an infusion over a period 
of 30 minutes, every 3 weeks for the first 4 doses (combination phase). Thereafter it will be given as 
an infusion over a period of 30 or 60 minutes, every 2 weeks or 4 weeks, depending on the dose you 
are receiving (single-agent phase).  
 
When OPDIVO is given in combination with ipilimumab and chemotherapy for the treatment of 
advanced non-small cell lung cancer, you will be given an infusion over a period of 30 minutes, 
every 3 weeks. 
 
If you miss a dose of OPDIVO 
It is very important for you to keep all your appointments to receive OPDIVO. If you miss an 
appointment, ask your doctor when to schedule your next dose. 
 
If you stop using OPDIVO 
Stopping your treatment may stop the effect of the medicine. Do not stop treatment with OPDIVO 
unless you have discussed this with your doctor. 
 
If you have any further questions about your treatment or on the use of this medicine, ask your doctor. 
 
When OPDIVO is given in combination with ipilimumab or in combination with ipilimumab and 
chemotherapy, you will first be given OPDIVO followed by ipilimumab and then by chemotherapy. 
Please refer to the package leaflet of the other anti-cancer medicines in order to understand the use of 
these medicines. If you have questions about these medicines, please ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. Your 
doctor will discuss these with you and will explain the risks and benefits of your treatment. 
 
Be aware of important symptoms of inflammation. OPDIVO acts on your immune system and may 
cause inflammation in parts of your body. Inflammation may cause serious damage to your body and 
some inflammatory conditions may be life-threatening and need treatment or withdrawal of OPDIVO. 
 
The following side effects have been reported with OPDIVO alone: 
 



94 

Very common (may affect more than 1 in 10 people) 
 Decrease in some white blood cells 
 Diarrhoea (watery, loose or soft stools), nausea 
 Skin rash sometimes with blisters, itching 
 Feeling tired or weak 
 
Common (may affect up to 1 in 10 people) 
 Infections of the upper respiratory tract 
 Allergic reaction, reactions related to the infusion of the medicine 
 Underactive thyroid gland (which can cause tiredness or weight gain), overactive thyroid gland 

(which can cause rapid heart rate, sweating and weight loss) 
 Decreased appetite 
 Inflammation of the nerves (causing numbness, weakness, tingling or burning pain of the arms and 

legs), headache, dizziness 
 High blood pressure (hypertension) 
 Inflammation of the lungs (pneumonitis, characterised by coughing and difficulty breathing), 

shortness of breath (dyspnoea), cough 
 Inflammation of the intestines (colitis), mouth ulcers and cold sores (stomatitis), vomiting, 

stomach pain, constipation, dry mouth 
 Skin colour change in patches (vitiligo), dry skin, redness of the skin, unusual hair loss or thinning 
 Pain in the muscles, bones (musculoskeletal pain) and joints (arthralgia) 
 Fever, oedema (swelling) 
 
Uncommon (may affect up to 1 in 100 people) 
 Serious lung infection (pneumonia), bronchitis 
 Increase in some white blood cells 
 Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys), 

underactive function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland 
situated at the base of the brain, swelling of the thyroid gland, diabetes  

 Dehydration, increased acid levels in the blood 
 Damage to nerves causing numbness and weakness (polyneuropathy), inflammation of the nerves 

caused by the body attacking itself, causing numbness, weakness, tingling or burning pain 
(autoimmune neuropathy) 

 Inflammation of the eye (which causes pain and redness), blurred vision, dry eyes 
 Fast heart rate, inflammation of the covering of the heart and accumulation of fluid around the 

heart (pericardial disorders) 
 Fluid around the lungs 
 Inflammation of the pancreas (pancreatitis), inflammation of the stomach (gastritis) 
 Inflammation of the liver (hepatitis) 
 Severe condition of the skin that causes red, often itchy spots, similar to the rash of measles, 

which starts on the limbs and sometimes on the face and the rest of the body (erythema 
multiforme), skin disease with thickened patches of red skin, often with silvery scales (psoriasis), 
skin condition of the face where the nose and cheeks are unusually red (rosacea), hives (itchy, 
bumpy rash) 

 Inflammation of the muscles causing pain or stiffness (polymyalgia rheumatica), inflammation of 
the joints (arthritis) 

 Inflammation of the kidney, kidney failure (including abrupt loss of kidney function) 
 Pain, chest pain 
 
Rare (may affect up to 1 in 1000 people) 
 A disease causing the inflammation or enlargement of a lymph node (Kikuchi lymphadenitis) 
 Life-threatening allergic reaction 
 Acid in the blood produced from diabetes (diabetic ketoacidosis) 
 A temporary inflammation of the nerves that causes pain, weakness, and paralysis in the 

extremities (Guillain-Barré syndrome), loss of the protective sheath around nerves 
(demyelination), a condition in which the muscles become weak and tire easily (myasthenic 
syndrome) 



95 

 Inflammation of the brain 
 Changes in the rhythm or rate of the heartbeat, abnormal heart rhythm, inflammation of the heart 

muscle 
 Inflammatory disease of blood vessels 
 Fluid in the lungs 
 Ulcer of the small intestines 
 Blockage of bile ducts 
 Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis or Stevens-Johnson 

syndrome) 
 Disease in which the immune system attacks the glands that make moisture for the body, such as 

tears and saliva (Sjogren’s syndrome), aching muscles, muscle tenderness or weakness, not caused 
by exercise (myopathy), inflammation of the muscles (myositis), stiffness in muscles and joints, 
muscle spasm (rhabdomyolysis) 

 
Other side effects that have been reported with frequency not known (cannot be estimated from 
the available data): 
 Temporary and reversible non-infectious inflammation of the protective membranes surrounding 

the brain and spinal cord (aseptic meningitis) 
 Solid organ transplant rejection 
 Chronic diseases associated with a build-up of inflammatory cells in various organs and tissues, 

most commonly the lungs (sarcoidosis) 
 Decreased function of the parathyroid gland 
 A group of metabolic complications occurring after cancer treatment characterised by high blood 

levels of potassium and phosphate, and low blood levels of calcium (tumour lysis syndrome) 
 An inflammatory disorder (most likely of autoimmune origin) affecting the eyes, skin and the 

membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada syndrome)  
 A condition where the immune system makes too many infection-fighting cells called histiocytes 

and lymphocytes that may cause various symptoms (called haemophagocytic lymphohistiocytosis) 
 

The following side effects have been reported with OPDIVO in combination (the frequency and 
severity of side effects may vary with the combination of anti-cancer medicines received): 
 
Very common (may affect more than 1 in 10 people) 
 Underactive thyroid gland (which can cause tiredness or weight gain),overactive thyroid gland 

(which can cause rapid heart rate, sweating and weight loss) 
 Decreased appetite 
 Headache 
 Shortness of breath (dyspnoea) 
 Inflammation of the intestines (colitis), diarrhoea (watery, loose or soft stools), vomiting, nausea, 

stomach pain 
 Skin rash sometimes with blisters, itching 
 Pain in the joints (arthralgia), pain in the muscles and bones (musculoskeletal pain) 
 Feeling tired or weak, fever 
 
Common (may affect up to 1 in 10 people) 
 Serious lung infection (pneumonia), infections of the upper respiratory tract, inflammation of the 

eye (conjunctivitis) 
 Increase in some white blood cells, decrease in neutrophils with fever 
 Allergic reaction, reactions related to the infusion of the medicine 
 Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys), 

underactive function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland 
situated at the base of the brain, swelling of the thyroid gland, diabetes 

 Dehydration, decreased levels of albumin and phosphate in the blood 
 Inflammation of the nerves (causing numbness, weakness, tingling or burning pain of the arms and 

legs), dizziness 
 Inflammation of the eye (which causes pain and redness), blurred vision, dry eye 
 Fast heart rate 



96 

 High blood pressure (hypertension) 
 Inflammation of the lungs (pneumonitis, characterised by coughing and difficulty breathing), fluid 

around the lungs, blood clots, cough 
 Mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation, 

dry mouth 
 Inflammation of the liver 
 Skin colour change in patches (vitiligo), dry skin, redness of the skin, unusual hair loss or 

thinning, hives (itchy rash) 
 Inflammation of the joints (arthritis), muscle spasm, muscle weakness 
 Kidney failure (including abrupt loss of kidney function) 
 Oedema (swelling), pain, chest pain, chills 

 
Uncommon (may affect up to 1 in 100 people) 
 Bronchitis 
 Temporary and reversible non-infectious inflammation of the protective membranes surrounding 

the brain and spinal cord (aseptic meningitis) 
 Chronic diseases associated with a build-up of inflammatory cells in various organs and tissues, 

most commonly the lungs (sarcoidosis) 
 Increased acid levels in the blood  
 Acid in the blood produced from diabetes (diabetic ketoacidosis) 
 Decreased function of the parathyroid gland 
 A temporary inflammation of the nerves that causes pain, weakness and paralysis in the 

extremities (Guillain-Barré syndrome); damage to nerves causing numbness and weakness 
(polyneuropathy); inflammation of the nerves; foot drop (peroneal nerve palsy); inflammation of 
the nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning 
pain (autoimmune neuropathy); muscle weakness and tiredness without atrophy (myasthenia 
gravis) 

 Inflammation of the brain 
 Changes in the rhythm or rate of the heartbeat, abnormal heart rhythm, inflammation of the heart 

muscle, slow heart rate 
 Intestinal perforation, inflammation of the stomach (gastritis), inflammation of the duodenum 
 Skin disease with thickened patches of red skin, often with silvery scales (psoriasis), severe 

condition of the skin that causes red, often itchy spots, similar to the rash of measles, which starts 
on the limbs and sometimes on the face and the rest of the body (erythema multiforme) 

 Severe and possibly fatal peeling of the skin (Stevens-Johnson syndrome) 
 Chronic disease of joints (spondyloarthropathy), disease in which the immune system attacks the 

glands that make moisture for the body, such as tears and saliva (Sjogren’s syndrome), aching 
muscles, muscle tenderness of weakness, not caused by exercise (myopathy), inflammation of the 
muscles (myositis), stiffness in muscles and joints, muscle spasm (rhabdomyolysis), inflammation 
of the muscles causing pain or stiffness (polymyalgia rheumatica) 

 Inflammation of the kidney 
 
Rare (may affect up to 1 in 1000 people) 
 Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis) 
 
Other side effects that have been reported frequency not known (cannot be estimated from the 
available data): 
 Solid organ transplant rejection 
 A group of metabolic complications occurring after cancer treatment characterised by high blood 

levels of potassium and phosphate, and low blood levels of calcium (tumour lysis syndrome) 
 An inflammatory disorder (most likely of autoimmune origin) affecting the eyes, skin and the 

membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada syndrome)  
 Inflammation of the covering of the heart and accumulation of fluid around the heart (pericardial 

disorders) 
 A condition where the immune system makes too many infection-fighting cells called histiocytes 

and lymphocytes that may cause various symptoms (called haemophagocytic lymphohistiocytosis) 
 



97 

Tell your doctor immediately if you get any of the side effects listed above. Do not try to treat your 
symptoms with other medicines on your own. 
 
Changes in test results 
OPDIVO alone or in combination may cause changes in the results of tests carried out by your doctor. 
These include: 
 Abnormal liver function tests (increased amounts of the liver enzymes aspartate aminotransferase, 

alanine aminotransferase, gamma-glutamyltransferase, or alkaline phosphatase in your blood, 
higher blood levels of the waste product bilirubin) 

 Abnormal kidney function tests (increased amounts of creatinine in your blood) 
 High (hyperglycaemia) or low (hypoglycaemia) sugar levels in the blood 
 A decreased number of red blood cells (which carry oxygen), white blood cells (which are 

important in fighting infection) or platelets (cells which help the blood to clot) 
 An increased level of the enzyme that breaks down fats and of the enzyme that breaks down starch 
 Increased or decreased amount of calcium or potassium 
 Increased or decreased blood levels of magnesium or sodium 
 Decrease in body weight 
 Increased amount of thyroid stimulating hormone 
 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in 
this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store OPDIVO 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the vial label after 
EXP. The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C to 8°C). 
Do not freeze. 
Store in the original package in order to protect from light. 
The unopened vial can be stored at controlled room temperature up to 25°C with room light for up to 
48 hours. 
 
Do not store any unused portion of the infusion solution for reuse. Any unused medicine or waste 
material should be disposed of in accordance with local requirements. 
 
 
6. Contents of the pack and other information 
 
What OPDIVO contains  
 The active substance is nivolumab. 
Each mL of concentrate for solution for infusion contains 10 mg of nivolumab. 
Each vial contains either 40 mg (in 4 mL), 100 mg (in 10 mL) or 240 mg (in 24 mL) of nivolumab. 
 
 The other ingredients are sodium citrate dihydrate, sodium chloride (see section 2 "OPDIVO 

contains sodium"), mannitol (E421), pentetic acid, polysorbate 80 (E433), sodium hydroxide, 
hydrochloric acid and water for injections. 

 
What OPDIVO looks like and contents of the pack 
OPDIVO concentrate for solution for infusion (sterile concentrate) is a clear to opalescent, colourless 
to pale yellow liquid that may contain few light particles. 



98 

 
It is available in packs containing either 1 vial of 4 mL, 1 vial of 10 mL or 1 vial of 24 mL. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
Manufacturer 
CATALENT ANAGNI S.R.L. 
Loc. Fontana del Ceraso snc 
Strada Provinciale 12 Casilina, 41 
03012 ANAGNI (FR) 
Italy 
 
Swords Laboratories t/a Bristol-Myers Squibb Cruiserath Biologics 
Cruiserath Road, Mulhuddart 
Dublin 15, D15 H6EF 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: +370 52 369140 

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 2 4942 480 
 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel.: + 36 1 808 9433 
 

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
Bristol-Myers Squibb S.r.l. 
Tel: + 356 23976333 
 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: 0800 0752002 (+49 (0)89 121 42-350) 
 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 
 

Eesti 
Bristol-Myers Squibb Kft. 
Tel: +372 640 1030 
 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 
 

Ελλάδα 
Bristol-Myers Squibb A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 



99 

España 
Bristol-Myers Squibb, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
Bristol-Myers Squibb Polska Sp. z o.o. 
Tel.: + 48 22 2606400 
 

France 
Bristol-Myers Squibb SARL 
Tél: + 33 (0)1 58 83 84 96 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 
 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
TEL: +385 1 2078 508 
 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: +386 1 2355 100 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 20833 600 

Italia 
Bristol-Myers Squibb S.r.l. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 

Κύπρος 
Bristol-Myers Squibb A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 
 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: +371 66164750 
 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 
 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
Preparation and administration of OPDIVO 
 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
Calculating the dose 
 
More than one vial of OPDIVO concentrate may be needed to give the total dose for the patient. 
 
Nivolumab monotherapy: 
The prescribed dose for the patient is 240 mg or 480 mg given regardless of body weight depending on 
indication. 
 



100 

Nivolumab in combination with ipilimumab: 
The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the 
total dose to be given. 
 
 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).  
 
Nivolumab in combination with ipilimumab and chemotherapy: 
The prescribed dose for the patient is 360 mg given regardless of body weight. 
 
Preparing the infusion 
Take care to ensure aseptic handling when you prepare the infusion. 
 
OPDIVO can be used for intravenous administration either: 
 without dilution, after transfer to an infusion container using an appropriate sterile syringe; 
or 
 after diluting according to the following instructions:  
 the final infusion concentration should range between 1 and 10 mg/mL. 
 the total volume of infusion must not exceed 160 mL. For patients weighing less than 40 kg, 

the total volume of infusion must not exceed 4 mL per kilogram of patient weight. 
 
 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. Discard the vial if 
the solution is cloudy, is discoloured, or contains particulate matter other than a few 
translucent-to-white 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. For ease of preparation, the concentrate 
can be transferred directly into a pre-filled bag containing the appropriate 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 30 or 60 minutes depending on 
the dose. 
 
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 containers 
 Polyolefin containers 
 Glass bottles 



101 

 PVC infusion sets 
 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. 
 
Storage conditions and shelf life 
Unopened vial 
OPDIVO must be stored in a refrigerator (2°C to 8°C). The vials must be kept in the original 
package in order to protect from light. OPDIVO should not be frozen. 
The unopened vial can be stored at controlled room temperature up to 25°C with room light for up to 
48 hours. 
 
Do not use OPDIVO after the expiry date which is stated on the carton and on the vial label after EXP. 
The expiry date refers to the last day of that month. 
 
OPDIVO infusion 
Chemical and physical in-use stability from the time of preparation has been demonstrated as follows 
(times are inclusive of the administration period): 
 

Infusion preparation 
In-use stability 

Storage at 2ºC to 8ºC 
protected from light 

Storage at room temperature 
(≤ 25°C) and room light 

Undiluted or diluted with sodium 
chloride 9 mg/mL (0.9%) solution 
for injection 

30 days 24 hours (of total 30 days storage) 

Diluted with 50 mg/mL (5%) 
glucose solution for injection 24 hours 

8 hours 
(of total 24 hours storage) 

 
From a microbiological point of view the prepared solution for infusion, regardless of the diluent, 
should be used immediately. If not used immediately, in-use storage times and conditions prior to use 
are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C or 
8 hours (of the total 24 hours of storage) at room temperature (≤ 25°C), unless infusion preparation has 
taken place in controlled and validated aseptic conditions. 
 
Disposal 
Do not store any unused portion of the infusion solution for reuse. Any unused medicine or waste 
material should be disposed of in accordance with local requirements. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE ANDMANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET