Keytruda

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 



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1. NAME OF THE MEDICINAL PRODUCT

KEYTRUDA 50 mg powder for concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of powder contains 50 mg of pembrolizumab.

After reconstitution, 1 mL of concentrate contains 25 mg of pembrolizumab.

Pembrolizumab is a humanised monoclonal anti-programmed cell death-1 (PD-1) antibody
(IgG4/kappa isotype with a stabilising sequence alteration in the Fc region) produced in Chinese 
hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

White to off-white lyophilised powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Melanoma
KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) 
melanoma in adults.

KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III 
melanoma and lymph node involvement who have undergone complete resection (see section 5.1).

Non-small cell lung carcinoma (NSCLC)
KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung 
carcinoma in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) with 
no EGFR or ALK positive tumour mutations.

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the
first-line treatment of metastatic non-squamous non-small cell lung carcinoma in adults whose 
tumours have no EGFR or ALK positive mutations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for 
the first-line treatment of metastatic squamous non-small cell lung carcinoma in adults.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic 
non-small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥ 1% TPS and who 
have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour 
mutations should also have received targeted therapy before receiving KEYTRUDA.

Classical Hodgkin lymphoma (cHL)
KEYTRUDA as monotherapy is indicated for the treatment of adult patients with relapsed or 
refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) and 
brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV.

 



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Urothelial carcinoma
KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic 
urothelial carcinoma in adults who have received prior platinum-containing chemotherapy (see 
section 5.1).

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic 
urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose 
tumours express PD-L1 with a combined positive score (CPS) ≥ 10 (see section 5.1).

Head and neck squamous cell carcinoma (HNSCC)
KEYTRUDA, as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) 
chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and 
neck squamous cell carcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 (see 
section 5.1).

KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic head and neck 
squamous cell carcinoma in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing 
on or after platinum-containing chemotherapy (see section 5.1).

Renal cell carcinoma (RCC)
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal 
cell carcinoma in adults (see section 5.1).

4.2 Posology and method of administration

Therapy must be initiated and supervised by specialist physicians experienced in the treatment of 
cancer. 

PD-L1 testing for patients with NSCLC, urothelial carcinoma, or HNSCC
For treatment with KEYTRUDA as monotherapy, testing for PD-L1 tumour expression using a 
validated test is recommended to select patients with NSCLC or previously untreated urothelial 
carcinoma (see sections 4.1, 4.4, 4.8, and 5.1).

Patients with HNSCC should be selected for treatment with KEYTRUDA as monotherapy or in 
combination with platinum and 5-fluorouracil (5-FU) chemotherapy based on the tumour expression
of PD-L1 confirmed by a validated test (see sections 4.1, 4.4, 4.8, and 5.1).

Posology
The recommended dose of KEYTRUDA as monotherapy is either 200 mg every 3 weeks or 400 mg 
every 6 weeks administered as an intravenous infusion over 30 minutes.

The recommended dose of KEYTRUDA as part of combination therapy is 200 mg every 3 weeks 
administered as an intravenous infusion over 30 minutes.

Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity. 
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 for clinically stable patients with initial evidence of disease progression until disease 
progression is confirmed.

For the adjuvant treatment of melanoma, KEYTRUDA should be administered until disease 
recurrence, unacceptable toxicity, or for a duration of up to one year.

 



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Dose delay or discontinuation (see also section 4.4)
No dose reductions of KEYTRUDA are recommended. KEYTRUDA should be withheld or 
discontinued to manage adverse reactions as described in Table 1.

Table 1: Recommended treatment modifications for KEYTRUDA

Immune-related adverse 
reactions

Severity Treatment modification

Pneumonitis Grade 2 Withhold until adverse reactions 
recover to Grades 0-1*

Grades 3 or 4, or recurrent Grade 2 Permanently discontinue
Colitis Grades 2 or 3 Withhold until adverse reactions 

recover to Grades 0-1*
Grade 4 or recurrent Grade 3 Permanently discontinue

Nephritis Grade 2 with creatinine > 1.5 to ≤ 3 
times upper limit of normal (ULN) 

Withhold until adverse reactions 
recover to Grades 0-1*

Grade ≥ 3 with creatinine > 3 times 
ULN 

Permanently discontinue

Endocrinopathies Grade 2 adrenal insufficiency and 
hypophysitis

Withhold treatment until 
controlled by hormone 
replacement

Grades 3 or 4 adrenal insufficiency 
or symptomatic hypophysitis

Type 1 diabetes associated with 
Grade ≥ 3 hyperglycaemia (glucose 
> 250 mg/dL or > 13.9 mmol/L) or 
associated with ketoacidosis

Hyperthyroidism Grade ≥ 3

Withhold until adverse reactions 
recover to Grades 0-1*

For patients with Grade 3 or 
Grade 4 endocrinopathies that 
improved to Grade 2 or lower and 
are controlled with hormone 
replacement, if indicated, 
continuation of pembrolizumab 
may be considered after 
corticosteroid taper, if needed. 
Otherwise treatment should be 
discontinued.

Hypothyroidism Hypothyroidism may be managed 
with replacement therapy without 
treatment interruption.

Hepatitis

NOTE: for RCC patients 
treated with
pembrolizumab in 
combination with axitinib
with liver enzyme 
elevations, see dosing 
guidelines following this 
table.

Grade 2 with aspartate 
aminotransferase (AST) or alanine
aminotransferase (ALT) > 3 to 
5 times ULN or total bilirubin > 1.5 
to 3 times ULN

Withhold until adverse reactions 
recover to Grades 0-1*

Grade ≥ 3 with AST or ALT 
> 5 times ULN or total bilirubin 
> 3 times ULN

Permanently discontinue

In case of liver metastasis with 
baseline Grade 2 elevation of AST 
or ALT, hepatitis with AST or ALT 
increases ≥ 50% and lasts ≥ 1 week

Permanently discontinue

Skin reactions Grade 3 or suspected 
Stevens-Johnson syndrome (SJS) or 
toxic epidermal necrolysis (TEN)

Withhold until adverse reactions 
recover to Grades 0-1*

Grade 4 or confirmed SJS or TEN Permanently discontinue

 



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Immune-related adverse 
reactions

Severity Treatment modification

Other immune-related 
adverse reactions

Based on severity and type of 
reaction (Grade 2 or Grade 3)

Grades 3 or 4 myocarditis
Grades 3 or 4 encephalitis 
Grades 3 or 4 Guillain-Barré 
syndrome

Grade 4 or recurrent Grade 3

Withhold until adverse reactions 
recover to Grades 0-1*

Permanently discontinue

Permanently discontinue
Infusion-related reactions Grades 3 or 4 Permanently discontinue

Note: toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 4.0 (NCI-CTCAE v.4).
* If treatment-related toxicity does not resolve to Grades 0-1 within 12 weeks after last dose of KEYTRUDA, or if 

corticosteroid dosing cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks, KEYTRUDA 
should be permanently discontinued.

The safety of re-initiating pembrolizumab therapy in patients previously experiencing immune-related 
myocarditis is not known.

KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued for 
Grade 4 or recurrent Grade 3 immune-related adverse reactions, unless otherwise specified in Table 1.

For Grade 4 haematological toxicity, only in patients with cHL, KEYTRUDA should be withheld until 
adverse reactions recover to Grades 0-1.

KEYTRUDA in combination with axitinib in RCC
For RCC patients treated with KEYTRUDA in combination with axitinib, see the Summary of Product 
Characteristics (SmPC) regarding dosing of axitinib. When used in combination with pembrolizumab, 
dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or 
longer (see section 5.1).

For liver enzyme elevations, in patients with RCC being treated with KEYTRUDA in combination with 
axitinib:
 If ALT or AST ≥ 3 times ULN but < 10 times ULN without concurrent total bilirubin ≥ 2 times 

ULN, both KEYTRUDA and axitinib should be withheld until these adverse reactions recover to 
Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or 
sequential rechallenge with both medicines after recovery may be considered. If rechallenging 
with axitinib, dose reduction as per the axitinib SmPC may be considered.

 If ALT or AST ≥ 10 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times 
ULN, both KEYTRUDA and axitinib should be permanently discontinued and corticosteroid 
therapy may be considered. 

Patients treated with KEYTRUDA must be given the patient alert card and be informed about the risks 
of KEYTRUDA (see also package leaflet).

Special populations
Elderly
No dose adjustment is necessary in patients ≥ 65 years (see section 5.1). Data from patients ≥ 65 years 
are too limited to draw conclusions on cHL population (see section 5.1). Data from pembrolizumab 
monotherapy in patients with resected Stage III melanoma, from pembrolizumab in combination with 
axitinib in patients with advanced RCC, from chemotherapy combination in patients with metastatic 
NSCLC, and from pembrolizumab (with or without chemotherapy) in patients receiving first-line 
treatment for metastatic or unresectable recurrent HNSCC ≥ 75 years are limited (see sections 4.4 and 
5.1).

 



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Renal impairment
No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA has 
not been studied in patients with severe renal impairment (see sections 4.4 and 5.2).

Hepatic impairment
No dose adjustment is needed for patients with mild hepatic impairment. KEYTRUDA has not been 
studied in patients with moderate or severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of KEYTRUDA in children below 18 years of age have not yet been 
established. Currently available data are described in sections 4.8, 5.1 and 5.2.

Method of administration
KEYTRUDA is for intravenous use. It must be administered by infusion over 30 minutes.
KEYTRUDA must not be administered as an intravenous push or bolus injection.

For use in combination, see the SmPC for the concomitant therapies. When administering 
KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be 
administered first. 

For instructions on reconstitution and dilution 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

In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded.

Assessment of PD-L1 status
When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust 
methodology is chosen to minimise false negative or false positive determinations.

Immune-related adverse reactions
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving 
pembrolizumab. Most immune-related adverse reactions occurring during treatment with 
pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the 
last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system 
can occur simultaneously.

For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology or exclude 
other causes should be ensured. Based on the severity of the adverse reaction, pembrolizumab should 
be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid taper 
should be initiated and continued over at least 1 month. Based on limited data from clinical studies in 
patients whose immune-related adverse reactions could not be controlled with corticosteroid use, 
administration of other systemic immunosuppressants can be considered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse 
reaction recovers to Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or 
equivalent per day.

 



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Pembrolizumab must be permanently discontinued for any Grade 3 immune-related adverse reaction 
that recurs and for any Grade 4 immune-related adverse reaction toxicity, except for endocrinopathies 
that are controlled with replacement hormones (see sections 4.2 and 4.8).

Immune-related pneumonitis
Pneumonitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should 
be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed 
with radiographic imaging and other causes excluded. Corticosteroids should be administered for 
Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper); 
pembrolizumab should be withheld for Grade 2 pneumonitis, and permanently discontinued for 
Grade 3, Grade 4 or recurrent Grade 2 pneumonitis (see section 4.2).

Immune-related colitis
Colitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be 
monitored for signs and symptoms of colitis, and other causes excluded. Corticosteroids should be 
administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by 
a taper); pembrolizumab should be withheld for Grade 2 or Grade 3 colitis, and permanently 
discontinued for Grade 4 or recurrent Grade 3 colitis (see section 4.2). The potential risk of 
gastrointestinal perforation should be taken into consideration.

Immune-related hepatitis
Hepatitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be 
monitored for changes in liver function (at the start of treatment, periodically during treatment and as 
indicated based on clinical evaluation) and symptoms of hepatitis, and other causes excluded. 
Corticosteroids should be administered (initial dose of 0.5-1 mg/kg/day (for Grade 2 events) and 
1-2 mg/kg/day (for Grade ≥ 3 events) prednisone or equivalent followed by a taper) and, based on 
severity of liver enzyme elevations, pembrolizumab should be withheld or discontinued (see 
section 4.2).

Immune-related nephritis
Nephritis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be 
monitored for changes in renal function, and other causes of renal dysfunction excluded.
Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone 
or equivalent followed by a taper) and, based on severity of creatinine elevations, pembrolizumab 
should be withheld for Grade 2, and permanently discontinued for Grade 3 or Grade 4 nephritis (see 
section 4.2).

Immune-related endocrinopathies
Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, 
diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with pembrolizumab 
treatment.

Long-term hormone replacement therapy may be necessary in cases of immune-related 
endocrinopathies.

Adrenal insufficiency (primary and secondary) has been reported in patients receiving pembrolizumab.
Hypophysitis has also been reported in patients receiving pembrolizumab. (See section 4.8). Patients 
should be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (including 
hypopituitarism) and other causes excluded. Corticosteroids to treat adrenal insufficiency and other 
hormone replacement should be administered as clinically indicated. Pembrolizumab should be 
withheld for Grade 2 adrenal insufficiency or symptomatic hypophysitis until the event is controlled 
with hormone replacement. Pembrolizumab should be withheld or discontinued for Grades 3 or 4 
adrenal insufficiency or hypophysitis. Continuation of pembrolizumab may be considered, after 
corticosteroid taper, if needed (see section 4.2). Pituitary function and hormone levels should be 
monitored to ensure appropriate hormone replacement.

 



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Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving 
pembrolizumab (see section 4.8). Patients should be monitored for hyperglycaemia or other signs and 
symptoms of diabetes. Insulin should be administered for type 1 diabetes, and pembrolizumab should 
be withheld in cases of type 1 diabetes associated with Grade ≥ 3 hyperglycaemia or ketoacidosis until 
metabolic control is achieved (see section 4.2).

Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in 
patients receiving pembrolizumab and can occur at any time during treatment. Hypothyroidism is 
more frequently reported in patients with HNSCC with prior radiation therapy. Patients should be 
monitored for changes in thyroid function (at the start of treatment, periodically during treatment and 
as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. 
Hypothyroidism may be managed with replacement therapy without treatment interruption and 
without corticosteroids. Hyperthyroidism may be managed symptomatically. Pembrolizumab should 
be withheld for Grade ≥ 3 until recovery to Grade ≤ 1 hyperthyroidism. Thyroid function and hormone 
levels should be monitored to ensure appropriate hormone replacement.

For patients with Grade 3 or Grade 4 endocrinopathies that improved to Grade 2 or lower and are
controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered 
after corticosteroid taper, if needed. Otherwise treatment should be discontinued (see sections 4.2 and
4.8). 

Immune-related skin adverse reactions 
Immune-related severe skin reactions have been reported in patients receiving pembrolizumab (see 
section 4.8). Patients should be monitored for suspected severe skin reactions and other causes should 
be excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld for 
Grade 3 skin reactions until recovery to Grade ≤ 1 or permanently discontinued for Grade 4 skin 
reactions, and corticosteroids should be administered (see section 4.2).

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported
in patients receiving pembrolizumab (see section 4.8). For suspected SJS or TEN, pembrolizumab 
should be withheld and the patient should be referred to a specialised unit for assessment and 
treatment. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued (see 
section 4.2).

Caution should be used when considering the use of pembrolizumab in a patient who has previously 
experienced a severe or life-threatening skin adverse reaction on prior treatment with other 
immune-stimulatory anti-cancer agents.

Other immune-related adverse reactions
The following additional clinically significant, immune-related adverse reactions have been reported 
in clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, 
pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis, 
encephalitis and myelitis (see sections 4.2 and 4.8).

Based on the severity and type of the adverse reaction, pembrolizumab should be withheld for Grade 2 
or Grade 3 events and corticosteroids administered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse 
reaction recovers to Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or 
equivalent per day. 

Pembrolizumab must be permanently discontinued for any Grade 3 immune-related adverse reaction 
that recurs and for any Grade 4 immune-related adverse reaction.

For Grades 3 or 4 myocarditis, encephalitis or Guillain-Barré syndrome, pembrolizumab should be 
permanently discontinued (see sections 4.2 and 4.8).

 



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Transplant-related adverse reactions

Solid organ transplant rejection
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with 
PD-1 inhibitors. Treatment with pembrolizumab may increase the risk of rejection in solid organ 
transplant recipients. The benefit of treatment with pembrolizumab versus the risk of possible organ 
rejection should be considered in these patients.

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT)

Allogeneic HSCT after treatment with pembrolizumab
Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been 
observed in patients with cHL undergoing allogeneic HSCT after previous exposure to 
pembrolizumab. 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).

Allogeneic HSCT prior to treatment with pembrolizumab
In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported 
after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure 
may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of 
treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of 
allogeneic HSCT.

Infusion-related reactions
Severe infusion-related reactions, including hypersensitivity and anaphylaxis, have been reported in 
patients receiving pembrolizumab (see section 4.8). For Grades 3 or 4 infusion reactions, infusion 
should be stopped and pembrolizumab permanently discontinued (see section 4.2). Patients with 
Grades 1 or 2 infusion reaction may continue to receive pembrolizumab with close monitoring; 
premedication with antipyretic and antihistamine may be considered.

Disease-specific precautions

Use of pembrolizumab in urothelial carcinoma patients who have received prior platinum-containing 
chemotherapy
Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in 
patients with poorer prognostic features and/or aggressive disease. In urothelial carcinoma, a higher 
number of deaths within 2 months was observed in pembrolizumab compared to chemotherapy (see 
section 5.1). Factors associated with early deaths were fast progressive disease on prior platinum 
therapy and liver metastases.

Use of pembrolizumab in urothelial carcinoma for patients who are considered ineligible for 
cisplatin-containing chemotherapy and whose tumours express PD-L1 with CPS ≥ 10
The baseline and prognostic disease characteristics of the study population of KEYNOTE-052 
included a proportion of patients eligible for a carboplatin-based combination, for whom the benefit is 
being assessed in a comparative study, and patients eligible for mono-chemotherapy, for whom no 
randomised data are available. In addition, no safety and efficacy data are available in frailer patients 
(e.g. ECOG performance status 3) considered not eligible for chemotherapy. In the absence of these 
data, pembrolizumab should be used with caution in this population after careful consideration of the 
potential risk-benefit on an individual basis.

Use of pembrolizumab for first-line treatment of patients with NSCLC
In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed to 
be higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions of
each of these components (see sections 4.2 and 4.8). A direct comparison of pembrolizumab when 
used in combination with chemotherapy to pembrolizumab monotherapy is not available.

 



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Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab 
monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in 
previously untreated patients with NSCLC whose tumours express PD-L1. 

In KEYNOTE-042, a higher number of deaths within 4 months of treatment initiation followed by a 
long-term survival benefit was observed with pembrolizumab monotherapy compared to 
chemotherapy (see section 5.1).

Efficacy and safety data from patients ≥ 75 years are limited. For patients ≥ 75 years, pembrolizumab 
combination therapy should be used with caution after careful consideration of the potential 
benefit/risk on an individual basis (see section 5.1).

Use of pembrolizumab for first-line treatment of patients with HNSCC
In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed to 
be higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions of 
each of these components (see section 4.8). 

Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab 
monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in 
patients with HNSCC whose tumours express PD-L1 (see section 5.1).

Use of pembrolizumab for adjuvant treatment of patients with melanoma
A trend toward increased frequency of severe and serious adverse reactions in patients ≥ 75 years was 
observed. Safety data of pembrolizumab in the adjuvant melanoma setting in patients ≥ 75 years are 
limited.

Use of pembrolizumab in combination with axitinib for first-line treatment of patients with RCC
When pembrolizumab is given with axitinib, higher than expected frequencies of Grades 3 and 4 ALT 
and AST elevations have been reported in patients with advanced RCC (see section 4.8). Liver 
enzymes should be monitored before initiation of and periodically throughout treatment. More 
frequent monitoring of liver enzymes as compared to when the medicines are used in monotherapy 
may be considered. Medical management guidelines for both medicines should be followed (see 
section 4.2 and refer to the SmPC for axitinib). 

Patients excluded from clinical studies
Patients with the following conditions were excluded from clinical studies: active CNS metastases; 
ECOG PS ≥ 2 (except for urothelial carcinoma and RCC); HIV infection, hepatitis B or hepatitis C 
infection; active systemic autoimmune disease; interstitial lung disease; prior pneumonitis requiring 
systemic corticosteroid therapy; a history of severe hypersensitivity to another monoclonal antibody; 
receiving immunosuppressive therapy and a history of severe immune-related adverse reactions from 
treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid 
treatment (> 10 mg/day prednisone or equivalent) for greater than 12 weeks. Patients with active 
infections were excluded from clinical studies and were required to have their infection treated prior to 
receiving pembrolizumab. Patients with active infections occurring during treatment with 
pembrolizumab were managed with appropriate medical therapy. Patients with clinically significant 
renal (creatinine > 1.5 x ULN) or hepatic (bilirubin > 1.5 x ULN, ALT, AST > 2.5 x ULN in the 
absence of liver metastases) abnormalities at baseline were excluded from clinical studies, therefore 
information is limited in patients with severe renal and moderate to severe hepatic impairment.

There are limited data on the safety and efficacy of KEYTRUDA in patients with ocular melanoma 
(see section 5.1).

For subjects with relapsed or refractory cHL, clinical data for the use of pembrolizumab in patients 
ineligible to ASCT due to reasons other than failure to salvage chemotherapy are limited (see
section 5.1).

 



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After careful consideration of the potential increased risk, pembrolizumab may be used with 
appropriate medical management in these patients. 

Patient alert card
All prescribers of KEYTRUDA must be familiar with the Physician Information and Management 
Guidelines. The prescriber must discuss the risks of KEYTRUDA 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

No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. Since 
pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug 
interactions are expected. 

The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be 
avoided because of their potential interference with the pharmacodynamic activity and efficacy of 
pembrolizumab. However, systemic corticosteroids or other immunosuppressants can be used after 
starting pembrolizumab to treat immune-related adverse reactions (see section 4.4). Corticosteroids 
can also be used as premedication, when pembrolizumab is used in combination with chemotherapy, 
as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
Women of childbearing potential should use effective contraception during treatment with 
pembrolizumab and for at least 4 months after the last dose of pembrolizumab.

Pregnancy
There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have 
not been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1 
signalling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss
(see section 5.3). These results indicate a potential risk, based on its mechanism of action, that 
administration of pembrolizumab during pregnancy could cause foetal harm, including increased rates 
of abortion or stillbirth. Human immunoglobulins G4 (IgG4) are known to cross the placental barrier; 
therefore, being an IgG4, pembrolizumab has the potential to be transmitted from the mother to the 
developing foetus. Pembrolizumab should not be used during pregnancy unless the clinical condition 
of the woman requires treatment with pembrolizumab.

Breast-feeding
It is unknown whether pembrolizumab is secreted in human milk. Since it is known that antibodies can 
be secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision should be 
made whether to discontinue breast-feeding or to discontinue pembrolizumab, taking into account the 
benefit of breast-feeding for the child and the benefit of pembrolizumab therapy for the woman.

Fertility
No clinical data are available on the possible effects of pembrolizumab on fertility. There were no 
notable effects in the male and female reproductive organs in monkeys based on 1-month and 6-month 
repeat-dose toxicity studies (see section 5.3).

4.7 Effects on ability to drive and use machines

Pembrolizumab has a minor influence on the ability to drive and use machines. In some patients, 
dizziness and fatigue have been reported following administration of pembrolizumab (see section 4.8).

 



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4.8 Undesirable effects

Summary of the safety profile
Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these, 
including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal 
of pembrolizumab (see “Description of selected adverse reactions” below).

The safety of pembrolizumab as monotherapy has been evaluated in 5,884 patients with advanced 
melanoma, resected Stage III melanoma (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, or 
HNSCC across four doses (2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 
3 weeks) in clinical studies. The frequencies included below and in Table 2 are based on all reported 
adverse drug reactions, regardless of the investigator assessment of causality. In this patient 
population, the median observation time was 7.3 months (range: 1 day to 31 months) and the most 
frequent adverse reactions with pembrolizumab were fatigue (32%), nausea (20%), and 
diarrhoea (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 
severity. The most serious adverse reactions were immune-related adverse reactions and severe 
infusion-related reactions (see section 4.4).

The safety of pembrolizumab in combination with chemotherapy has been evaluated in 1,067 patients 
with NSCLC or HNSCC receiving 200 mg, 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks, in 
clinical studies. The frequencies included below and in Table 2 are based on all reported adverse drug 
reactions, regardless of the investigator assessment of causality. In this patient population, the most 
frequent adverse reactions were anaemia (50%), nausea (50%), fatigue (37%), constipation (35%), 
diarrhoea (30%), neutropaenia (30%), decreased appetite (28%) and vomiting (25%). Incidences of 
Grades 3-5 adverse reactions in patients with NSCLC were 67% for pembrolizumab combination 
therapy and 66% for chemotherapy alone and in patients with HNSCC were 85% for pembrolizumab 
combination therapy and 84% for chemotherapy plus cetuximab.

The safety of pembrolizumab in combination with axitinib has been evaluated in a clinical study of 
429 patients with advanced RCC receiving 200 mg pembrolizumab every 3 weeks and 5 mg axitinib 
twice daily. In this patient population, the most frequent adverse reactions were diarrhoea (54%), 
hypertension (45%), fatigue (38%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar 
erythrodysaesthesia syndrome (28%), nausea (28%), ALT increased (27%), AST increased (26%), 
dysphonia (25%), cough (21%), and constipation (21%). Incidences of Grades 3-5 adverse reactions 
were 76% for pembrolizumab combination therapy and 71% for sunitinib alone.

Tabulated list of adverse reactions
Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination 
with chemotherapy or other anti-tumour medicines or reported from post-marketing use of 
pembrolizumab are listed in Table 2. Adverse reactions known to occur with pembrolizumab or 
chemotherapies given alone may occur during treatment with these medicinal products in 
combination, even if these reactions were not reported in clinical studies with combination therapy. 
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); and not known (cannot be estimated from the 
available data). Within each frequency grouping, adverse reactions are presented in the order of 
decreasing seriousness.

Table 2: Adverse reactions in patients treated with pembrolizumab*

Monotherapy Combination with 
chemotherapy

Combination with 
axitinib

Infections and infestations
Common pneumonia pneumonia pneumonia
Blood and lymphatic system disorders
Very common anaemia anaemia, neutropaenia, 

thrombocytopaenia

 



13

Monotherapy Combination with 
chemotherapy

Combination with 
axitinib

Common thrombocytopaenia, 
lymphopaenia

febrile neutropaenia, 
leukopaenia, 
lymphopaenia

anaemia, neutropaenia, 
leukopaenia, 
thrombocytopaenia

Uncommon neutropaenia, leukopaenia, 
eosinophilia

lymphopaenia, 
eosinophilia

Rare immune thrombocytopenic 
purpura, haemolytic 
anaemia, pure red cell 
aplasia, haemophagocytic 
lymphohistiocytosis

eosinophilia

Immune system disorders
Common infusion-related reactiona infusion-related reactiona infusion-related 

reactiona

Uncommon sarcoidosis
Not known solid organ transplant 

rejection
Endocrine disorders
Very common hypothyroidismb hyperthyroidism, 

hypothyroidismb

Common hyperthyroidism hypothyroidism, 
hyperthyroidism

hypophysitisd, 
thyroiditise, adrenal 
insufficiencyc

Uncommon adrenal insufficiencyc, 
hypophysitisd, thyroiditise

hypophysitisd, 
thyroiditise, adrenal 
insufficiencyc

Metabolism and nutrition disorders
Very common decreased appetite hypokalaemia, decreased 

appetite
decreased appetite

Common hyponatraemia, 
hypokalaemia, 
hypocalcaemia

hyponatraemia, 
hypocalcaemia 

hypokalaemia, 
hyponatraemia, 
hypocalcaemia

Uncommon type 1 diabetes mellitusf type 1 diabetes mellitus type 1 diabetes mellitusf

Psychiatric disorders
Common insomnia insomnia insomnia
Nervous system disorders
Very common headache dizziness, headache, 

neuropathy peripheral, 
dysgeusia

headache, dysgeusia

Common dizziness, neuropathy 
peripheral, lethargy,
dysgeusia

lethargy dizziness, lethargy, 
neuropathy peripheral

Uncommon epilepsy epilepsy myasthenic syndromei

Rare encephalitis, Guillain-Barré 
syndromeg, myelitish, 
myasthenic syndromei, 
meningitis (aseptic)j

Eye disorders 
Common dry eye dry eye dry eye
Uncommon uveitisk uveitisk

Rare Vogt-Koyanagi-Harada 
syndrome

Cardiac disorders

 



14

Monotherapy Combination with 
chemotherapy

Combination with 
axitinib

Common cardiac arrhythmia†

(including atrial 
fibrillation)

cardiac arrhythmia†

(including atrial 
fibrillation)

cardiac arrhythmia†

(including atrial 
fibrillation)

Uncommon pericardial effusion, 
pericarditis

pericardial effusion myocarditisl

Rare myocarditisl myocarditisl, pericarditis
Vascular disorders
Very common hypertension
Common hypertension hypertension
Respiratory, thoracic and mediastinal 
disorders
Very common dyspnoea, cough dyspnoea, cough dyspnoea, cough, 

dysphonia
Common pneumonitism pneumonitism pneumonitism

Gastrointestinal disorders
Very common diarrhoea, abdominal painn, 

nausea, vomiting, 
constipation

diarrhoea, nausea, 
vomiting, constipation, 
abdominal painn

diarrhoea, abdominal 
painn, nausea, vomiting, 
constipation

Common colitiso, dry mouth colitiso, dry mouth colitiso, dry mouth
Uncommon pancreatitisp,

gastrointestinal ulcerationq
pancreatitisp,
gastrointestinal 
ulcerationq

pancreatitisp,
gastrointestinal 
ulcerationq

Rare small intestinal perforation
Hepatobiliary disorders
Common hepatitisr

Uncommon hepatitisr hepatitisr

Skin and subcutaneous tissue disorders
Very common rashs, pruritust rashs, alopecia, pruritust palmar-plantar 

erythrodysaesthesia 
syndrome, rashs, 
pruritust

Common severe skin reactionsu, 
erythema, dry skin, 
vitiligov, eczema, alopecia, 
dermatitis acneiform

severe skin reactionsu, 
erythema, dry skin

severe skin reactionsu, 
dermatitis acneiform, 
dermatitis, dry skin, 
alopecia, eczema, 
erythema 

Uncommon lichenoid keratosisw, 
psoriasis, dermatitis, 
papule, hair colour changes

psoriasis, dermatitis 
acneiform, dermatitis, 
vitiligov, eczema

hair colour changes, 
lichenoid keratosis, 
papule, psoriasis, 
vitiligov

Rare toxic epidermal necrolysis, 
Stevens-Johnson syndrome, 
erythema nodosum

hair colour changes, 
lichenoid keratosis, 
papule

Musculoskeletal and connective tissue 
disorders 
Very common musculoskeletal painx, 

arthralgia
musculoskeletal painx, 
arthralgia

musculoskeletal painx, 
arthralgia, pain in 
extremity

Common pain in extremity, 
myositisy, arthritisz

myositisy, pain in 
extremity, arthritisz

myositisy, arthritisz, 
tenosynovitisaa

Uncommon tenosynovitisaa tenosynovitisaa Sjogren’s syndrome
Rare Sjogren’s syndrome Sjogren’s syndrome

 



15

Monotherapy Combination with 
chemotherapy

Combination with 
axitinib

Renal and urinary disorders
Common nephritisbb, acute kidney 

injury
acute kidney injury,
nephritisbb

Uncommon nephritisbb

General disorders and administration site 
conditions
Very common fatigue, asthenia, oedemacc, 

pyrexia
fatigue, asthenia, pyrexia, 
oedemacc

fatigue, asthenia, 
pyrexia

Common influenza-like illness, chills chills, influenza-like 
illness

oedemacc, influenza-like 
illness, chills

Investigations 
Very common blood creatinine 

increased
alanine aminotransferase 
increased, aspartate 
aminotransferase 
increased, blood 
creatinine increased

Common aspartate aminotransferase 
increased, alanine 
aminotransferase increased, 
hypercalcaemia, blood 
alkaline phosphatase 
increased, blood bilirubin 
increased, blood creatinine 
increased

hypercalcaemia, alanine 
aminotransferase 
increased, aspartate 
aminotransferase 
increased, blood alkaline 
phosphatase increased

blood alkaline 
phosphatase increased, 
hypercalcaemia, blood 
bilirubin increased

Uncommon amylase increased blood bilirubin increased, 
amylase increased

amylase increased

*Adverse reaction frequencies presented in Table 2 may not be fully attributable to pembrolizumab alone but may contain 
contributions from the underlying disease or from other medicinal products used in a combination.
†Based upon a standard query including bradyarrhythmias and tachyarrhythmias.

 



16

The following terms represent a group of related events that describe a medical condition rather than a single event:
a. infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity and 

cytokine release syndrome)
b. hypothyroidism (myxoedema)
c. adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency)
d. hypophysitis (hypopituitarism)
e. thyroiditis (autoimmune thyroiditis and thyroid disorder)
f. type 1 diabetes mellitus (diabetic ketoacidosis)
g. Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy)
h. myelitis (including transverse myelitis)
i. myasthenic syndrome (myasthenia gravis, including exacerbation)
j. meningitis aseptic (meningitis, meningitis non-infective)
k. uveitis (iritis and iridocyclitis)
l. myocarditis (autoimmune myocarditis)
m. pneumonitis (interstitial lung disease and organising pneumonia)
n. abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)
o. colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, and autoimmune colitis)
p. pancreatitis (autoimmune pancreatitis and pancreatitis acute)
q. gastrointestinal ulceration (gastric ulcer and duodenal ulcer)
r. hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis)
s. rash (rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash 

pruritic, rash vesicular and genital rash)
t. pruritus (urticaria, urticaria papular, pruritus generalised and pruritus genital) 
u. severe skin reactions (dermatitis bullous, dermatitis exfoliative, dermatitis exfoliative generalised, erythema 

multiforme, exfoliative rash, pemphigus, skin necrosis, toxic skin eruption and Grade ≥ 3 of the following: acute 
febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis psoriasiform, drug eruption, jaundice, 
pemphigoid, pruritus, pruritus generalised, rash, rash erythematous, rash generalised, rash maculo-papular, rash 
pruritic, rash pustular and skin lesion)

v. vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid)
w. lichenoid keratosis (lichen planus and lichen sclerosus)
x. musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain 

and torticollis)
y. myositis (myalgia, myopathy, polymyalgia rheumatica and rhabdomyolysis)
z. arthritis (joint swelling, polyarthritis and joint effusion)
aa. tenosynovitis (tendonitis, synovitis and tendon pain)
bb. nephritis (nephritis autoimmune, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney 

injury with evidence of nephritis, nephrotic syndrome and glomerulonephritis membranous)
cc. oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face 

oedema, localised oedema and periorbital oedema)

Description of selected adverse reactions
Data for the following immune-related adverse reactions are based on patients who received 
pembrolizumab across four doses (2 mg/kg every 3 weeks, 10 mg/kg every 2 or 3 weeks, or 200 mg 
every 3 weeks) in clinical studies (see section 5.1). The management guidelines for these adverse 
reactions are described in section 4.4.

Immune-related adverse reactions (see section 4.4)

Immune-related pneumonitis
Pneumonitis occurred in 253 (4.3%) patients, including Grade 2, 3, 4 or 5 cases in 106 (1.8%), 
69 (1.2%), 13 (0.2%) and 9 (0.2%) patients, respectively, receiving pembrolizumab. The median time 
to onset of pneumonitis was 3.3 months (range 2 days to 26.8 months). The median duration was 
1.9 months (range 1 day to 25.3+ months). Pneumonitis occurred more frequently in patients with a 
history of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation 
(3.4%). Pneumonitis led to discontinuation of pembrolizumab in 98 (1.7%) patients. Pneumonitis 
resolved in 138 patients, 2 with sequelae.

In patients with NSCLC, pneumonitis occurred in 160 (5.7%), including Grade 2, 3, 4 or 5 cases in 62 
(2.2%), 47 (1.7%), 14 (0.5%) and 10 (0.4%), respectively. In patients with NSCLC, pneumonitis 
occurred in 8.9% with a history of prior thoracic radiation.

Immune-related colitis
Colitis occurred in 107 (1.8%) patients, including Grade 2, 3 or 4 cases in 31 (0.5%), 62 (1.1%) and 
3 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 

 



17

4.3 months (range 7 days to 24.3 months). The median duration was 0.9 months (range 1 day to 
8.7+ months). Colitis led to discontinuation of pembrolizumab in 29 (0.5%) patients. Colitis resolved 
in 84 patients, 2 with sequelae.

Immune-related hepatitis
Hepatitis occurred in 50 (0.8%) patients, including Grade 2, 3 or 4 cases in 8 (0.1%), 31 (0.5%) and 
8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 
3.6 months (range 8 days to 21.4 months). The median duration was 1.1 months (range 1 day to 
20.9+ months). Hepatitis led to discontinuation of pembrolizumab in 19 (0.3%) patients. Hepatitis 
resolved in 36 patients.

Immune-related nephritis 
Nephritis occurred in 22 (0.4%) patients, including Grade 2, 3 or 4 cases in 5 (0.1%), 14 (0.2%) and 
1 (< 0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset 
of nephritis was 5.0 months (range 12 days to 21.4 months). The median duration was 2.6 months 
(range 6 days to 12.0 months). Nephritis led to discontinuation of pembrolizumab in 10 (0.2%) 
patients. Nephritis resolved in 13 patients, 3 with sequelae. In patients with non-squamous NSCLC 
treated with pembrolizumab in combination with pemetrexed and platinum chemotherapy (n=488), the 
incidence of nephritis was 1.4% (all Grades) with 0.8% Grade 3 and 0.4% Grade 4.

Immune-related endocrinopathies
Adrenal insufficiency occurred in 46 (0.8%) patients, including Grade 2, 3 or 4 cases in 19 (0.3%), 
20 (0.3%) and 3 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of 
adrenal insufficiency was 5.4 months (range 1 day to 17.7 months). The median duration was not 
reached (range 3 days to 26.2+ months). Adrenal insufficiency led to discontinuation of 
pembrolizumab in 4 (0.1%) patients. Adrenal insufficiency resolved in 16 patients, 4 with sequelae.

Hypophysitis occurred in 36 (0.6%) patients, including Grade 2, 3 or 4 cases in 13 (0.2%), 19 (0.3%) 
and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of 
hypophysitis was 5.9 months (range 1 day to 17.7 months). The median duration was 3.3 months 
(range 3 days to 18.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 8 (0.1%) 
patients. Hypophysitis resolved in 17 patients, 8 with sequelae.

Hyperthyroidism occurred in 244 (4.1%) patients, including Grade 2 or 3 cases in 64 (1.1%) and 
7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of 
hyperthyroidism was 1.4 months (range 1 day to 22.5 months). The median duration was 1.8 months 
(range 4 days to 29.2+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 3 (0.1%) 
patients. Hyperthyroidism resolved in 191 (78.3%) patients, 5 with sequelae.

Hypothyroidism occurred in 645 (11.0%) patients, including Grade 2 or 3 cases in 475 (8.1%) and 
8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of 
hypothyroidism was 3.5 months (range 1 day to 19.6 months). The median duration was not reached 
(range 2 days to 32.6+ months). Two patients (< 0.1%) discontinued pembrolizumab due to 
hypothyroidism. Hypothyroidism resolved in 153 (23.7%) patients, 10 with sequelae. In patients with 
cHL (n=241) the incidence of hypothyroidism was 14.1% (all Grades) with 0.4% Grade 3. In patients 
with HNSCC treated with pembrolizumab as monotherapy (n=909), the incidence of hypothyroidism 
was 16.1% (all Grades) with 0.3% Grade 3. In patients with HNSCC treated with pembrolizumab in 
combination with platinum and 5-FU chemotherapy (n=276), the incidence of hypothyroidism 
was 15.2%, all of which were Grade 1 or 2.

Immune-related skin adverse reactions
Immune-related severe skin reactions occurred in 89 (1.5%) patients, including Grade 2, 3 or 5 cases 
in 10 (0.2%), 65 (1.1%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median 
time to onset of severe skin reactions was 3.3 months (range 3 days to 19.4 months). The median 
duration was 1.6 months (range 1 day to 27.3+ months). Severe skin reactions led to discontinuation of 
pembrolizumab in 9 (0.2%) patients. Severe skin reactions resolved in 64 patients.

 



18

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed (see sections 4.2 
and 4.4).

Complications of allogeneic HSCT in cHL
Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with pembrolizumab, 
6 patients (26%) developed GVHD, one of which was fatal, and 2 patients (9%) developed severe 
hepatic VOD after reduced-intensity conditioning, one of which was fatal. The 23 patients had a 
median follow-up from subsequent allogeneic HSCT of 5.1 months (range: 0-26.2 months).

Elevated liver enzymes when pembrolizumab is combined with axitinib in RCC
In a clinical study of previously untreated patients with RCC receiving pembrolizumab in combination 
with axitinib, a higher than expected incidence of Grades 3 and 4 ALT increased (20%) and AST 
increased (13%) were observed. The median time to onset of ALT increased was 2.3 months (range: 
7 days to 19.8 months). In patients with ALT ≥ 3 times ULN (Grades 2-4, n=116), ALT resolved to 
Grades 0-1 in 94%. Fifty-nine percent of the patients with increased ALT received systemic 
corticosteroids. Of the patients who recovered, 92 (84%) were rechallenged with either 
pembrolizumab (3%) or axitinib (31%) monotherapy or with both (50%). Of these patients, 55% had 
no recurrence of ALT > 3 times ULN, and of those patients with recurrence of ALT > 3 times ULN, 
all recovered. There were no Grade 5 hepatic events. 

Laboratory abnormalities 
In patients treated with pembrolizumab monotherapy, the proportion of patients who experienced a 
shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 10.9% for lymphocytes 
decreased, 8.2% for sodium decreased, 6.3% for haemoglobin decreased, 5.2% for phosphate 
decreased, 4.8% for glucose increased, 2.8% for AST increased, 2.7% for alkaline phosphatase 
increased, 2.7% for ALT increased, 2.2% for potassium decreased, 1.8% for calcium increased, 1.8% 
for neutrophils decreased, 1.8% for potassium increased, 1.7% for bilirubin increased, 1.7% for 
platelets decreased, 1.6% for albumin decreased, 1.5% for calcium decreased, 1.3% for creatinine 
increased, 0.8% for leucocytes decreased, 0.7% for magnesium increased, 0.6% for glucose decreased, 
0.2% for magnesium decreased, and 0.2% for sodium increased.

In patients treated with pembrolizumab in combination with chemotherapy, the proportion of patients 
who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 26.7% 
for neutrophils decreased, 23.9% for lymphocytes decreased, 19.1% for haemoglobin decreased, 
17.9% for leucocytes decreased, 12.2% for platelets decreased, 10.2% for sodium decreased, 8.9% for 
phosphate decreased, 7.4% for glucose increased, 6.5% for potassium decreased, 3.3 for creatinine 
increased, 3.1% for ALT increased, 3.1% for AST increased, 3.1% for calcium decreased, 3.0% for 
potassium increased, 2.9% for albumin decreased, 2.3% for calcium increased, 1.2% for alkaline 
phosphatase increased, 0.8% for glucose decreased, 0.7% for bilirubin increased, and 0.3% for sodium 
increased.

In patients treated with pembrolizumab in combination with axitinib, the proportion of patients who 
experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 20.1% for 
ALT increased, 13.2% for AST increased, 10.8% for lymphocytes decreased, 8.9% for glucose 
increased, 7.8% for sodium decreased, 6.4% for phosphate decreased, 6.2% for potassium increased, 
4.3% for creatinine increased, 3.6% for potassium decreased, 2.1% for bilirubin increased, 2.1% for 
haemoglobin decreased, 1.7% for alkaline phosphatase increased, 1.5% for prothrombin INR 
increased, 1.4% for leukocytes decreased, 1.4% for platelets decreased, 1.2% for activated partial 
thromboplastin time prolonged, 1.2% for neutrophils decreased, 1.2% for sodium increased, 0.7% for 
calcium decreased, 0.7% for calcium increased, 0.5% for albumin decreased, and 0.2% for glucose 
decreased.

Immunogenicity
In clinical studies in patients treated with pembrolizumab 2 mg/kg every three weeks, 200 mg every 
three weeks, or 10 mg/kg every two or three weeks as monotherapy, 36 (1.8%) of 2,034 evaluable
patients tested positive for treatment-emergent antibodies to pembrolizumab, of which 9 (0.4%) 
patients had neutralising antibodies against pembrolizumab. There was no evidence of an altered 

 



19

pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody 
development.

Paediatric population
The safety of pembrolizumab as monotherapy has been evaluated in 154 paediatric patients with 
advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours at
2 mg/kg every 3 weeks in the Phase I/II study KEYNOTE-051. The safety profile in these paediatric 
patients was generally similar to that seen in adults treated with pembrolizumab. The most common 
adverse reactions (reported in at least 20% of paediatric patients) were pyrexia (31%), 
vomiting (26%), headache (22%), abdominal pain (21%), anaemia (21%) and constipation (20%). The 
majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. 
Sixty-nine (44.8%) patients had 1 or more Grades 3 to 5 adverse reactions of which 6 (3.9%) patients
had 1 or more adverse reactions that resulted in death. The frequencies are based on all reported 
adverse drug reactions, regardless of the investigator assessment of causality.

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

There is no information on overdose with pembrolizumab. 

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions,
and appropriate symptomatic treatment instituted.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC18

Mechanism of action
KEYTRUDA is a humanised monoclonal antibody which binds to the programmed cell death-1 
(PD-1) receptor and blocks its interaction with ligands 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. KEYTRUDA potentiates T-cell responses, including anti-tumour responses, 
through blockade of PD-1 binding to 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.

Clinical efficacy and safety
Pembrolizumab doses of 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 
2 weeks were evaluated in melanoma or previously treated NSCLC clinical studies. Based on the 
modelling and simulation of dose/exposure relationships for efficacy and safety for pembrolizumab, 
there are no clinically significant differences in efficacy or safety among the doses of 200 mg every 
3 weeks, 2 mg/kg every 3 weeks, and 400 mg every 6 weeks as monotherapy (see section 4.2).

Melanoma
KEYNOTE-006: Controlled study in melanoma patients naïve to treatment with ipilimumab
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-006, a multicentre, 
open-label, controlled, Phase III study for the treatment of advanced melanoma in patients who were 
naïve to ipilimumab. Patients were randomised (1:1:1) to receive pembrolizumab 10 mg/kg every 2 
(n=279) or 3 weeks (n=277) or ipilimumab 3 mg/kg every 3 weeks (n=278). Patients with BRAF 
V600E mutant melanoma were not required to have received prior BRAF inhibitor therapy.

 

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20

Patients were treated with pembrolizumab until disease progression or unacceptable toxicity.
Clinically stable patients with initial evidence of disease progression were permitted to remain on 
treatment until disease progression was confirmed. Assessment of tumour status was performed at 
12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. 

Of the 834 patients, 60% were male, 44% were ≥ 65 years (median age was 62 years [range 18-89]) 
and 98% were white. Sixty-five percent of patients had M1c stage, 9% had a history of brain 
metastases, 66% had no and 34% had one prior therapy. Thirty-one percent had an ECOG 
Performance Status of 1, 69% had ECOG Performance Status of 0 and 32% had elevated LDH. BRAF 
mutations were reported in 302 (36%) patients. Among patients with BRAF mutant tumours, 
139 (46%) were previously treated with a BRAF inhibitor.

The primary efficacy outcome measures were progression free survival (PFS; as assessed by 
Integrated Radiology and Oncology Assessment [IRO] review using Response Evaluation Criteria in 
Solid Tumours [RECIST], version 1.1) and overall survival (OS). Secondary efficacy outcome 
measures were objective response rate (ORR) and response duration. Table 3 summarises key efficacy 
measures in patients naïve to treatment with ipilimumab at the final analysis performed after a 
minimum of 21 months of follow-up. Kaplan-Meier curves for OS and PFS based on the final analysis 
are shown in Figures 1 and 2.

 



21

Table 3: Efficacy results in KEYNOTE-006

Endpoint Pembrolizumab
10 mg/kg every 

3 weeks
n=277

Pembrolizumab
10 mg/kg every 

2 weeks
n=279

Ipilimumab
3 mg/kg every 

3 weeks
n=278

OS
Number (%) of 
patients with event

119 (43%) 122 (44%) 142 (51%)

Hazard ratio*
(95% CI)

0.68 (0.53, 0.86) 0.68 (0.53, 0.87) ---

p-Value† < 0.001 < 0.001 ---
Median in months 
(95% CI)

Not reached
(24, NA)

Not reached
(22, NA)

16
(14, 22)

PFS
Number (%) of 
patients with event

183 (66%) 181 (65%) 202 (73%)

Hazard ratio*
(95% CI)

0.61 (0.50, 0.75) 0.61 (0.50, 0.75) ---

p-Value† < 0.001 < 0.001 ---
Median in months 
(95% CI)

4.1
(2.9, 7.2)

5.6
(3.4, 8.2)

2.8
(2.8, 2.9)

Best objective
response

ORR % (95% CI) 36%
(30, 42)

37%
(31, 43)

13%
(10, 18)

Complete 
response %

13% 12% 5%

Partial response % 23% 25% 8%
Response duration‡

Median in months 
(range)

Not reached
(2.0, 22.8+)

Not reached
(1.8, 22.8+)

Not reached
(1.1+, 23.8+)

% ongoing at 18 
months

68%§ 71%§ 70%§

* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportional 
hazard model

† Based on stratified log-rank test
‡ Based on patients with a best objective response as confirmed complete or partial response
§ Based on Kaplan-Meier estimation
NA = not available

 



22

Figure 1: Kaplan-Meier curve for overall survival by treatment arm in 
KEYNOTE-006 (intent to treat population)

Figure 2: Kaplan-Meier curve for progression-free survival by treatment arm in 
KEYNOTE-006 (intent to treat population)

ipilimumab:

Pembrolizumab 10 mg/kg every 3 weeks:

Pembrolizumab 10 mg/kg every 2 weeks:

278 213 170 145 122 110 28 0

279 249 221 202 176 156 44 0

277 251 215 184 174 156 43 0

Number at Risk

Treatment arm                                           OS rate at 24 months         HR (95% CI)          p-value
Pembrolizumab 10 mg/kg every 2 weeks              55.1%                 0.68 (0.53, 0.87)        0.00085
Pembrolizumab 10 mg/kg every 3 weeks              55.3%                 0.68 (0.53, 0.86)        0.00083
ipilimumab                                                              43.0%                             

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ipilimumab:

Pembrolizumab 10 mg/kg every 3 weeks:

Pembrolizumab 10 mg/kg every 2 weeks:

278 88 48 34 29 16 5 0

279 148 116 98 82 52 16 0

277 136 111 91 84 60 13 0

Number at Risk

Treatment arm                                          PFS rate at 18 months          HR (95% CI)           p-value
Pembrolizumab 10 mg/kg every 2 weeks                32.4%                  0.61 (0.50, 0.75)        0.00000
Pembrolizumab 10 mg/kg every 3 weeks                32.9%                  0.61 (0.50, 0.75)        0.00000
ipilimumab                                                                15.2% 

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KEYNOTE-002: Controlled study in melanoma patients previously treated with ipilimumab
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-002, a multicentre, 
double-blind, controlled study for the treatment of advanced melanoma in patients previously treated 
with ipilimumab and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor. Patients were 
randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=180) or 10 mg/kg (n=181) every 
3 weeks or chemotherapy (n=179; including dacarbazine, temozolomide, carboplatin, paclitaxel, or 
carboplatin+paclitaxel). The study excluded patients with autoimmune disease or those receiving 
immunosuppression; further exclusion criteria were a history of severe or life-threatening 
immune-related adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or 
Grade 3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent dose) for 
greater than 12 weeks; ongoing adverse reactions ≥ Grade 2 from previous treatment with ipilimumab; 
previous severe hypersensitivity to other monoclonal antibodies; a history of pneumonitis or interstitial 
lung disease; HIV, hepatitis B or hepatitis C infection and ECOG Performance Status ≥ 2. 

Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. 
Clinically stable patients with initial evidence of disease progression were permitted to remain on 
treatment until disease progression was confirmed. Assessment of tumour status was performed at 
12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. Patients on 
chemotherapy who experienced independently-verified progression of disease after the first scheduled 
disease assessment were able to crossover and receive 2 mg/kg or 10 mg/kg of pembrolizumab every 
3 weeks in a double-blind fashion.

Of the 540 patients, 61% were male, 43% were ≥ 65 years (median age was 62 years [range 15-89]) 
and 98% were white. Eighty-two percent had M1c stage, 73% had at least two and 32% of patients had 
three or more prior systemic therapies for advanced melanoma. Forty-five percent had an ECOG 
Performance Status of 1, 40% had elevated LDH and 23% had a BRAF mutated tumour. 

The primary efficacy outcome measures were PFS as assessed by IRO using RECIST version 1.1 and 
OS. Secondary efficacy outcome measures were ORR and response duration. Table 4 summarises key 
efficacy measures at the final analysis in patients previously treated with ipilimumab, and the 
Kaplan-Meier curve for PFS is shown in Figure 3. Both pembrolizumab arms were superior to 
chemotherapy for PFS, and there was no difference between pembrolizumab doses. There was no 
statistically significant difference between pembrolizumab and chemotherapy in the final OS analysis 
that was not adjusted for the potentially confounding effects of crossover. Of the patients randomised 
to the chemotherapy arm, 55% crossed over and subsequently received treatment with pembrolizumab.

 



24

Table 4: Efficacy results in KEYNOTE-002

Endpoint Pembrolizumab
2 mg/kg every 

3 weeks
n=180

Pembrolizumab
10 mg/kg every 

3 weeks
n=181

Chemotherapy

n=179
PFS

Number (%) 
of patients 
with event

150 (83%) 144 (80%) 172 (96%)

Hazard ratio* 
(95% CI)

0.58 (0.46, 0.73) 0.47 (0.37, 0.60) ---

p-Value† < 0.001 < 0.001 ---
Median in 
months 
(95% CI)

2.9 (2.8, 3.8) 3.0 (2.8, 5.2) 2.8 (2.6, 2.8)

OS
Number (%) 
of patients 
with event

123 (68%) 117 (65%) 128 (72%)

Hazard ratio* 
(95% CI)

0.86 (0.67, 1.10) 0.74 (0.57, 0.96) ---

p-Value† 0.1173 0.0106‡ ---
Median in 
months 
(95% CI)

13.4 (11.0, 16.4) 14.7 (11.3, 19.5) 11.0 (8.9, 13.8)

Best objective
response

ORR % 
(95% CI)

22% (16, 29) 28% (21, 35) 5% (2, 9)

Complete 
response %

3% 7% 0%

Partial 
response %

19% 20% 5%

Response 
duration§

Median in 
months 
(range)

22.8 
(1.4+, 25.3+)

Not reached 
(1.1+, 28.3+)

6.8
(2.8, 11.3)

% ongoing at 
12 months

73% ¶ 79% ¶ 0% ¶

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox 
proportional hazard model

† Based on stratified log-rank test 
‡ Not statistically significant after adjustment for multiplicity
§ Based on patients with a best objective response as confirmed complete or partial 

response from the final analysis
¶ Based on Kaplan-Meier estimation

 



25

Figure 3: Kaplan-Meier curve for progression-free survival by treatment arm in 
KEYNOTE-002 (intent to treat population)

KEYNOTE-001: Open-label study in melanoma patients naïve and previously treated with ipilimumab
The safety and efficacy of pembrolizumab for patients with advanced melanoma were investigated in 
an uncontrolled, open-label study, KEYNOTE-001. Efficacy was evaluated for 276 patients from two 
defined cohorts, one which included patients previously treated with ipilimumab (and if BRAF V600 
mutation-positive, with a BRAF or MEK inhibitor) and the other which included patients naïve to 
treatment with ipilimumab. Patients were randomly assigned to receive pembrolizumab at a dose of 
2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. Patients were treated with pembrolizumab until 
disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease 
progression were permitted to remain on treatment until disease progression was confirmed. Exclusion 
criteria were similar to those of KEYNOTE-002.

Of the 89 patients receiving 2 mg/kg of pembrolizumab who were previously treated with ipilimumab, 
53% were male, 33% were ≥ 65 years of age and the median age was 59 years (range 18-88). All but 
two patients were white. Eighty-four percent had M1c stage and 8% of patients had a history of brain 
metastases. Seventy percent had at least two and 35% of patients had three or more prior systemic 
therapies for advanced melanoma. BRAF mutations were reported in 13% of the study population. All 
patients with BRAF mutant tumours were previously treated with a BRAF inhibitor.

Of the 51 patients receiving 2 mg/kg of pembrolizumab who were naïve to treatment with ipilimumab, 
63% were male, 35% were ≥ 65 years of age and the median age was 60 years (range 35-80). All but 
one patient was white. Sixty-three percent had M1c stage and 2% of patients had a history of brain 
metastases. Forty-five percent had no prior therapies for advanced melanoma. BRAF mutations were 
reported in 20 (39%) patients. Among patients with BRAF mutant tumours, 10 (50%) were previously 
treated with a BRAF inhibitor.

The primary efficacy outcome measure was ORR as assessed by independent review using 
RECIST 1.1. Secondary efficacy outcome measures were disease control rate (DCR; including 
complete response, partial response and stable disease), response duration, PFS and OS. Tumour 

Chemotherapy:

Pembrolizumab 10 mg/kg every 3 weeks:

Pembrolizumab   2 mg/kg every 3 weeks:

179 31 9 2 1 0 0

180 59 36 29 19 1 0

181 69 48 42 30 5 0

Number at Risk

Treatment arm                                          PFS rate at 18 months        HR (95% CI)          p-value
Pembrolizumab   2 mg/kg every 3 weeks                  19.6%               0.58 (0.46, 0.73)      <0.0001
Pembrolizumab 10 mg/kg every 3 weeks                  25.0%               0.47 (0.37, 0.60)      <0.0001
Chemotherapy                                                              1.3% 

0 3 6 9 12 15 18 21 24 27 30 33 36

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response was assessed at 12-week intervals. Table 5 summarises key efficacy measures in patients 
previously treated or naïve to treatment with ipilimumab, receiving pembrolizumab at a dose of 
2 mg/kg based on a minimum follow-up time of 30 months for all patients.

Table 5: Efficacy results in KEYNOTE-001

Endpoint Pembrolizumab 2 mg/kg 
every 3 weeks in patients 
previously treated with 

ipilimumab
n=89

Pembrolizumab 2 mg/kg 
every 3 weeks in patients 
naïve to treatment with 

ipilimumab
n=51

Best objective response* by 
IRO†

ORR %, (95% CI) 26% (17, 36) 35% (22, 50)
Complete response 7% 12%
Partial response 19% 24%

Disease control rate %‡ 48% 49%
Response duration§

Median in months (range) 30.5 (2.8+, 30.6+) 27.4 (1.6+, 31.8+)
% ongoing at 24 months¶ 75% 71%

PFS
Median in months (95% CI) 4.9 (2.8, 8.3) 4.7 (2.8, 13.8)
PFS rate at 12 months 34% 38%

OS
Median in months (95% CI) 18.9 (11, not available) 28.0 (14, not available)
OS rate at 24 months 44% 56%

* Includes patients without measurable disease at baseline by independent radiology
† IRO = Integrated radiology and oncologist assessment using RECIST 1.1
‡ Based on best response of stable disease or better
§ Based on patients with a confirmed response by independent review, starting from the date the response was first 

recorded; n=23 for patients previously treated with ipilimumab; n=18 for patients naïve to treatment with ipilimumab
¶ Based on Kaplan-Meier estimation

Results for patients previously treated with ipilimumab (n=84) and naïve to treatment with ipilimumab 
(n=52) who received 10 mg/kg of pembrolizumab every 3 weeks were similar to those seen in patients 
who received 2 mg/kg of pembrolizumab every 3 weeks. 

Sub-population analyses

BRAF mutation status in melanoma 
A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients who 
were BRAF wild type (n=414; 77%) or BRAF mutant with prior BRAF treatment (n=126; 23%) as 
summarised in Table 6.

 



27

Table 6: Efficacy results by BRAF mutation status in KEYNOTE-002

BRAF wild type BRAF mutant with prior BRAF treatment

Endpoint

Pembrolizumab
2 mg/kg every 

3 weeks (n=136)

Chemotherapy
(n=137)

Pembrolizumab
2 mg/kg every 3 weeks 

(n=44)

Chemotherapy 
(n=42)

PFS 
Hazard 
ratio* 
(95% CI)

0.50 (0.39, 0.66) --- 0.79 (0.50, 1.25) ---

OS
Hazard 
ratio* 
(95% CI)

0.78 (0.58, 1.04) --- 1.07 (0.64, 1.78) ---

ORR % 26% 6% 9% 0%
* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who 
were BRAF wild type (n=525; 63%), BRAF mutant without prior BRAF treatment (n=163; 20%) and 
BRAF mutant with prior BRAF treatment (n=139; 17%) as summarised in Table 7.

Table 7: Efficacy results by BRAF mutation status in KEYNOTE-006

BRAF wild type BRAF mutant without prior 
BRAF treatment

BRAF mutant with prior BRAF 
treatment

Endpoint

Pembrolizumab
10 mg/kg every 

2 or 3 weeks 
(pooled)

Ipilimumab 
(n=170)

Pembrolizumab
10 mg/kg every 2 

or 3 weeks 
(pooled)

Ipilimumab 
(n=55)

Pembrolizumab
10 mg/kg every 2 

or 3 weeks 
(pooled)

Ipilimumab 
(n=52)

PFS 
Hazard 
ratio* 
(95% CI)

0.61 (0.49, 0.76) --- 0.52 (0.35, 0.78) --- 0.76 (0.51, 1.14) ---

OS
Hazard 
ratio* 
(95% CI)

0.68 (0.52, 0.88) --- 0.70 (0.40, 1.22) --- 0.66 (0.41, 1.04) ---

ORR % 38% 14% 41% 15% 24% 10%
* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportional hazard model

PD-L1 status in melanoma
A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients who 
were PD-L1 positive (PD-L1 expression in ≥ 1% of tumour and tumour-associated immune cells
relative to all viable tumour cells – MEL score) vs. PD-L1 negative. PD-L1 expression was tested 
retrospectively by immunohistochemistry assay with the 22C3 anti-PD-L1 antibody. Among patients 
who were evaluable for PD-L1 expression (79%), 69% (n=294) were PD-L1 positive and 31% 
(n=134) were PD-L1 negative. Table 8 summarises efficacy results by PD-L1 expression.

 



28

Table 8: Efficacy results by PD-L1 expression in KEYNOTE-002

Endpoint Pembrolizumab
2 mg/kg every 

3 weeks

Chemotherapy Pembrolizumab
2 mg/kg every 

3 weeks

Chemotherapy

PD-L1 positive PD-L1 negative
PFS Hazard 
ratio*
(95% CI)

0.55 (0.40, 0.76) --- 0.81 (0.50, 1.31) ---

OS Hazard 
ratio*
(95% CI)

0.90 (0.63, 1.28) --- 1.18 (0.70, 1.99) ---

ORR % 25% 4% 10% 8%
* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional 
hazard model

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who 
were PD-L1 positive (n=671; 80%) vs. PD-L1 negative (n=150; 18%). Among patients who were 
evaluable for PD-L1 expression (98%), 82% were PD-L1 positive and 18% were PD-L1 negative. 
Table 9 summarises efficacy results by PD-L1 expression.

Table 9: Efficacy results by PD-L1 expression in KEYNOTE-006

Endpoint Pembrolizumab
10 mg/kg every 2 or 

3 weeks (pooled) 

Ipilimumab Pembrolizumab
10 mg/kg every 2 or 

3 weeks (pooled)

Ipilimumab

PD-L1 positive PD-L1 negative
PFS Hazard ratio* (95% CI) 0.53 (0.44, 0.65) --- 0.87 (0.58, 1.30) ---
OS Hazard ratio* (95% CI) 0.63 (0.50, 0.80) --- 0.76 (0.48, 1.19) ---
ORR % 40% 14% 24% 13%

* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportional hazard model

Ocular melanoma
In 20 subjects with ocular melanoma included in KEYNOTE-001, no objective responses were 
reported; stable disease was reported in 6 patients.

KEYNOTE-054: Placebo-controlled study for the adjuvant treatment of patients with completely 
resected melanoma
The efficacy of pembrolizumab was evaluated in KEYNOTE-054, a multicentre, randomised,
double-blind, placebo-controlled study in patients with completely resected stage IIIA (> 1 mm lymph 
node metastasis), IIIB or IIIC melanoma. A total of 1,019 adult patients were randomised (1:1) to 
receive pembrolizumab 200 mg every three weeks (n=514) or placebo (n=505), for up to one year 
until disease recurrence or unacceptable toxicity. Randomisation was stratified by American Joint 
Committee on Cancer (AJCC) 7th edition stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. 
IIIC ≥ 4 positive lymph nodes) and geographic region (North America, European countries, Australia 
and other countries as designated). Patients must have undergone lymph node dissection, and if 
indicated, radiotherapy within 13 weeks prior to starting treatment. Patients with active autoimmune 
disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were 
ineligible. Patients who received prior therapy for melanoma other than surgery or interferon for thick 
primary melanomas without evidence of lymph node involvement were ineligible. Patients underwent 
imaging every 12 weeks after the first dose of pembrolizumab for the first two years, then every 
6 months from year 3 to 5, and then annually.

Among the 1,019 patients, the baseline characteristics were: median age of 54 years (25% age 65 or 
older); 62% male; and ECOG PS of 0 (94%) and 1 (6%). Sixteen percent had stage IIIA; 46% had 
stage IIIB; 18% had stage IIIC (1-3 positive lymph nodes) and 20% had stage IIIC (≥ 4 positive lymph 
nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type. PD-L1 expression 

 



29

was tested retrospectively by immunohistochemistry assay with the 22C3 anti-PD-L1 antibody; 84% 
of patients had PD-L1-positive melanoma (PD-L1 expression in ≥ 1% of tumour and 
tumour-associated immune cells relative to all viable tumour cells). The same scoring system was used 
for metastatic melanoma (MEL score).

The primary efficacy outcome measures were investigator-assessed recurrence-free survival (RFS) in 
the whole population and in the population with PD-L1 positive tumours, where RFS was defined as 
the time between the date of randomisation and the date of first recurrence (local, regional, or distant 
metastasis) or death, whichever occurs first. The study demonstrated a statistically significant 
improvement in RFS for patients randomised to the pembrolizumab arm compared with placebo at the 
pre-specified interim analysis. Efficacy results based on an additional seven months of follow-up are
summarised in Table 10 and Figure 4.

Table 10: Efficacy results in KEYNOTE-054

Endpoint KEYTRUDA
200 mg every 

3 weeks
n=514

Placebo

n=505
Number (%) of patients with 
event 

158 (31%) 246 (49%)

Median in months (95% CI) NR 21.7 (17.1, NR)
Hazard ratio* (98% CI) 0.56 (0.44, 0.72)

p-Value (stratified log-rank) < 0.0001
RFS at 6 months

RFS rate 82% 73%
RFS at 12 months

RFS rate 76% 61%
RFS at 18 months

RFS rate 72% 54%
* Based on the stratified Cox proportional hazard model

NR = not reached

KEYNOTE-054 enrolled patients per AJCC 7th edition and a subgroup analysis of RFS per AJCC 
8th edition was performed after the RFS study results were reported. A statistically significant 
improvement in RFS for patients randomised to the pembrolizumab arm compared with placebo was 
demonstrated in the overall population across resected stage III melanoma per AJCC 7th edition. 
Stage IIIA melanoma according to the AJCC 8th edition identifies a patient population with a better 
prognosis compared to stage IIIA according to AJCC 7th edition. Per the AJCC 8th edition 
classification, a total of 82 subjects were classified as stage IIIA; 42 in the pembrolizumab arm and 40 
in the placebo arm; with a total of 13 RFS events; 6 in the pembrolizumab arm and 7 in the placebo 
arm. There is limited data on subjects with stage IIIA according to AJCC 8th edition at the time of this 
RFS analysis.

 



30

Figure 4: Kaplan-Meier curve for recurrence-free survival by treatment arm in KEYNOTE-054 
(intent to treat population)

While the analysis in patients with PD-L1 positive tumours was a co-primary endpoint, pre-defined
subgroup analyses were performed in patients whose tumours were PD-L1 negative, BRAF mutation 
positive or negative. Table 11 summarises efficacy results by PD-L1 expression and BRAF mutation 
status.

Table 11: Efficacy results by PD-L1 expression and BRAF mutation status in KEYNOTE-054

Endpoint Pembrolizumab
200 mg every 3 weeks

Placebo Pembrolizumab
200 mg every 3 weeks

Placebo

PD-L1 positive PD-L1 negative
n=428 n=425 n=59 n=57

RFS Hazard ratio* (95% CI) 0.54 (0.42, 0.69) --- 0.47 (0.26, 0.85) ---
RFS rate at 6 months 84% 75% 81% 64%

BRAF mutation positive BRAF mutation negative
n=245 n=262 n=233 n=214

RFS Hazard ratio* (95% CI) 0.49 (0.36, 0.67) --- 0.64 (0.47, 0.87) ---
RFS rate at 6 months 83% 73% 80% 72%

*Based on the stratified Cox proportional hazard model

NSCLC
KEYNOTE-024: Controlled study of NSCLC patients naïve to treatment
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-024, a multicentre, 
open-label, controlled study for the treatment of previously untreated metastatic NSCLC. Patients had 
PD-L1 expression with a ≥ 50% TPS based on the PD-L1 IHC 22C3 pharmDxTM Kit. Patients were 
randomised (1:1) to receive pembrolizumab at a dose of 200 mg every 3 weeks (n=154) or 
investigator’s choice platinum-containing chemotherapy (n=151; including pemetrexed+carboplatin, 
pemetrexed+cisplatin, gemcitabine+cisplatin, gemcitabine+carboplatin, or paclitaxel+carboplatin. 
Patients with non-squamous NSCLC could receive pemetrexed maintenance.). Patients were treated 
with pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue 
beyond disease progression if the patient was clinically stable and was considered to be deriving 
clinical benefit by the investigator. Patients without disease progression could be treated for up to 

 



31

24 months. The study excluded patients with EGFR or ALK genomic tumour aberrations; autoimmune 
disease that required systemic therapy within 2 years of treatment; a medical condition that required 
immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 
26 weeks. Assessment of tumour status was performed every 9 weeks. Patients on chemotherapy who 
experienced independently-verified progression of disease were able to crossover and receive 
pembrolizumab.

Among the 305 patients in KEYNOTE-024, baseline characteristics were: median age 65 years (54% 
age 65 or older); 61% male; 82% White, 15% Asian; and ECOG performance status 0 and 1 in 35% 
and 65%, respectively. Disease characteristics were squamous (18%) and non-squamous (82%); M1 
(99%); and brain metastases (9%).

The primary efficacy outcome measure was PFS as assessed by blinded independent central review
(BICR) using RECIST 1.1. Secondary efficacy outcome measures were OS and ORR (as assessed by 
BICR using RECIST 1.1). Table 12 summarises key efficacy measures for the entire intent to treat 
(ITT) population. PFS and ORR results are reported from an interim analysis at a median follow-up of 
11 months. OS results are reported from the final analysis at a median follow-up of 25 months.

Table 12: Efficacy results in KEYNOTE-024

Endpoint Pembrolizumab
200 mg every 

3 weeks
n=154

Chemotherapy

n=151
PFS

Number (%) of patients with 
event

73 (47%) 116 (77%)

Hazard ratio* (95% CI) 0.50 (0.37, 0.68)
p-Value† < 0.001
Median in months (95% CI) 10.3 (6.7, NA) 6.0 (4.2, 6.2)

OS
Number (%) of patients with 
event

73 (47%) 96 (64%)

Hazard ratio* (95% CI) 0.63 (0.47, 0.86)
p-Value† 0.002
Median in months (95% CI) 30.0

(18.3, NA)
14.2

(9.8, 19.0)
Objective response rate

ORR % (95% CI) 45% (37, 53) 28% (21, 36)
Complete response % 4% 1%
Partial response % 41% 27%

Response duration‡

Median in months (range) Not reached 
(1.9+, 14.5+)

6.3 
(2.1+, 12.6+)

% with duration ≥ 6 months 88%§ 59%¶

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox 
proportional hazard model

† Based on stratified log-rank test
‡ Based on patients with a best objective response as confirmed complete or partial 

response
§ Based on Kaplan-Meier estimates; includes 43 patients with responses of 6 months or 

longer
¶ Based on Kaplan-Meier estimates; includes 16 patients with responses of 6 months or 

longer
NA = not available

 



32

Figure 5: Kaplan-Meier curve for progression-free survival by treatment arm in 
KEYNOTE-024 (intent to treat population)

Figure 6: Kaplan-Meier curve for overall survival by treatment arm in 
KEYNOTE-024 (intent to treat population)

In a subgroup analysis, a reduced survival benefit of pembrolizumab compared to chemotherapy was 
observed in the small number of patients who were never-smokers; however, due to the small number 
of patients, no definitive conclusions can be drawn from these data.

KEYNOTE-042: Controlled study of NSCLC patients naïve to treatment
The safety and efficacy of pembrolizumab were also investigated in KEYNOTE-042, a multicentre, 
controlled study for the treatment of previously untreated locally advanced or metastatic NSCLC. The 

Treatment arm     PFS rate at 6 months    PFS rate at 12 months     HR (95% CI)       p-value
Pembrolizumab                   62%                                 48%                0.50 (0.37, 0.68)    <0.001
Chemotherapy                     50%                                 15% 

0 3 6 9 12 15 18

Time in Months

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154 104 89 44 22 3 1

151 99 70 18 9 1 0

Number at Risk

Pembrolizumab:

Chemotherapy:

0 3 6 9 12 15 18 21 24 27 30 33

Time in Months

0

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Treatment arm     OS rate at 12 months    OS rate at 24 months     HR (95% CI)       p-value
Pembrolizumab                70%                                52%                 0.63 (0.47, 0.86)        0.002
Chemotherapy                  55%                                35%

154 136 121 112 106 96 89 83 52 22 5 0

151 123 107 88 80 70 61 55 31 16 5 0

Number at Risk

Pembrolizumab:

Chemotherapy:

 



33

study design was similar to that of KEYNOTE-024, except that patients had PD-L1 expression with a 
≥ 1% TPS based on the PD-L1 IHC 22C3 pharmDxTM Kit. Patients were randomised (1:1) to receive 
pembrolizumab at a dose of 200 mg every 3 weeks (n=637) or investigator’s choice platinum-
containing chemotherapy (n=637; including pemetrexed+carboplatin or paclitaxel+carboplatin. 
Patients with non-squamous NSCLC could receive pemetrexed maintenance.). Assessment of tumour 
status was performed every 9 weeks for the first 45 weeks, and every 12 weeks thereafter.

Among the 1,274 patients in KEYNOTE-042, 599 (47%) had tumours that expressed PD-L1 with TPS 
≥ 50% based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these 599 
patients included: median age 63 years (45% age 65 or older); 69% male; 63% White and 32% Asian; 
17% Hispanic or Latino; and ECOG performance status 0 and 1 in 31% and 69%, respectively. 
Disease characteristics were squamous (37%) and non-squamous (63%); stage IIIA (0.8%); stage IIIB 
(9%); stage IV (90%); and treated brain metastases (6%).

The primary efficacy outcome measure was OS. Secondary efficacy outcome measures were PFS and 
ORR (as assessed by BICR using RECIST 1.1). The trial demonstrated a statistically significant 
improvement in OS for patients whose tumours expressed PD-L1 TPS ≥ 1% randomised to 
pembrolizumab monotherapy compared to chemotherapy (HR 0.82; 95% CI 0.71, 0.93 at the final 
analysis) and in patients whose tumours expressed PD-L1 TPS ≥ 50% randomised to pembrolizumab 
monotherapy compared to chemotherapy. Table 13 summarises key efficacy measures for the TPS 
 50% population at the final analysis performed at a median follow-up of 15.4 months. The Kaplan-
Meier curve for OS for the TPS ≥ 50% population based on the final analysis is shown in Figure 7.

Table 13: Efficacy results (PD-L1 TPS  50%) in KEYNOTE-042

Endpoint Pembrolizumab
200 mg every 

3 weeks
n=299

Chemotherapy

n=300
OS

Number (%) of patients with 
event

180 (60%) 220 (73%)

Hazard ratio* (95% CI) 0.70 (0.58, 0.86)
p-Value† 0.0003
Median in months (95% CI) 20.0 (15.9, 24.2) 12.2 (10.4, 14.6)

PFS
Number (%) of patients with 
event

238 (80%) 250 (83%)

Hazard ratio* (95% CI) 0.84 (0.70, 1.01)
Median in months (95% CI) 6.5 (5.9, 8.5) 6.4 (6.2, 7.2)

Objective response rate
ORR % (95% CI) 39% (34, 45) 32% (27, 38)

Complete response % 1% 0.3%
Partial response % 38% 32%

Response duration‡

Median in months (range) 22.0
(2.1+, 36.5+)

10.8
(1.8+, 30.4+)

% with duration ≥ 18 months 57% 34%
* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox 

proportional hazard model
† Based on stratified log-rank test
‡ Based on patients with a best objective response as confirmed complete or partial 

response

 



34

Figure 7: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-042 (patients 
with PD-L1 expression TPS ≥ 50%, intent to treat population)

The results of a post-hoc exploratory subgroup analysis indicated a trend towards reduced survival 
benefit of pembrolizumab compared to chemotherapy, during both the first 4 months and throughout 
the entire duration of treatment, in patients who were never-smokers. However, due to the exploratory 
nature of this subgroup analysis, no definitive conclusions can be drawn.

KEYNOTE-189: Controlled study of combination therapy in non-squamous NSCLC patients naïve to 
treatment
The efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy was 
investigated in a multicentre, randomised, active-controlled, double-blind study, KEYNOTE-189. Key 
eligibility criteria were metastatic non-squamous NSCLC, no prior systemic treatment for metastatic 
NSCLC, and no EGFR or ALK genomic tumour aberrations. Patients with autoimmune disease that 
required systemic therapy within 2 years of treatment; a medical condition that required 
immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 
26 weeks were ineligible. Patients were randomised (2:1) to receive one of the following regimens:

 Pembrolizumab 200 mg with pemetrexed 500 mg/m2 and investigator’s choice of 
cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 
4 cycles followed by pembrolizumab 200 mg and pemetrexed 500 mg/m2 intravenously 
every 3 weeks (n=410)

 Placebo with pemetrexed 500 mg/m2 and investigator’s choice of cisplatin 75 mg/m2 or 
carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by 
placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks (n=206)

Treatment with pembrolizumab continued until RECIST 1.1-defined progression of disease as 
determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of 
pembrolizumab was permitted beyond RECIST-defined disease progression by BICR or beyond 
discontinuation of pemetrexed if the patient was clinically stable and deriving clinical benefit as 

 



35

determined by the investigator. For patients who completed 24 months of therapy or had a complete 
response, treatment with pembrolizumab could be reinitiated for disease progression and administered 
for up to 1 additional year. Assessment of tumour status was performed at Week 6 and Week 12, 
followed by every 9 weeks thereafter. Patients receiving placebo plus chemotherapy who experienced 
independently-verified progression of disease were offered pembrolizumab as monotherapy.

Among the 616 patients in KEYNOTE-189, baseline characteristics were: median age of 64 years 
(49% age 65 or older); 59% male; 94% White and 3% Asian; 43% and 56% ECOG performance status 
of 0 or 1 respectively; 31% PD-L1 negative (TPS < 1%); and 18% with treated or untreated brain 
metastases at baseline.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). 
Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using 
RECIST 1.1. Table 14 summarises key efficacy measures and Figures 8 and 9 show the Kaplan-Meier 
curves for OS and PFS based on the final analysis with a median follow-up of 18.8 months.

Table 14: Efficacy results in KEYNOTE-189

Endpoint Pembrolizumab + 
Pemetrexed + 

Platinum 
Chemotherapy

n=410

Placebo + 
Pemetrexed + 

Platinum 
Chemotherapy

n=206
OS*

Number (%) of patients with 
event

258 (63%) 163 (79%)

Hazard ratio† (95% CI) 0.56 (0.46, 0.69)
p-Value‡ < 0.00001
Median in months (95% CI) 22.0

(19.5, 24.5)
10.6

(8.7, 13.6)
PFS

Number (%) of patients with 
event

337 (82%) 197 (96%)

Hazard ratio† (95% CI) 0.49 (0.41, 0.59)
p-Value‡ < 0.00001
Median in months (95% CI) 9.0 (8.1, 10.4) 4.9 (4.7, 5.5)

Objective response rate
ORR§ % (95% CI) 48% (43, 53) 20% (15, 26)

Complete response % 1.2% 0.5%
Partial response % 47% 19%

p-Value¶ < 0.0001
Response duration

Median in months (range) 12.5
(1.1+, 34.9+)

7.1
(2.4, 27.8+)

% with duration ≥ 12 months# 53% 27%
* A total of 113 patients (57%) who discontinued study treatment in the placebo plus 

chemotherapy arm crossed over to receive monotherapy pembrolizumab or received a 
checkpoint inhibitor as subsequent therapy

† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test
§ Based on patients with a best objective response as confirmed complete or partial 

response
¶ Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum 

chemotherapy and smoking status 
# Based on Kaplan-Meier estimation

 



36

Figure 8: Kaplan-Meier curve for overall survival by treatment arm in
KEYNOTE-189 (intent to treat population)

Treatment arm     OS rate at 12 months      OS rate at 24 months     HR (95% CI)      p-value
Pembrolizumab                    70%                                 46%                 0.56 (0.46, 0.69) < 0.00001
Control                                  48%                               27%

O
ve

ra
ll 

S
u
rv

iv
a

l (
%

)

Time in Months
Number at Risk
Pembrolizumab:

Control:

 



37

Figure 9: Kaplan-Meier curve for progression-free survival by treatment arm in
KEYNOTE-189 (intent to treat population)

An analysis was performed in KEYNOTE-189 in patients who had PD-L1 TPS < 1% [pembrolizumab 
combination: n=127 (31%) vs. chemotherapy: n=63 (31%)], TPS 1-49% [pembrolizumab 
combination: n=128 (31%) vs. chemotherapy: n=58 (28%)] or ≥ 50% [pembrolizumab combination: 
n=132 (32%) vs. chemotherapy: n=70 (34%)] (see Table 15).

Table 15: Efficacy results by PD-L1 Expression in KEYNOTE-189*

Endpoint Pembrolizumab 
combination 

therapy

Chemotherapy Pembrolizumab 
combination 

therapy

Chemotherapy Pembrolizumab 
combination 

therapy

Chemotherapy

TPS < 1% TPS 1 to 49% TPS ≥ 50%
OS Hazard 
ratio†

(95% CI)
0.51 (0.36, 0.71) 0.66 (0.46, 0.96) 0.59 (0.40, 0.86)

PFS Hazard 
ratio†

(95% CI)
0.67 (0.49, 0.93) 0.53 (0.38, 0.74) 0.35 (0.25, 0.49)

ORR % 33% 14% 50% 21% 62% 26%
* Based on final analysis
† Hazard ratio (pembrolizumab combination therapy compared to chemotherapy) based on the stratified Cox proportional hazard 

model

At final analysis, a total of 57 NSCLC patients aged ≥ 75 years were enrolled in study KEYNOTE-189 
(35 in the pembrolizumab combination and 22 in the control). A HR=1.54 [95% CI 0.76, 3.14] in OS 
and HR=1.12 [95% CI 0.56, 2.22] in PFS for pembrolizumab combination vs. chemotherapy was 
reported within this study subgroup. Data about efficacy and safety of pembrolizumab in combination 
with platinum chemotherapy are limited in this patient population.

P
ro

g
re

s
s
io

n
-F

re
e
 S

u
rv

iv
a
l 
(%

)

Time in Months
Number at Risk
Pembrolizumab:

Control:

Treatment arm     PFS rate at 12 months      PFS rate at 24 months     HR (95% CI)      p-value
Pembrolizumab                     39%                                   22%                 0.49 (0.41, 0.59) < 0.00001
Control                                   18%                                    3%

 



38

KEYNOTE-407: Controlled study of combination therapy in squamous NSCLC patients naïve to 
treatment
The efficacy of pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel 
was investigated in Study KEYNOTE-407, a randomised, double-blind, multicentre, 
placebo-controlled study. The key eligibility criteria for this study were metastatic squamous NSCLC, 
regardless of tumour PD-L1 expression status, and no prior systemic treatment for metastatic disease. 
Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a 
medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic 
radiation within the prior 26 weeks were ineligible. Randomisation was stratified by tumour PD-L1 
expression (TPS < 1% [negative] vs. TPS ≥ 1%), investigator’s choice of paclitaxel or nab-paclitaxel, 
and geographic region (East Asia vs. non-East Asia). Patients were randomised (1:1) to one of the 
following treatment arms via intravenous infusion:

 Pembrolizumab 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day 
cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 
4 cycles or nab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 
4 cycles, followed by pembrolizumab 200 mg every 3 weeks. Pembrolizumab was 
administered prior to chemotherapy on Day 1.

 Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 
4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or 
nab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, 
followed by placebo every 3 weeks.

Treatment with pembrolizumab or placebo continued until RECIST 1.1-defined progression of disease 
as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of 
pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was 
clinically stable and deriving clinical benefit as determined by the investigator. 

Patients in the placebo arm were offered pembrolizumab as a single agent at the time of disease 
progression.

Assessment of tumour status was performed every 6 weeks through Week 18, every 9 weeks through 
Week 45 and every 12 weeks thereafter. 

A total of 559 patients were randomised. The study population characteristics were: median age of 
65 years (range: 29 to 88); 55% age 65 or older; 81% male; 77% White; ECOG performance status of 
0 (29%) and 1 (71%); and 8% with treated brain metastases at baseline. Thirty-five percent had 
tumour PD-L1 expression TPS < 1% [negative]; 19% were East Asian; and 60% received paclitaxel.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). 
Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using 
RECIST 1.1. Table 16 summarises key efficacy measures and Figures 10 and 11 show the
Kaplan-Meier curves for OS and PFS based on the final analysis with a median follow-up of 
14.3 months. 

 



39

Table 16: Efficacy Results in KEYNOTE-407

Endpoint Pembrolizumab
Carboplatin

Paclitaxel/Nab-paclitaxel
n=278

Placebo
Carboplatin

Paclitaxel/Nab-paclitaxel
n=281

OS*
Number of events (%) 168 (60%) 197 (70%)
Median in months (95% CI) 17.1 (14.4, 19.9) 11.6 (10.1, 13.7)
Hazard ratio† (95% CI) 0.71 (0.58, 0.88)
p-Value‡ 0.0006

PFS
Number of events (%) 217 (78%) 252 (90%)
Median in months (95% CI) 8.0 (6.3, 8.4) 5.1 (4.3, 6.0)
Hazard ratio† (95% CI) 0.57 (0.47, 0.69)
p-Value‡ < 0.0001

Objective response rate
ORR % (95% CI) 63% (57, 68) 38% (33, 44)

Complete response % 2.2% 3.2%
Partial response % 60% 35%

p-Value§ < 0.0001
Response duration

Median duration of response in 
months (range)

8.8 (1.3+, 28.4+) 4.9 (1.3+, 28.3+)

% with duration ≥ 12 months¶ 38% 25%
* A total of 138 patients (51%) who discontinued study treatment in the placebo plus chemotherapy arm 

crossed over to receive monotherapy pembrolizumab or received a checkpoint inhibitor as subsequent 
therapy

† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test 
§ Based on method by Miettinen and Nurminen
¶ Based on Kaplan-Meier estimation

 



40

Figure 10: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407

Treatment arm     OS rate at 12 months      OS rate at 18 months     HR (95% CI)      p-value
Pembrolizumab                    65%                                 48%                 0.71 (0.58, 0.88) 0.0006
Control                                  50%                               37%

O
ve

ra
ll 

S
u
rv

iv
a

l (
%

)

Number at Risk
Pembrolizumab:

Control:

Time in Months

 



41

Figure 11: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-407

An analysis was performed in KEYNOTE-407 in patients who had PD-L1 TPS < 1% [pembrolizumab 
plus chemotherapy arm: n=95 (34%) vs. placebo plus chemotherapy arm: n=99 (35%)], TPS 1% to 
49% [pembrolizumab plus chemotherapy arm: n=103 (37%) vs. placebo plus chemotherapy arm: 
n=104 (37%)] or TPS ≥ 50% [pembrolizumab plus chemotherapy arm: n=73 (26%) vs. placebo plus 
chemotherapy arm: n=73 (26%)] (see Table 17).

Table 17: Efficacy results by PD-L1 Expression in KEYNOTE-407*

Endpoint Pembrolizumab 
combination 

therapy

Chemotherapy Pembrolizumab 
combination 

therapy

Chemotherapy Pembrolizumab 
combination 

therapy

Chemotherapy

TPS < 1% TPS 1 to 49% TPS ≥ 50%
OS Hazard 
ratio†

(95% CI)
0.79 (0.56, 1.11) 0.59 (0.42, 0.84) 0.79 (0.52, 1.21)

PFS Hazard 
ratio†

(95% CI)
0.67 (0.49, 0.91) 0.52 (0.38, 0.71) 0.43 (0.29, 0.63)

ORR % 67% 41% 55% 42% 64% 30%
* Based on final analysis
† Hazard ratio (pembrolizumab combination therapy compared to chemotherapy) based on the stratified Cox proportional hazard 

model

At final analysis, a total of 65 NSCLC patients aged ≥ 75 years were enrolled in study KEYNOTE-407 
(34 in the pembrolizumab combination and 31 in the control). An HR=0.81 [95% CI 0.43, 1.55] in OS, 
an HR=0.61 [95% CI 0.34, 1.09] in PFS, and an ORR of 62% and 45% for pembrolizumab 
combination vs. chemotherapy was reported within this study subgroup. Data about efficacy and 
safety of pembrolizumab in combination with platinum chemotherapy are limited in this patient 
population.

P
ro

g
re

s
s
io

n
-F

re
e
 S

u
rv

iv
a
l 
(%

)
Treatment arm     PFS rate at 12 months      PFS rate at 18 months     HR (95% CI)      p-value
Pembrolizumab                     36%                                   26%                 0.57 (0.47, 0.69) < 0.0001
Control                                   18%                                   11%

Time in MonthsNumber at Risk
Pembrolizumab:

Control:

 



42

KEYNOTE-010: Controlled study of NSCLC patients previously treated with chemotherapy
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-010, a multicentre, 
open-label, controlled study for the treatment of advanced NSCLC in patients previously treated with 
platinum-containing chemotherapy. Patients had PD-L1 expression with a  1% TPS based on the 
PD-L1 IHC 22C3 pharmDxTM Kit. Patients with EGFR activation mutation or ALK translocation also 
had disease progression on approved therapy for these mutations prior to receiving pembrolizumab. 
Patients were randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=344) or 10 mg/kg 
(n=346) every 3 weeks or docetaxel at a dose of 75 mg/m2 every 3 weeks (n=343) until disease 
progression or unacceptable toxicity. The study excluded patients with autoimmune disease; a medical 
condition that required immunosuppression; or who had received more than 30 Gy of thoracic 
radiation within the prior 26 weeks. Assessment of tumour status was performed every 9 weeks. 

The baseline characteristics for this population included: median age 63 years (42% age 65 or older); 
61% male; 72% White and 21% Asian and 34% and 66% with an ECOG performance status 0 and 1, 
respectively. Disease characteristics were squamous (21%) and non-squamous (70%); stage IIIA (2%); 
stage IIIB (7%); stage IV (91%); stable brain metastases (15%) and the incidence of mutations was 
EGFR (8%) or ALK (1%). Prior therapy included platinum-doublet regimen (100%); patients received 
one (69%) or two or more (29%) treatment lines.

The primary efficacy outcome measures were OS and PFS as assessed by BICR using RECIST 1.1. 
Secondary efficacy outcome measures were ORR and response duration. Table 18 summarises key 
efficacy measures for the entire population (TPS  1%) and for the patients with TPS  50%, and 
Figure 12 shows the Kaplan-Meier curve for OS (TPS  1%), based on a final analysis with median 
follow up of 42.6 months.

 



43

Table 18: Response to pembrolizumab 2 or 10 mg/kg every 3 weeks in previously treated 
patients with NSCLC in KEYNOTE-010

Endpoint Pembrolizumab 
2 mg/kg every 

3 weeks

Pembrolizumab 
10 mg/kg every 

3 weeks

Docetaxel
75 mg/m2 every 

3 weeks

TPS ≥ 1%
Number of patients 344 346 343

OS
Number (%) of patients with event 284 (83%) 264 (76%) 295 (86%)
Hazard ratio* (95% CI) 0.77 (0.66, 0.91) 0.61 (0.52, 0.73) ---
p-Value† 0.00128 < 0.001 ---
Median in months (95% CI) 10.4 (9.5, 11.9) 13.2 (11.2, 16.7) 8.4 (7.6, 9.5)

PFS‡

Number (%) of patients with event 305 (89%) 292 (84%) 314 (92%)
Hazard ratio* (95% CI) 0.88 (0.75, 1.04) 0.75 (0.63, 0.89) ---
p-Value† 0.065 < 0.001 ---
Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.7, 4.5) 4.1 (3.8, 4.5)

Objective response rate‡

ORR % (95% CI) 20% (16, 25) 21% (17, 26) 9% (6, 13)
Complete response % 2% 3% 0%
Partial response % 18% 18% 9%

Response duration‡,§

Median in months (range) Not reached
(2.8, 46.2+)

37.8
(2.0+, 49.3+)

7.1
(1.4+, 16.8)

% ongoing¶ 42% 43% 6%

TPS  50%
Number of patients 139 151 152

OS
Number (%) of patients with event 97 (70%) 102 (68%) 127 (84%)
Hazard ratio* (95% CI) 0.56 (0.43, 0.74) 0.50 (0.38, 0.65) ---
p-Value† < 0.001 < 0.001 ---
Median in months (95% CI) 15.8 (10.8, 22.5) 18.7 (12.1, 25.3) 8.2 (6.4, 9.8)

PFS‡

Number (%) of patients with event 107 (77%) 115 (76%) 138 (91%)
Hazard ratio* (95% CI) 0.59 (0.45, 0.77) 0.53 (0.41, 0.70) ---
p-Value† < 0.001 < 0.001 ---
Median in months (95% CI) 5.3 (4.1, 7.9) 5.2 (4.1, 8.1) 4.2 (3.8, 4.7)

Objective response rate‡

ORR % (95% CI) 32% (24, 40) 32% (25, 41) 9% (5, 14)
Complete response % 4% 4% 0%
Partial response % 27% 28% 9%

Response duration‡,§

Median in months (range) Not reached
(2.8, 44.0+)

37.5
(2.0+, 49.3+)

8.1
(2.6, 16.8)

% ongoing¶ 55% 47% 8%
* Hazard ratio (pembrolizumab compared to docetaxel) based on the stratified Cox proportional hazard model
† Based on stratified log-rank test
‡ Assessed by BICR using RECIST 1.1
§ Based on patients with a best objective response as confirmed complete or partial response
¶ Ongoing response includes all responders who at the time of analysis were alive, progression free, did not initiate new 

anti-cancer therapies and had not been determined to be lost to follow-up

 



44

Figure 12: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-010
(patients with PD-L1 expression TPS  1%, intent to treat population)

Efficacy results were similar for the 2 mg/kg and 10 mg/kg pembrolizumab arms. Efficacy results for 
OS were consistent regardless of the age of tumour specimen (new vs. archival) based on an 
intergroup comparison.

In subgroup analyses, a reduced survival benefit of pembrolizumab compared to docetaxel was 
observed for patients who were never-smokers or patients with tumours harbouring EGFR activating 
mutations who received at least platinum-based chemotherapy and a tyrosine kinase inhibitor; 
however, due to the small numbers of patients, no definitive conclusions can be drawn from these 
data.

The efficacy and safety of pembrolizumab in patients with tumours that do not express PD-L1 have
not been established.

Classical Hodgkin lymphoma
KEYNOTE-087 and KEYNOTE-013: Open-label studies in patients with relapsed or refractory cHL
The efficacy of pembrolizumab was investigated in KEYNOTE-087 and KEYNOTE-013, two 
multicentre, open-label studies for the treatment of 241 patients with cHL. These studies enrolled 
patients who failed ASCT and BV, who were ineligible for ASCT because they were unable to 
achieve a complete or partial remission to salvage chemotherapy and failed BV, or who failed ASCT 
and did not receive BV. Five study subjects were ineligible to ASCT due to reasons other than failure 
to salvage chemotherapy. Both studies included patients regardless of PD-L1 expression. Patients with 
active, non-infectious pneumonitis, an allogeneic transplant within the past 5 years (or > 5 years but 
with GVHD), active autoimmune disease or a medical condition that required immunosuppression 
were ineligible for either study. Patients received pembrolizumab 200 mg every 3 weeks (n=210; 
KEYNOTE-087) or 10 mg/kg every 2 weeks (n=31; KEYNOTE-013) until unacceptable toxicity or 
documented disease progression.

0 5 10 15 20 25 30 35 40 45 50 55 60

Time in Months

0

10

20

30

40

50

60

70

80

90

100

O
ve

ra
ll 

S
u

rv
iv

a
l 
(%

)

Treatment arm                  OS rate at 24 months   OS rate at 36 months     HR (95% CI)          p-value
Pembrolizumab 2 mg/kg               28%                               20%                  0.77 (0.66, 0.91)        0.00128
Pembrolizumab 10 mg/kg             36%                               26%                  0.61 (0.52, 0.73)        0.00001
Docetaxel                                        14%                               11%

343 226 135 90 57 44 40 35 20 13 2 0 0

344 261 177 136 111 91 72 67 36 17 2 0 0
346 262 197 159 137 120 99 84 50 28 3 0 0

Number at Risk

Pembrolizumab 2 mg/kg:
Pembrolizumab 10 mg/kg:
Docetaxel:

 



45

Among KEYNOTE-087 patients, the baseline characteristics were median age 35 years (9% age 65 or 
older); 54% male; 88% White; and 49% and 51% had an ECOG performance status 0 and 1, 
respectively. The median number of prior lines of therapy administered for the treatment of cHL was 4 
(range 1 to 12). Eighty-one percent were refractory to at least one prior therapy, including 35% who 
were refractory to first line therapy. Sixty-one percent of patients had received Auto-SCT, 38% were 
transplant ineligible; 17% had no prior brentuximab vedotin use; and 36% of patients had prior 
radiation therapy. Disease subtypes were 80% nodular sclerosis, 11% mixed cellularity, 4% 
lymphocyte-rich and 2% lymphocyte-depleted. 

Among KEYNOTE-013 patients, the baseline characteristics were median age 32 years (7% age 65 or 
older), 58% male, 94% White; and 45% and 55% had an ECOG performance status 0 and 1, 
respectively. The median number of prior lines of therapy administered for the treatment of cHL was 5 
(range 2 to 15). Eighty-four percent were refractory to at least one prior therapy, including 35% who 
were refractory to first line therapy. Seventy-four percent of patients had received Auto-SCT, 26% 
were transplant ineligible, and 45% of patients had prior radiation therapy. Disease subtypes were 97% 
nodular sclerosis and 3% mixed cellularity.

The major efficacy outcome measures (ORR and CRR) were assessed by BICR according to the 2007 
revised International Working Group (IWG) criteria. Secondary efficacy outcome measures were 
duration of response, PFS and OS. Response was assessed in KEYNOTE-087 and KEYNOTE-013 
every 12 and 8 weeks, respectively, with the first planned post-baseline assessment at Week 12.
Efficacy results are summarised in Table 19. 

 



46

Table 19: Efficacy results in KEYNOTE-087 and KEYNOTE-013

KEYNOTE-087a KEYNOTE-013b

Endpoint Pembrolizumab
200 mg every 3 weeks

n=210

Pembrolizumab
10 mg/kg every 2 weeks

n=31
Objective response ratec

ORR % (95% CI) 69% (62.3, 75.2) 58% (39.1, 75.5)
Complete remission 22% 19%
Partial remission 47% 39%

Response durationc

Median in months (range) 11.1 (0.0+, 11.1)d Not reached (0.0+, 45.6+)e

% with duration ≥ 6-months 76%f 80%g

% with duration ≥ 12-months --- 70%h

Time to response
Median in months (range) 2.8 (2.1, 8.8)d 2.8 (2.4, 8.6)e

PFSc

Number (%) of patients with event 70 (33%) 19 (61%)
Median in months (95% CI) 11.3 (10.8, Not reached) 11.4 (4.9, 27.8)
6-month PFS rate 72% 66%
9-month PFS rate 62% ---
12-month PFS rate --- 48%

OS
Number (%) of patients with event 4 (2%) 6 (19%)
6-month OS rate 99.5% 100%
12-month OS rate 97.6% 87.1%

a Median follow-up time of 10.1 months
b Median follow-up time of 52.8 months
c Assessed by BICR according to the 2007 revised International Working Group (IWG) criteria by PET CT 

scans
d Based on patients (n=145) with a response by independent review
e Based on patients (n=18) with a response by independent review
f Based on Kaplan-Meier estimation; includes 31 patients with responses of 6 months or longer
g Based on Kaplan-Meier estimation; includes 9 patients with responses of 6 months or longer
h Based on Kaplan-Meier estimation; includes 7 patients with responses of 12 months or longer

Safety and efficacy in elderly patients 
Overall, 20 cHL patients ≥ 65 years were treated with pembrolizumab in studies KEYNOTE-087 and 
KEYNOTE-013. Data from these patients are too limited to draw any conclusion on safety or efficacy 
in this population.

Urothelial Carcinoma
KEYNOTE-045: Controlled study in urothelial carcinoma patients who have received prior 
platinum-containing chemotherapy
The safety and efficacy of pembrolizumab were evaluated in KEYNOTE-045, a multicentre, 
open-label, randomised (1:1), controlled study for the treatment of locally advanced or metastatic 
urothelial carcinoma in patients with disease progression on or after platinum-containing 
chemotherapy. Patients must have received first line platinum-containing regimen for locally 
advanced/metastatic disease or as neoadjuvant/adjuvant treatment, with recurrence/progression 
≤ 12 months following completion of therapy. Patients were randomised (1:1) to receive either 
pembrolizumab 200 mg every 3 weeks (n=270) or investigator’s choice of any of the following
chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=84), 
docetaxel 75 mg/m2 (n=84), or vinflunine 320 mg/m2 (n=87). Patients were treated with 
pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyond 
progression if the patient was clinically stable and was considered to be deriving clinical benefit by the 
investigator. Patients without disease progression could be treated for up to 24 months. The study 
excluded patients with autoimmune disease, a medical condition that required immunosuppression and 

 



47

patients with more than 2 prior lines of systemic chemotherapy for metastatic urothelial carcinoma. 
Patients with an ECOG performance status of 2 had to have a haemoglobin ≥ 10 g/dL, could not have 
liver metastases, and must have received the last dose of their last prior chemotherapy regimen 
≥ 3 months prior to enrolment. Assessment of tumour status was performed at 9 weeks after the first 
dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter. 

Among the 542 randomised patients in KEYNOTE-045, baseline characteristics were: median age 
66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 56% ECOG 
performance status of 1 and 1% ECOG performance status of 2; and 96% M1 disease and 4% 
M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver 
metastases. Eighty-six percent had a primary tumour in the lower tract and 14% had a primary tumour 
in the upper tract. Fifteen percent of patients had disease progression following prior 
platinum-containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 prior 
systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 
23% had prior carboplatin, and 1% was treated with other platinum-based regimens.

The primary efficacy outcomes were OS and PFS as assessed by BICR using RECIST v1.1. 
Secondary outcome measures were ORR (as assessed by BICR using RECIST v1.1) and duration of 
response. Table 20 summarises the key efficacy measures for the ITT population at the final analysis. 
The Kaplan-Meier curve based on the final analysis for OS is shown in Figure 13. The study 
demonstrated statistically significant improvements in OS and ORR for patients randomised to 
pembrolizumab as compared to chemotherapy. There was no statistically significant difference 
between pembrolizumab and chemotherapy with respect to PFS. 

 



48

Table 20: Response to pembrolizumab 200 mg every 3 weeks in patients with urothelial 
carcinoma previously treated with chemotherapy in KEYNOTE-045

Endpoint Pembrolizumab
200 mg every 

3 weeks
n=270

Chemotherapy

n=272

OS
Number (%) of patients with event 200 (74%) 219 (81%)
Hazard ratio* (95% CI) 0.70 (0.57, 0.85)
p-Value† < 0.001
Median in months (95% CI) 10.1 (8.0, 12.3) 7.3 (6.1, 8.1)

PFS‡

Number (%) of patients with event 233 (86%) 237 (87%)
Hazard ratio* (95% CI) 0.96 (0.79, 1.16)
p-Value† 0.313
Median in months (95% CI) 2.1 (2.0, 2.2) 3.3 (2.4, 3.6)

Objective response rate‡

ORR % (95% CI) 21% (16, 27) 11% (8, 15)
p-Value§ < 0.001

Complete response 9% 3%
Partial response 12% 8%
Stable disease 17% 34%

Response duration‡,¶

Median in months (range) Not reached
(1.6+, 30.0+)

4.4
(1.4+, 29.9+)

Number (%#) of patients with duration ≥ 6 months 46 (84%) 8 (47%)
Number (%#) of patients with duration ≥ 12 
months

35 (68%) 5 (35%)

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model
† Based on stratified log-rank test
‡ Assessed by BICR using RECIST 1.1
§ Based on method by Miettinen and Nurminen
¶ Based on patients with a best objective response as confirmed complete or partial response
# Based on Kaplan-Meier estimation

 



49

Figure 13: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-045 (intent 
to treat population)

An analysis was performed in KEYNOTE-045 in patients who had PD-L1 CPS < 10 [pembrolizumab: 
n=186 (69%) vs. chemotherapy: n= 176 (65%)] or ≥ 10 [pembrolizumab: n=74 (27%) vs. 
chemotherapy: n= 90 (33%)] in both pembrolizumab- and chemotherapy-treated arms (see Table 21).

Table 21: OS by PD-L1 Expression

PD-L1 Expression Pembrolizumab Chemotherapy
OS by PD-L1 Expression

Number (%) of patients with event*
Hazard

Ratio† (95% CI)
CPS < 10 140 (75%) 144 (82%) 0.75 (0.59, 0.95)
CPS ≥ 10 53 (72%) 72 (80%) 0.55 (0.37, 0.81)

* Based on final analysis
† Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model

Patient-reported outcomes (PROs) were assessed using EORTC QLQ-C30. A prolonged time to 
deterioration in EORTC QLQ-C30 global health status/QoL was observed for patients treated with 
pembrolizumab compared to investigator’s choice chemotherapy (HR 0.70; 95% CI 0.55-0.90). Over 
15 weeks of follow-up, patients treated with pembrolizumab had stable global health status/QoL, 
while those treated with investigator’s choice chemotherapy had a decline in global health status/QoL. 
These results should be interpreted in the context of the open-label study design and therefore taken 
cautiously.

KEYNOTE-052: Open-label study in urothelial carcinoma patients ineligible for cisplatin-containing 
chemotherapy
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-052, a multicentre, 
open-label study for the treatment of locally advanced or metastatic urothelial carcinoma in patients 

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Time in Months

0

10

20

30

40

50

60

70

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O
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S
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(%

)

Treatment arm     OS rate at 6 months    OS rate at 12 months     HR (95% CI)       p-value
Pembrolizumab                64%                              44%                  0.70 (0.57, 0.85)   0.00015
Control                             57%                               30%

272 234 173 140 109 91 73 62 59 47 42 35 34 24 18 10 4 0 0 0 0

270 226 195 170 148 132 116 105 98 86 80 76 67 52 33 14 7 0 0 0 0

Number at Risk

Pembrolizumab:

Control:

 



50

who were not eligible for cisplatin-containing chemotherapy. Patients received pembrolizumab at a 
dose of 200 mg every 3 weeks until unacceptable toxicity or disease progression. Treatment could 
continue beyond progression if the patient was clinically stable and was considered to be deriving 
clinical benefit by the investigator. Patients without disease progression could be treated for up to 
24 months. The study excluded patients with autoimmune disease or a medical condition that required 
immunosuppression. Assessment of tumour status was performed at 9 weeks after the first dose, then 
every 6 weeks through the first year, followed by every 12 weeks thereafter. 

Among 370 patients with urothelial carcinoma who were not eligible for cisplatin-containing 
chemotherapy baseline characteristics were: median age 74 years (82% age 65 or older); 77% male; 
and 89% White and 7% Asian. Eighty-eight percent had M1 disease and 12% had M0 disease. 
Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons 
for cisplatin ineligibility included: baseline creatinine clearance of < 60 mL/min (50%), ECOG 
performance status of 2 (32%), ECOG performance status of 2 and baseline creatinine clearance of 
< 60 mL/min (9%), and other (Class III heart failure, Grade 2 or greater peripheral neuropathy, and 
Grade 2 or greater hearing loss; 9%). Ninety percent of patients were treatment naïve, and 10% 
received prior adjuvant or neoadjuvant platinum-based chemotherapy. Eighty-one percent had a 
primary tumour in the lower tract, and 19% of patients had a primary tumour in the upper tract. 

The primary efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Secondary 
efficacy outcome measures were duration of response, PFS, and OS. Table 22 summarises the key 
efficacy measures for the study population at the final analysis based on a median follow-up time of 
11.4 months (range: 0.1, 41.2 months) for all patients.

Table 22: Response to pembrolizumab 200 mg every 3 weeks in patients with urothelial 
carcinoma ineligible for cisplatin-containing chemotherapy in KEYNOTE-052

Endpoint n=370

Objective response rate*

ORR %, (95% CI) 29% (24, 34)

Disease control rate† 47%

Complete response 9%

Partial response 20%

Stable disease 18%

Response duration

Median in months (range) 30.1
(1.4+, 35.9+)

% with duration ≥ 6-months 81%‡

Time to response

Median in months (range) 2.1 (1.3, 9.0)

PFS*

Median in months (95% CI) 2.2 (2.1, 3.4)

6-month PFS rate 33%

12-month PFS rate 22%

OS

Median in months (95% CI) 11.3 (9.7, 13.1)

6-month OS rate 67%

12-month OS rate 47%
* Assessed by BICR using RECIST 1.1
† Based on best response of stable disease or better 
‡ Based on Kaplan-Meier estimates; includes 84 patients with response of 6 months or longer

 



51

An analysis was performed in KEYNOTE-052 in patients who had tumours that expressed PD-L1 
with a CPS < 10 (n=251; 68%) or ≥ 10 (n=110; 30%) based on the PD-L1 IHC 22C3 pharmDxTM Kit
(see Table 23).

Table 23: ORR and OS by PD-L1 Expression

Endpoint CPS < 10
N=251

CPS ≥ 10
N=110

Objective response rate*

ORR %, (95% CI) 20% (16, 26) 47% (38, 57)

OS

Median in months (95% CI) 10 (8, 12) 19 (12, 29)

12-month OS rate 41% 61% 
* BICR using RECIST 1.1

KEYNOTE-361 is an ongoing Phase III, randomised, controlled, open-label clinical study of 
pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy as 
first-line treatment in subjects with advanced or metastatic urothelial carcinoma. Preliminary data 
from an early review showed a reduced survival with pembrolizumab monotherapy in patients whose 
tumours express PD-L1 with a CPS < 10 compared with standard chemotherapy.

Based on a recommendation by an external Data Monitoring Committee, the accrual in the 
pembrolizumab monotherapy arm was stopped for patients whose tumours express PD-L1 with a 
CPS < 10. The pembrolizumab monotherapy arm remains open only to patients whose tumours 
express PD-L1 with a CPS ≥ 10. Subjects whose tumours express PD-L1 CPS < 10 already enrolled 
into the pembrolizumab monotherapy arm can continue treatment. Randomisation to the chemotherapy 
and the chemotherapy-pembrolizumab arms remains open.

Head and Neck Squamous Cell Carcinoma
KEYNOTE-048: Controlled study of monotherapy and combination therapy in HNSCC patients naïve 
to treatment in the recurrent or metastatic setting
The efficacy of pembrolizumab was investigated in KEYNOTE-048, a multicentre, randomised, 
open-label, active-controlled study in patients with histologically confirmed metastatic or recurrent 
HNSCC of the oral cavity, pharynx or larynx, who had not previously received systemic therapy for 
recurrent or metastatic disease and who were considered incurable by local therapies. Patients with 
nasopharyngeal carcinoma, active autoimmune disease that required systemic therapy within two years 
of treatment or a medical condition that required immunosuppression were ineligible for the study. 
Randomisation was stratified by tumour PD-L1 expression (TPS ≥ 50% or < 50%), HPV status 
(positive or negative), and ECOG PS (0 vs. 1). Patients were randomised 1:1:1 to one of the following 
treatment arms:

 Pembrolizumab 200 mg every 3 weeks
 Pembrolizumab 200 mg every 3 weeks, carboplatin AUC 5 mg/mL/min every 3 weeks or 

cisplatin 100 mg/m2 every 3 weeks, and 5-FU 1,000 mg/m2/d 4 days continuous every 
3 weeks (maximum of 6 cycles of platinum and 5-FU)

 Cetuximab 400 mg/m2 load then 250 mg/m2 once weekly, carboplatin AUC 5 mg/mL/min 
every 3 weeks or cisplatin 100 mg/m2 every 3 weeks, and 5-FU 1,000 mg/m2/d 4 days 
continuous every 3 weeks (maximum of 6 cycles of platinum and 5-FU)

Treatment with pembrolizumab continued until RECIST 1.1-defined progression of disease as 
determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of 
pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was 
clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of
tumour status was performed at Week 9 and then every 6 weeks for the first year, followed by every 
9 weeks through 24 months. 

 



52

Among the 882 patients in KEYNOTE-048, 754 (85%) had tumours that expressed PD-L1 with a 
CPS ≥ 1 based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these 
754 patients included: median age of 61 years (range: 20 to 94); 36% age 65 or older; 82% male; 74% 
White and 19% Asian; 61% ECOG performance status of 1; and 77% former/current smokers. Disease 
characteristics were: 21% HPV positive and 95% had stage IV disease (stage IVa 21%, stage IVb 6%, 
and stage IVc 69%).

The primary efficacy outcome measures were OS and PFS (assessed by BICR according to 
RECIST 1.1). The study demonstrated a statistically significant improvement in OS for all patients 
randomised to pembrolizumab in combination with chemotherapy compared to standard treatment 
(HR 0.72; 95% CI 0.60-0.87) and in patients whose tumours expressed PD-L1 CPS ≥ 1 randomised to 
pembrolizumab monotherapy compared to standard treatment. Tables 24 and 25 summarise key 
efficacy results for pembrolizumab in patients whose tumours expressed PD-L1 with a CPS ≥ 1 in 
KEYNOTE-048 at the final analysis performed at a median follow-up of 13 months for 
pembrolizumab in combination with chemotherapy and at a median follow-up of 11.5 months for 
pembrolizumab monotherapy. Kaplan-Meier curves for OS based on the final analysis are shown in 
Figures 14 and 15.

Table 24: Efficacy results for pembrolizumab plus chemotherapy in KEYNOTE-048 with PD-L1 
expression (CPS ≥ 1)

Endpoint Pembrolizumab +
Platinum 

Chemotherapy +
5-FU
n=242

Standard
Treatment*

n=235

OS
Number (%) of patients with event 177 (73%) 213 (91%)
Median in months (95% CI) 13.6 (10.7, 15.5) 10.4 (9.1, 11.7)
Hazard ratio† (95% CI) 0.65 (0.53, 0.80)
p-Value‡ 0.00002
PFS
Number (%) of patients with event 212 (88%) 221 (94%)
Median in months (95% CI) 5.1 (4.7, 6.2) 5.0 (4.8, 6.0)
Hazard ratio† (95% CI) 0.84 (0.69, 1.02)
p-Value‡ 0.03697
Objective response rate
ORR§ % (95% CI) 36% (30.3, 42.8) 36% (29.6, 42.2)
Complete response 7% 3%
Partial response 30% 33%
p-Value¶ 0.4586
Response duration
Median in months (range) 6.7 (1.6+, 39.0+) 4.3 (1.2+, 31.5+)
% with duration ≥ 6 months 54% 34%
* Cetuximab, platinum, and 5-FU
† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test
§ Response: Best objective response as confirmed complete response or partial response
¶ Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positive vs. 

negative) and PD-L1 status (strongly positive vs. not strongly positive)

 



53

Figure 14: Kaplan-Meier curve for overall survival for pembrolizumab plus chemotherapy in 
KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

Treatment arm                    OS rate at 12 months    OS rate at 24 months     HR (95% CI)      p-value
Pembrolizumab + Chemo                   55%                                31%             0.65 (0.53, 0.80)    0.00002
Standard                                              44%                                17%

0 5 10 15 20 25 30 35 40 45 50

Time in Months

0

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30

40

50

60

70

80

90

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242 197 144 109 84 70 52 29 5 0 0

235 191 122 83 54 35 17 5 1 0 0

Number at Risk

Pembrolizumab + Chemo:

Standard:

 



54

Table 25: Efficacy results for pembrolizumab as monotherapy in KEYNOTE-048 with PD-L1 
expression (CPS ≥ 1)

Endpoint Pembrolizumab
n=257

Standard
Treatment*

n=255
OS
Number (%) of patients with event 197 (77%) 229 (90%)
Median in months (95% CI) 12.3 (10.8, 14.3) 10.3 (9.0, 11.5)
Hazard ratio† (95% CI) 0.74 (0.61, 0.90)
p-Value‡ 0.00133
PFS
Number (%) of patients with event 228 (89%) 237 (93%)
Median in months (95% CI) 3.2 (2.2, 3.4) 5.0 (4.8, 6.0)
Hazard ratio† (95% CI) 1.13 (0.94, 1.36)
p-Value‡ 0.89580
Objective response rate
ORR§ % (95% CI) 19.1% (14.5, 24.4) 35% (29.1, 41.1)
Complete response 5% 3%
Partial response 14% 32%
p-Value¶ 1.0000
Response duration
Median in months (range) 23.4 (1.5+, 43.0+) 4.5 (1.2+, 38.7+)
% with duration ≥ 6 months 81% 36%
* Cetuximab, platinum, and 5-FU
† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test
§ Response: Best objective response as confirmed complete response or partial response
¶ Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positive 

vs. negative) and PD-L1 status (strongly positive vs. not strongly positive)

 



55

Figure 15: Kaplan-Meier curve for overall survival for pembrolizumab as monotherapy in 
KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

An analysis was performed in KEYNOTE-048 in patients whose tumours expressed PD-L1 CPS ≥ 20 
[pembrolizumab plus chemotherapy: n=126 (49%) vs. standard treatment: n=110 (43%) and 
pembrolizumab monotherapy: n=133 (52%) vs. standard treatment: n=122 (48%)] (see Table 26).

Table 26: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab as 
monotherapy by PD-L1 Expression in KEYNOTE-048 (CPS ≥ 20)

Endpoint Pembrolizumab +
Platinum 

Chemotherapy +
5-FU
n=126

Standard
Treatment*

n=110

Pembrolizumab 
Monotherapy

n=133

Standard
Treatment*

n=122

OS

Number (%) of patients with 
event

84 (66.7) 98 (89.1) 94 (70.7) 108 (88.5)

Median in months (95% CI) 14.7 (10.3, 19.3) 11.0 (9.2, 13.0) 14.8 (11.5, 20.6) 10.7 (8.8, 12.8)

Hazard ratio† (95% CI) 0.60 (0.45, 0.82) 0.58 (0.44, 0.78)

p-Value‡ 0.00044 0.00010

OS rate at 6 months (95% CI) 74.6 (66.0, 81.3) 80.0 (71.2, 86.3) 74.4 (66.1, 81.0) 79.5 (71.2, 85.7)

OS rate at 12 months (95% CI) 57.1 (48.0, 65.2) 46.1 (36.6, 55.1) 56.4 (47.5, 64.3) 44.9 (35.9, 53.4)

OS rate at 24 months (95% CI) 35.4 (27.2, 43.8) 19.4 (12.6, 27.3) 35.3 (27.3, 43.4) 19.1 (12.7, 26.6)
PFS

Number (%) of patients with 
event

106 (84.1) 104 (94.5) 115 (86.5) 114 (93.4)

Treatment arm   OS rate at 12 months    OS rate at 24 months     HR (95% CI)      p-value
Pembrolizumab                50%                                29%                0.74 (0.61, 0.90)   0.00133
Standard                           44%                                17%

0 5 10 15 20 25 30 35 40 45 50

Time in Months

0

10

20

30

40

50

60

70

80

90

100

O
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ll 
S

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rv

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(%

)

257 197 152 110 91 70 43 21 13 1 0

255 207 131 89 59 40 21 9 5 0 0

Number at Risk

Pembrolizumab:

Standard:

 



56

Endpoint Pembrolizumab +
Platinum 

Chemotherapy +
5-FU
n=126

Standard
Treatment*

n=110

Pembrolizumab 
Monotherapy

n=133

Standard
Treatment*

n=122

Median in months (95% CI) 5.8 (4.7, 7.6) 5.3 (4.9, 6.3) 3.4 (3.2, 3.8) 5.3 (4.8, 6.3)

Hazard ratio† (95% CI) 0.76 (0.58, 1.01) 0.99 (0.76, 1.29)

p-Value‡ 0.02951 0.46791

PFS rate at 6 months (95% CI) 49.4 (40.3, 57.9) 47.2 (37.5, 56.2) 33.0 (25.2, 41.0) 46.6 (37.5, 55.2)

PFS rate at 12 months (95% CI) 23.9 (16.7, 31.7) 14.0 (8.2, 21.3) 23.5 (16.6, 31.1) 15.1 (9.3, 22.2)

PFS rate at 24 months (95% CI) 14.6 (8.9, 21.5) 5.0 (1.9, 10.5) 16.8 (10.9, 23.8) 6.1 (2.7, 11.6)
Objective response rate

ORR§ % (95% CI) 42.9 (34.1, 52.0) 38.2 (29.1, 47.9) 23.3 (16.4, 31.4) 36.1 (27.6, 45.3)
Response duration

Number of responders 54 42 31 44

Median in months (range) 7.1 (2.1+, 39.0+) 4.2 (1.2+, 31.5+) 22.6 (2.7+, 43.0+) 4.2 (1.2+, 31.5+)
* Cetuximab, platinum, and 5-FU
† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test
§ Response: Best objective response as confirmed complete response or partial response

An exploratory subgroup analysis was performed in KEYNOTE-048 in patients whose tumours 
expressed PD-L1 CPS ≥ 1 to < 20 [pembrolizumab plus chemotherapy: n=116 (45%) vs. standard 
treatment: n=125 (49%) and pembrolizumab monotherapy: n=124 (48%) vs. standard treatment: 
n=133 (52%)] (see Table 27).

Table 27: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab as 
monotherapy by PD-L1 Expression in KEYNOTE-048 (CPS ≥ 1 to < 20)

Endpoint Pembrolizumab +
Platinum 

Chemotherapy +
5-FU
n=116

Standard
Treatment*

n=125

Pembrolizumab 
Monotherapy

n=124

Standard
Treatment*

n=133

OS

Number (%) of patients with event 93 (80.2) 115 (92.0) 103 (83.1) 121 (91.0)

Median in months (95% CI) 12.7 (9.4, 15.3) 9.9 (8.6, 11.5) 10.8 (9.0, 12.6) 10.1 (8.7, 12.1)

Hazard ratio† (95% CI) 0.71 (0.54, 0.94) 0.86 (0.66, 1.12)

OS rate at 6 months (95% CI) 76.7 (67.9, 83.4) 77.4 (69.0, 83.8) 67.6 (58.6, 75.1) 78.0 (70.0, 84.2)

OS rate at 12 months (95% CI) 52.6 (43.1, 61.2) 41.1 (32.4, 49.6) 44.0 (35.1, 52.5) 42.4 (33.9, 50.7)

OS rate at 24 months (95% CI) 25.9 (18.3, 34.1) 14.5 (9.0, 21.3) 22.0 (15.1, 29.6) 15.9 (10.3, 22.6)
PFS

Number (%) of patients with event 106 (91.4) 117 (93.6) 113 (91.1) 123 (92.5)

Median in months (95% CI) 4.9 (4.2, 5.3) 4.9 (3.7, 6.0) 2.2 (2.1, 2.9) 4.9 (3.8, 6.0)

Hazard ratio† (95% CI) 0.93 (0.71, 1.21) 1.25 (0.96, 1.61)

PFS rate at 6 months (95% CI) 40.1 (31.0, 49.0) 40.0 (31.2, 48.5) 24.2 (17.1, 32.0) 41.4 (32.8, 49.7)

PFS rate at 12 months (95% CI) 15.1 (9.1, 22.4) 11.3 (6.4, 17.7) 17.5 (11.4, 24.7) 12.1 (7.2, 18.5)

PFS rate at 24 months (95% CI) 8.5 (4.2, 14.7) 5.0 (1.9, 10.1) 8.3 (4.3, 14.1) 6.3 (2.9, 11.5)
Objective response rate

ORR‡ % (95% CI) 29.3 (21.2, 38.5) 33.6 (25.4, 42.6) 14.5 (8.8, 22.0) 33.8 (25.9,42.5)
Response duration

Number of responders 34 42 18 45

Median in months (range) 5.6 (1.6+, 25.6+) 4.6 (1.4+, 31.4+) NR (1.5+, 38.9+) 5.0 (1.4+, 38.7+)
* Cetuximab, platinum, and 5-FU
† Based on the stratified Cox proportional hazard model
‡ Response: Best objective response as confirmed complete response or partial response

 



57

KEYNOTE-040: Controlled study in HNSCC patients previously treated with platinum-containing 
chemotherapy
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-040, a multicentre, 
open-label, randomised, controlled study for the treatment of histologically confirmed recurrent or 
metastatic HNSCC of the oral cavity, pharynx or larynx in patients who had disease progression on or 
after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following 
platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy, 
and were not amenable to local therapy with curative intent. Patients were stratified by PD-L1 
expression (TPS ≥ 50%), HPV status and ECOG performance status and then randomised (1:1) to 
receive either pembrolizumab 200 mg every 3 weeks (n=247) or one of three standard treatments
(n=248): methotrexate 40 mg/m2 once weekly (n=64), docetaxel 75 mg/m2 once every 3 weeks (n=99), 
or cetuximab 400 mg/m2 loading dose and then 250 mg/m2 once weekly (n=71). Treatment could 
continue beyond progression if the patient was clinically stable and was considered to be deriving 
clinical benefit by the investigator. The study excluded patients with nasopharyngeal carcinoma, active 
autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition 
that required immunosuppression, or who were previously treated with 3 or more systemic regimens 
for recurrent and/or metastatic HNSCC. Assessment of tumour status was performed at 9 weeks, then
every 6 weeks through Week 52, followed by every 9 weeks through 24 months.

Among the 495 patients in KEYNOTE-040, 129 (26%) had tumours that expressed PD-L1 with a 
TPS ≥ 50% based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these 
129 patients included: median age 62 years (40% age 65 or older); 81% male; 78% White, 11% Asian, 
and 2% Black; 23% and 77% with an ECOG performance status 0 or 1, respectively; and 19% with 
HPV positive tumours. Sixty-seven percent (67%) of patients had M1 disease and the majority had 
stage IV disease (stage IV 32%, stage IVa 14%, stage IVb 4%, and stage IVc 44%). Sixteen
percent (16%) had disease progression following platinum-containing neoadjuvant or adjuvant 
chemotherapy, and 84% had received 1-2 prior systemic regimens for metastatic disease.

The primary efficacy outcome was OS in the ITT population. The initial analysis resulted in a HR for 
OS of 0.82 (95% CI: 0.67, 1.01) with a one-sided p-value of 0.0316. The median OS was 8.4 months 
for pembrolizumab compared to 7.1 months for standard treatment. Table 28 summarises the key 
efficacy measures for the TPS ≥ 50% population. The Kaplan-Meier curve for OS for the TPS ≥ 50% 
population is shown in Figure 16.

 



58

Table 28: Efficacy of pembrolizumab 200 mg every 3 weeks in HNSCC patients with TPS ≥ 50% 
who were previously treated with platinum chemotherapy in KEYNOTE-040

Endpoint Pembrolizumab
200 mg every 3 weeks

n=64

Standard Treatment*
n=65

OS
   Number (%) of patients with event 41 (64) 56 (86)
   Hazard ratio† (95% CI) 0.53 (0.35, 0.81)
   p-Value‡ 0.001
   Median in months (95% CI) 11.6 (8.3, 19.5) 6.6 (4.8, 9.2)
PFS§

   Number (%) of patients with event 52 (81) 58 (89)
   Hazard ratio† (95% CI) 0.58 (0.39, 0.86)
   p-Value‡ 0.003
   Median in months (95% CI) 3.5 (2.1, 6.3) 2.1 (2.0, 2.4)
   Rate (%) at 6 months (95% CI) 40.1 (28.1, 51.9) 17.1 (8.8, 27.7)
Objective response rate§

ORR % (95% CI) 26.6 (16.3, 39.1) 9.2 (3.5, 19.0)
p-Value¶ 0.0009
          Complete response 5% 2%
          Partial response 22% 8%
          Stable disease 23% 23%
Response duration§,#

   Median in months (range) Not reached (2.7, 13.8+) 6.9 (4.2, 18.8)
Number (%Þ) of patients with duration 
≥ 6 months

9 (66) 2 (50)
* Methotrexate, docetaxel, or cetuximab
† Hazard ratio (pembrolizumab compared to standard treatment) based on the stratified Cox proportional hazard model
‡ One-sided p-Value based on log-rank test
§ Assessed by BICR using RECIST 1.1
¶ Based on method by Miettinen and Nurminen
# Based on patients with a best objective response as confirmed complete or partial response
Þ Based on Kaplan-Meier estimation 

 



59

Figure 16: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-040
patients with PD-L1 expression (TPS ≥ 50%)

Renal cell carcinoma
KEYNOTE-426: Controlled study of combination therapy in RCC patients naïve to treatment
The efficacy of pembrolizumab in combination with axitinib was investigated in KEYNOTE-426, 
a randomised, multicentre, open-label, active-controlled study conducted in patients with advanced 
RCC with clear cell component, regardless of PD-L1 tumour expression status and International 
Metastatic RCC Database Consortium (IMDC) risk group categories. The study excluded patients with 
autoimmune disease or a medical condition that required immunosuppression. Randomisation was 
stratified by risk categories (favourable versus intermediate versus poor) and geographic region (North 
America versus Western Europe versus “Rest of the World”). Patients were randomised (1:1) to one of 
the following treatment arms:

 pembrolizumab 200 mg intravenously every 3 weeks in combination with axitinib 5 mg 
orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive 
treatment cycles (i.e. 6 weeks) with no > Grade 2 treatment-related adverse events to 
axitinib and with blood pressure well controlled to ≤ 150/90 mm Hg were permitted 
dose escalation of axitinib to 7 mg twice daily. Dose escalation of axitinib to 10 mg 
twice daily was permitted using the same criteria. Axitinib could be interrupted or 
reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.

 sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.

Treatment with pembrolizumab and axitinib continued until RECIST v1.1-defined progression of 
disease as verified by BICR or confirmed by the investigator, unacceptable toxicity, or for 
pembrolizumab, a maximum of 24 months. Administration of pembrolizumab and axitinib was 
permitted beyond RECIST-defined disease progression if the patient was clinically stable and 
considered to be deriving clinical benefit by the investigator. Assessment of tumour status was 
performed at baseline, after randomisation at Week 12, then every 6 weeks thereafter until Week 54, 

Treatment arm          OS rate at 12 months        HR (95% CI)       p-value
Pembrolizumab                          47%                0.53 (0.35, 0.81)    0.00136
Standard Treatment                   25%

0 5 10 15 20 25

Time in Months

0

10

20

30

40

50

60

70

80

90

100

O
v
e
ra

ll 
S

u
rv

iv
a
l 
(%

)

64 49 35 19 7 1

65 38 22 9 2 0

Number at Risk

Pembrolizumab:

Standard Treatment:

 



60

and then every 12 weeks thereafter. Chemistry and haematology laboratory tests were performed at 
each cycle.

A total of 861 patients were randomised. The study population characteristics were: median age of 
62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 80% had a 
Karnofsky Performance Score (KPS) 90-100 and 20% had KPS 70-80; patient distribution by IMDC 
risk categories was 31% favourable, 56% intermediate and 13% poor.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). 
Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using 
RECIST 1.1. The median follow-up time was 12.8 months (range: 0.1 to 21.5 months). Table 29
summarises key efficacy measures from the pre-specified interim analysis. The Kaplan-Meier curves 
for OS and PFS based on an additional four months of follow up are shown in Figures 17 and 18.

Table 29: Efficacy Results in KEYNOTE-426

Endpoint Pembrolizumab
Axitinib
n=432

Sunitinib
n=429

OS
Number of events (%) 59 (14%) 97 (23%)
Median in months (95% CI) Not reached (NA, NA) Not reached (NA, NA)
Hazard ratio* (95% CI) 0.53 (0.38, 0.74)
p-Value† 0.00005

PFS‡

Number of events (%) 183 (42%) 213 (50%)
Median in months (95% CI) 15.1 (12.6, 17.7) 11.0 (8.7, 12.5)
Hazard ratio* (95% CI) 0.69 (0.56, 0.84)
p-Value† 0.00012

Objective response rate
ORR§ % (95% CI) 59 (54, 64) 36 (31, 40)
          Complete response 6% 2%
          Partial response 53% 34%
p-Value¶ < 0.0001

Response duration
Median in months (range) Not reached (1.4+, 18.2+) 15.2 (1.1+, 15.4+)
Number (%#) of patients with 
duration ≥ 6 months

161 (88%) 84 (81%)

Number (%#) of patients with 
duration ≥ 12 months

58 (71%) 26 (62%)

* Based on the stratified Cox proportional hazard model
† Based on stratified log-rank test 
‡ Assessed by BICR using RECIST 1.1
§ Based on patients with a best objective response as confirmed complete or partial response
¶ Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region
# Based on Kaplan-Meier estimation
NA = not available

 



61

Figure 17: Kaplan-Meier curve for overall survival by treatment arm in
KEYNOTE-426 (intent to treat population)*

*p-Value is nominal. See Table 29 for p-Value for inferential test of OS based on the pre-specified 
interim analysis, where statistical significance has been reached.

Treatment arm                OS rate at 12 months    OS rate at 18 months     HR (95% CI)      p-value
Pembrolizumab + Axitinib            90%                                 81%              0.59 (0.45, 0.78)   0.00010
Sunitinib                                        79%                                 71%

0 5 10 15 20 25 30

Time in Months

0

10

20

30

40

50

60

70

80

90

100

O
ve

ra
ll 

S
u

rv
iv

a
l 
(%

)

432 411 392 275 133 9 0

429 389 346 230 111 6 0

Number at Risk

Pembrolizumab + Axitinib:

Sunitinib:

 



62

Figure 18: Kaplan-Meier curve for progression-free survival by treatment arm in
KEYNOTE-426 (intent to treat population)*

*p-Value is nominal. See Table 29 for p-Value for inferential test of PFS based on the pre-specified 
interim analysis, where statistical significance has been reached.

Subgroup analyses by enrolment were performed in KEYNOTE-426 in patients with PD-L1 CPS ≥ 1 
[pembrolizumab/axitinib combination: n=243 (56%) vs. sunitinib: n=254 (59%)]; CPS < 1 
[pembrolizumab/axitinib combination: n=167 (39%) vs. sunitinib: n=158 (37%)], and in patients with 
IMDC risk categories of favourable [pembrolizumab/axitinib combination: n=138 (32%) vs. sunitinib: 
n=131 (31%)]; intermediate [pembrolizumab/axitinib combination: n=238 (55%) vs. sunitinib: n=246 
(57%)]; and poor [pembrolizumab/axitinib combination: n=56 (13%) vs. sunitinib: n=52 (12%)]. OS 
and PFS benefits were observed regardless of PD-L1 expression level.

The KEYNOTE-426 study was not powered to evaluate efficacy of individual subgroups. Table 30
summarises the efficacy measures by IMDC risk category from the pre-specified interim analysis.

Table 30: Efficacy Results in KEYNOTE-426 by IMDC Risk Category

Endpoint Pembrolizumab + 
Axitinib
N = 432

Sunitinib
N = 429

Pembrolizumab + Axitinib 
vs. Sunitinib

OS 12-month OS rate, % (95% CI) OS HR (95% CI)

  Favourable 95.2 (89.6, 97.9) 93.8 (87.4, 97.0) 0.64 (0.24, 1.68)

  Intermediate 92.1 (84.7, 96.0) 76.7 (70.6, 81.8) 0.53 (0.35, 0.82)

  Poor 70.3 (56.1, 80.7) 45.2 (30.0, 59.3) 0.43 (0.23, 0.81)

PFS Median (95% CI), months PFS HR (95% CI)

  Favourable 17.7 (15.2, NA) 12.7 (11.5, NA) 0.81 (0.53, 1.24)

Treatment arm              PFS rate at 12 months    PFS rate at 18 months    HR (95% CI)     p-value
Pembrolizumab + Axitinib         60%                                 48%                  0.69 (0.57, 0.83)  0.00005
Sunitinib                                     48%                                 36%

0 5 10 15 20 25 30

Time in Months

0

10

20

30

40

50

60

70

80

90

100

P
ro

g
re

s
si

o
n
-F

re
e
 S

u
rv

iv
a
l 
(%

)

432 324 247 145 51 0 0

429 277 175 90 32 0 0

Number at Risk

Pembrolizumab + Axitinib:

Sunitinib:

 



63

Endpoint Pembrolizumab + 
Axitinib
N = 432

Sunitinib
N = 429

Pembrolizumab + Axitinib 
vs. Sunitinib

  Intermediate 14.5 (12.4, 18.0) 9.5 (8.0, 12.5) 0.69 (0.53, 0.90)

  Poor 4.9 (2.9, 12.4) 2.9 (2.7, 4.2) 0.58 (0.35, 0.94)

Confirmed ORR % (95% CI) ORR difference, 
% (95% CI)

  Favourable 66.7 (58.1, 74.5) 49.6 (40.8, 58.5) 17.0 (5.3, 28.4)

  Intermediate 59.2 (52.7, 65.5) 33.7 (27.9, 40.0) 25.5 (16.7, 33.9)

  Poor 41.1 (28.1, 55.0) 9.6 (3.2, 21.0) 31.5 (15.7, 46.2)

NA = not available

An updated OS analysis was performed when patients had a median follow-up of 16.6 months (range: 
0.1 to 26.3 months). At the time of this analysis, the hazard ratio in the overall population (95% CI)
was 0.59 (0.45, 0.78) with 84/432 (19.4%) events in the combination arm and 122/429 (28.4%) events 
in the sunitinib arm. The 12-month OS rate was 89.5% (95% CI 86.2, 92.1) for pembrolizumab in 
combination with axitinib and 78.8% (95% CI 74.7, 82.4) for sunitinib. The 18-month OS rate was 
81.0% (95% CI 76.7, 84.6) for pembrolizumab in combination with axitinib and 70.7% (95% CI 65.8, 
75.1) for sunitinib. For the IMDC risk category, the OS hazard ratio for the favourable risk group was 
0.94 (95% CI 0.43, 2.07), for the intermediate risk group the OS hazard ratio was 0.52 (95% CI 0.36, 
0.75), and for the poor risk group the OS hazard ratio was 0.50 (95% CI 0.29, 0.87).

Paediatric population
In KEYNOTE-051, 154 paediatric patients (60 children aged 6 months to less than 12 years and
94 adolescents aged 12 years to 18 years) with advanced melanoma or PD-L1 positive advanced, 
relapsed, or refractory solid tumours or lymphoma were administered pembrolizumab 2 mg/kg every 
3 weeks. All patients received pembrolizumab for a median of 3 doses (range 1-35 doses), with 
130 patients (84.4%) receiving pembrolizumab for 2 doses or more. Participants were enrolled across 
28 tumour types by primary diagnosis. The most common tumour types by histology were Hodgkin 
lymphoma (11.7%), glioblastoma multiforme (9.1%), neuroblastoma (6.5%), osteosarcoma (6.5%) and 
melanoma (5.2%). Of the 154 patients, 134 were enrolled with solid tumours, 18 with Hodgkin 
lymphoma, and 2 with other lymphomas. In patients with solid tumours and other lymphomas, the 
ORR was 5.9%, no patient had a complete response and 8 patients (5.9%) had a partial response. In 
the Hodgkin lymphoma population, the ORR was 50.0%, 2 patients (11.1%) had a complete response 
and 7 patients (38.9%) had a partial response.

The European Medicines Agency has deferred the obligation to submit the results of studies with 
pembrolizumab in one or more subsets of the paediatric population in treatment of Hodgkin lymphoma 
(see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of pembrolizumab was studied in 2,993 patients with metastatic or unresectable 
melanoma, NSCLC, or carcinoma who received doses in the range of 1 to 10 mg/kg every 2 weeks, 
2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks.

Absorption
Pembrolizumab is administered via the intravenous route and therefore is immediately and completely 
bioavailable.

Distribution
Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab at 
steady-state is small (~6.0 L; CV: 20%). As expected for an antibody, pembrolizumab does not bind to 
plasma proteins in a specific manner.

 



64

Biotransformation
Pembrolizumab is catabolised through non-specific pathways; metabolism does not contribute to its 
clearance.

Elimination
Pembrolizumab CL is approximately 23% lower (geometric mean, 195 mL/day [CV%: 40%]) after 
achieving maximal change at steady-state compared with the first dose (252 mL/day [CV%: 37%]); 
this decrease in CL with time is not considered clinically meaningful. The geometric mean value 
(CV%) for the terminal half-life is 22 days (32%) at steady-state.

Linearity/non-linearity
Exposure to pembrolizumab as expressed by peak concentration (Cmax) or area under the plasma 
concentration time curve (AUC) increased dose proportionally within the dose range for efficacy. 
Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an 
every 3 week regimen and the systemic accumulation was 2.1-fold. The median trough concentrations 
(Cmin) at steady-state were approximately 22 mcg/mL at a dose of 2 mg/kg every 3 weeks and 
29 mcg/mL at a dose of 200 mg every 3 weeks. The median area under the concentration time curve at 
steady-state over 3 weeks (AUC0-3weeks) was 794 mcg∙day/mL at a dose of 2 mg/kg every 3 weeks and 
1,053 mcg∙day/mL at a dose of 200 mg every 3 weeks.

Following administration of pembrolizumab 200 mg every 3 weeks in patients with cHL, the observed 
median Cmin at steady-state was up to 40% higher than that in other tumour types treated with the same 
dosage; however, the range of trough concentrations is similar. There are no notable differences in 
median Cmax between cHL and other tumour types. Based on available safety data in cHL and other 
tumour types, these differences are not clinically meaningful.

Special populations
The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in 
population pharmacokinetic analyses. The following factors had no clinically important effect on the 
clearance of pembrolizumab: age (range 15-94 years), gender, race, mild or moderate renal 
impairment, mild hepatic impairment and tumour burden. The relationship between body weight and 
clearance supports the use of either fixed dose or body weight-based dosing to provide adequate and 
similar control of exposure. Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 
3 weeks in paediatric patients (2 to 17 years) are comparable to those of adults at the same dose.

Renal impairment
The effect of renal impairment on the clearance of pembrolizumab was evaluated by population 
pharmacokinetic analyses in patients with mild or moderate renal impairment compared to patients 
with normal renal function. No clinically important differences in the clearance of pembrolizumab 
were found between patients with mild or moderate renal impairment and patients with normal renal 
function. Pembrolizumab has not been studied in patients with severe renal impairment. 

Hepatic impairment
The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by population 
pharmacokinetic analyses in patients with mild hepatic impairment (as defined using the US National 
Cancer Institute criteria of hepatic dysfunction) compared to patients with normal hepatic function. No 
clinically important differences in the clearance of pembrolizumab were found between patients with 
mild hepatic impairment and normal hepatic function. Pembrolizumab has not been studied in patients 
with moderate or severe hepatic impairment (see section 4.2).

5.3 Preclinical safety data

The safety of pembrolizumab was evaluated in a 1-month and a 6-month repeat-dose toxicity study in 
Cynomolgus monkeys administered intravenous doses of 6, 40 or 200 mg/kg once a week in the 
1-month study and once every two weeks in the 6-month study, followed by a 4-month treatment-free 
period. No findings of toxicological significance were observed and the no observed adverse effect 
level (NOAEL) in both studies was ≥ 200 mg/kg, which produced exposure multiples of 19 and 

 



65

94 times the exposure in humans at doses of 10 and 2 mg/kg, respectively. The exposure multiple 
between the NOAEL and a human dose of 200 mg was 74.

Animal reproduction studies have not been conducted with pembrolizumab. The PD-1/PD-L1 pathway 
is thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of 
PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and 
to result in an increase in foetal loss. 

Animal fertility studies have not been conducted with pembrolizumab. In 1 month and 6 month 
repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female 
reproductive organs; however, many animals in these studies were not sexually mature.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

L-histidine
L-histidine hydrochloride monohydrate
Sucrose
Polysorbate 80

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial
3 years.

After reconstitution
From a microbiological point of view, the reconstituted or diluted solution should be used 
immediately. The reconstituted or diluted solution must not be frozen. If not used immediately, 
chemical and physical in-use stability of KEYTRUDA has been demonstrated for 96 hours at 2°C to 
8°C. This 96-hour total hold from reconstitution may include up to 6 hours at room temperature (at or 
below 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to come to room 
temperature prior to use.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

For storage conditions after reconstitution or dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

15 mL Type I glass vial, with a grey bromobutyl stopper and an aluminium seal with an avocado 
coloured flip-off cap, containing 50 mg pembrolizumab.

Each carton contains one vial.

 



66

6.6 Special precautions for disposal and other handling

Preparation and administration
 Prior to reconstitution, the vial of lyophilised powder can be out of refrigeration (temperatures 

at or below 25°C) for up to 24 hours.
 Aseptically add 2.3 mL of water for injections to yield a 25 mg/mL (pH 5.2-5.8) solution of 

KEYTRUDA. Each vial contains an excess fill of 10 mg (0.4 mL) to ensure the recovery of 
50 mg of KEYTRUDA per vial. After reconstitution, 1 mL of concentrate contains 25 mg of 
pembrolizumab.

 To avoid foaming, deliver the water along the walls of the vial and not directly on the 
lyophilised powder.

 Slowly swirl the vial to allow reconstitution of the lyophilised powder. Allow up to 5 minutes 
for the bubbles to clear. Do not shake the vial.

 Parenteral medicinal products should be inspected visually for particulate matter and 
discolouration prior to administration. Reconstituted KEYTRUDA is a clear to slightly 
opalescent, colourless to slightly yellow solution. Discard the vial if visible particles are 
observed.

 Withdraw the required volume up to 2 mL (50 mg) of KEYTRUDA and transfer into an 
intravenous bag containing sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) to 
prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted 
solution by gentle inversion.

 From a microbiological point of view, the reconstituted or diluted solution should be used 
immediately. The reconstituted or diluted solution must not be frozen. If not used immediately, 
chemical and physical in-use stability of KEYTRUDA has been demonstrated for 96 hours at 
2°C to 8°C. This 96-hour total hold from reconstitution may include up to 6 hours at room 
temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must be 
allowed to come to room temperature prior to use. Translucent to white proteinaceous particles 
may be seen in diluted solution. Administer the infusion solution intravenously over 30 minutes 
using a sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line or add-on filter.

 Do not co-administer other medicinal products through the same infusion line.
 KEYTRUDA is for single use only. Discard any unused portion left in the vial. 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1024/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 July 2015
Date of latest renewal: 24 March 2020

 



67

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.

 

http://www.ema.europa.eu/


68

1. NAME OF THE MEDICINAL PRODUCT

KEYTRUDA 25 mg/mL concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of 4 mL of concentrate contains 100 mg of pembrolizumab.
Each mL of concentrate contains 25 mg of pembrolizumab.

Pembrolizumab is a humanised monoclonal anti-programmed cell death-1 (PD-1) antibody 
(IgG4/kappa isotype with a stabilising sequence alteration in the Fc region) produced in Chinese 
hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear to slightly opalescent, colourless to slightly yellow solution, pH 5.2 – 5.8.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Melanoma
KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) 
melanoma in adults.

KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III 
melanoma and lymph node involvement who have undergone complete resection (see section 5.1).

Non-small cell lung carcinoma (NSCLC)
KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung 
carcinoma in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) with 
no EGFR or ALK positive tumour mutations.

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-
line treatment of metastatic non-squamous non-small cell lung carcinoma in adults whose tumours
have no EGFR or ALK positive mutations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for 
the first-line treatment of metastatic squamous non-small cell lung carcinoma in adults.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic 
non-small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥ 1% TPS and who 
have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour 
mutations should also have received targeted therapy before receiving KEYTRUDA.

Classical Hodgkin lymphoma (cHL)
KEYTRUDA as monotherapy is indicated for the treatment of adult patients with relapsed or 
refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) and 
brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV.

 



69

Urothelial carcinoma
KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic 
urothelial carcinoma in adults who have received prior platinum-containing chemotherapy (see 
section 5.1).

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic 
urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose 
tumours express PD-L1 with a combined positive score (CPS) ≥ 10 (see section 5.1).

Head and neck squamous cell carcinoma (HNSCC)
KEYTRUDA, as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) 
chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and 
neck squamous cell carcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 (see 
section 5.1).

KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic head and neck 
squamous cell carcinoma in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing 
on or after platinum-containing chemotherapy (see section 5.1).

Renal cell carcinoma (RCC)
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal 
cell carcinoma in adults (see section 5.1).

4.2 Posology and method of administration

Therapy must be initiated and supervised by specialist physicians experienced in the treatment of 
cancer. 

PD-L1 testing for patients with NSCLC, urothelial carcinoma, or HNSCC
For treatment with KEYTRUDA as monotherapy, testing for PD-L1 tumour expression using a 
validated test is recommended to select patients with NSCLC or previously untreated urothelial 
carcinoma (see sections 4.1, 4.4, 4.8, and 5.1).

Patients with HNSCC should be selected for treatment with KEYTRUDA as monotherapy or in 
combination with platinum and 5-fluorouracil (5-FU) chemotherapy based on the tumour expression
of PD-L1 confirmed by a validated test (see sections 4.1, 4.4, 4.8, and 5.1).

Posology
The recommended dose of KEYTRUDA as monotherapy is either 200 mg every 3 weeks or 400 mg 
every 6 weeks administered as an intravenous infusion over 30 minutes.

The recommended dose of KEYTRUDA as part of combination therapy is 200 mg every 3 weeks 
administered as an intravenous infusion over 30 minutes.

Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity. 
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 for clinically stable patients with initial evidence of disease progression until disease 
progression is confirmed.

For the adjuvant treatment of melanoma, KEYTRUDA should be administered until disease 
recurrence, unacceptable toxicity, or for a duration of up to one year.

 



70

Dose delay or discontinuation (see also section 4.4)
No dose reductions of KEYTRUDA are recommended. KEYTRUDA should be withheld or 
discontinued to manage adverse reactions as described in Table 1.

Table 1: Recommended treatment modifications for KEYTRUDA

Immune-related adverse 
reactions

Severity Treatment modification

Pneumonitis Grade 2 Withhold until adverse reactions 
recover to Grades 0-1*

Grades 3 or 4, or recurrent Grade 2 Permanently discontinue
Colitis Grades 2 or 3 Withhold until adverse reactions 

recover to Grades 0-1*
Grade 4 or recurrent Grade 3 Permanently discontinue

Nephritis Grade 2 with creatinine > 1.5 to ≤ 3 
times upper limit of normal (ULN) 

Withhold until adverse reactions 
recover to Grades 0-1*

Grade ≥ 3 with creatinine > 3 times 
ULN 

Permanently discontinue

Endocrinopathies Grade 2 adrenal insufficiency and 
hypophysitis

Withhold treatment until 
controlled by hormone 
replacement

Grades 3 or 4 adrenal insufficiency or 
symptomatic hypophysitis

Type 1 diabetes associated with 
Grade ≥ 3 hyperglycaemia (glucose 
> 250 mg/dL or > 13.9 mmol/L) or 
associated with ketoacidosis

Hyperthyroidism Grade ≥ 3

Withhold until adverse reactions 
recover to Grades 0-1*

For patients with Grade 3 or 
Grade 4 endocrinopathies that 
improved to Grade 2 or lower 
and are controlled with 
hormone replacement, if 
indicated, continuation of 
pembrolizumab may be 
considered after corticosteroid 
taper, if needed. Otherwise 
treatment should be 
discontinued.

Hypothyroidism Hypothyroidism may be 
managed with replacement 
therapy without treatment 
interruption.

Hepatitis

NOTE: for RCC patients 
treated with
pembrolizumab in 
combination with axitinib
with liver enzyme 
elevations, see dosing 
guidelines following this 
table.

Grade 2 with aspartate 
aminotransferase (AST) or alanine 
aminotransferase (ALT) > 3 to 5 times 
ULN or total bilirubin > 1.5 to 3 times 
ULN

Withhold until adverse reactions 
recover to Grades 0-1*

Grade ≥ 3 with AST or ALT > 5 times 
ULN or total bilirubin > 3 times ULN

Permanently discontinue

In case of liver metastasis with 
baseline Grade 2 elevation of AST or 
ALT, hepatitis with AST or ALT 
increases ≥ 50% and lasts ≥ 1 week

Permanently discontinue

Skin reactions Grade 3 or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal 
necrolysis (TEN)

Withhold until adverse reactions 
recover to Grades 0-1*

Grade 4 or confirmed SJS or TEN Permanently discontinue

 



71

Immune-related adverse 
reactions

Severity Treatment modification

Other immune-related 
adverse reactions

Based on severity and type of reaction 
(Grade 2 or Grade 3)

Grades 3 or 4 myocarditis
Grades-3 or 4 encephalitis 
Grades-3 or 4 Guillain-Barré 
syndrome

Grade 4 or recurrent Grade 3

Withhold until adverse reactions 
recover to Grades 0-1*

Permanently discontinue

Permanently discontinue

Infusion-related reactions Grades 3 or 4 Permanently discontinue

Note: toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 4.0 (NCI-CTCAE v.4).
* If treatment-related toxicity does not resolve to Grades 0-1 within 12 weeks after last dose of KEYTRUDA, or if 

corticosteroid dosing cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks, KEYTRUDA 
should be permanently discontinued.

The safety of re-initiating pembrolizumab therapy in patients previously experiencing immune-related 
myocarditis is not known.

KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued for 
Grade 4 or recurrent Grade 3 immune-related adverse reactions, unless otherwise specified in Table 1.

For Grade 4 haematological toxicity, only in patients with cHL, KEYTRUDA should be withheld until 
adverse reactions recover to Grades 0-1.

KEYTRUDA in combination with axitinib in RCC
For RCC patients treated with KEYTRUDA in combination with axitinib, see the Summary of Product 
Characteristics (SmPC) regarding dosing of axitinib. When used in combination with pembrolizumab, 
dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or 
longer (see section 5.1).

For liver enzyme elevations, in patients with RCC being treated with KEYTRUDA in combination with 
axitinib:
 If ALT or AST ≥ 3 times ULN but < 10 times ULN without concurrent total bilirubin ≥ 2 times 

ULN, both KEYTRUDA and axitinib should be withheld until these adverse reactions recover to 
Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or 
sequential rechallenge with both medicines after recovery may be considered. If rechallenging 
with axitinib, dose reduction as per the axitinib SmPC may be considered.

 If ALT or AST ≥ 10 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times 
ULN, both KEYTRUDA and axitinib should be permanently discontinued and corticosteroid 
therapy may be considered.

Patients treated with KEYTRUDA must be given the patient alert card and be informed about the risks 
of KEYTRUDA (see also package leaflet).

Special populations
Elderly
No dose adjustment is necessary in patients ≥ 65 years (see section 5.1). Data from patients ≥ 65 years 
are too limited to draw conclusions on cHL population (see section 5.1). Data from pembrolizumab 
monotherapy in patients with resected Stage III melanoma, from pembrolizumab in combination with 
axitinib in patients with advanced RCC, from chemotherapy combination in patients with metastatic 
NSCLC, and from pembrolizumab (with or without chemotherapy) in patients receiving first-line 
treatment for metastatic or unresectable recurrent HNSCC ≥ 75 years are limited (see sections 4.4 and 
5.1).

 



72

Renal impairment
No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA has 
not been studied in patients with severe renal impairment (see sections 4.4 and 5.2).

Hepatic impairment
No dose adjustment is needed for patients with mild hepatic impairment. KEYTRUDA has not been 
studied in patients with moderate or severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of KEYTRUDA in children below 18 years of age have not yet been 
established. Currently available data are described in sections 4.8, 5.1 and 5.2.

Method of administration
KEYTRUDA is for intravenous use. It must be administered by infusion over 30 minutes.
KEYTRUDA must not be administered as an intravenous push or bolus injection.

For use in combination, see the SmPC for the concomitant therapies. When administering 
KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be 
administered first. 

For instructions on dilution 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

In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded.

Assessment of PD-L1 status
When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust 
methodology is chosen to minimise false negative or false positive determinations.

Immune-related adverse reactions
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving 
pembrolizumab. Most immune-related adverse reactions occurring during treatment with 
pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the 
last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system 
can occur simultaneously.

For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology or exclude 
other causes should be ensured. Based on the severity of the adverse reaction, pembrolizumab should 
be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid taper 
should be initiated and continued over at least 1 month. Based on limited data from clinical studies in 
patients whose immune-related adverse reactions could not be controlled with corticosteroid use, 
administration of other systemic immunosuppressants can be considered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse 
reaction recovers to Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or 
equivalent per day.

Pembrolizumab must be permanently discontinued for any Grade 3 immune-related adverse reaction 
that recurs and for any Grade 4 immune-related adverse reaction toxicity, except for endocrinopathies 
that are controlled with replacement hormones (see sections 4.2 and 4.8).

 



73

Immune-related pneumonitis
Pneumonitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should 
be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed 
with radiographic imaging and other causes excluded. Corticosteroids should be administered for 
Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper); 
pembrolizumab should be withheld for Grade 2 pneumonitis, and permanently discontinued for 
Grade 3, Grade 4 or recurrent Grade 2 pneumonitis (see section 4.2).

Immune-related colitis
Colitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be 
monitored for signs and symptoms of colitis, and other causes excluded. Corticosteroids should be 
administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by 
a taper); pembrolizumab should be withheld for Grade 2 or Grade 3 colitis, and permanently 
discontinued for Grade 4 or recurrent Grade 3 colitis (see section 4.2). The potential risk of 
gastrointestinal perforation should be taken into consideration.

Immune-related hepatitis
Hepatitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be 
monitored for changes in liver function (at the start of treatment, periodically during treatment and as 
indicated based on clinical evaluation) and symptoms of hepatitis, and other causes excluded. 
Corticosteroids should be administered (initial dose of 0.5-1 mg/kg/day (for Grade 2 events) and 
1-2 mg/kg/day (for Grade ≥ 3 events) prednisone or equivalent followed by a taper) and, based on 
severity of liver enzyme elevations, pembrolizumab should be withheld or discontinued (see 
section 4.2).

Immune-related nephritis
Nephritis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be 
monitored for changes in renal function, and other causes of renal dysfunction excluded. 
Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone 
or equivalent followed by a taper) and, based on severity of creatinine elevations, pembrolizumab 
should be withheld for Grade 2, and permanently discontinued for Grade 3 or Grade 4 nephritis (see 
section 4.2).

Immune-related endocrinopathies
Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, 
diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with pembrolizumab 
treatment.

Long-term hormone replacement therapy may be necessary in cases of immune-related 
endocrinopathies.

Adrenal insufficiency (primary and secondary) has been reported in patients receiving pembrolizumab.
Hypophysitis has also been reported in patients receiving pembrolizumab. (See section 4.8). Patients 
should be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (including 
hypopituitarism) and other causes excluded. Corticosteroids to treat adrenal insufficiency and other 
hormone replacement should be administered as clinically indicated. Pembrolizumab should be 
withheld for Grade 2 adrenal insufficiency or symptomatic hypophysitis until the event is controlled 
with hormone replacement. Pembrolizumab should be withheld or discontinued for Grades 3 or 4 
adrenal insufficiency or hypophysitis. Continuation of pembrolizumab may be considered, after 
corticosteroid taper, if needed (see section 4.2). Pituitary function and hormone levels should be 
monitored to ensure appropriate hormone replacement.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving 
pembrolizumab (see section 4.8). Patients should be monitored for hyperglycaemia or other signs and 
symptoms of diabetes. Insulin should be administered for type 1 diabetes, and pembrolizumab should 

 



74

be withheld in cases of type 1 diabetes associated with Grade ≥ 3 hyperglycaemia or ketoacidosis until 
metabolic control is achieved (see section 4.2).

Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in 
patients receiving pembrolizumab and can occur at any time during treatment. Hypothyroidism is 
more frequently reported in patients with HNSCC with prior radiation therapy. Patients should be 
monitored for changes in thyroid function (at the start of treatment, periodically during treatment and 
as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. 
Hypothyroidism may be managed with replacement therapy without treatment interruption and 
without corticosteroids. Hyperthyroidism may be managed symptomatically. Pembrolizumab should 
be withheld for Grade ≥ 3 until recovery to Grade ≤ 1 hyperthyroidism. Thyroid function and hormone 
levels should be monitored to ensure appropriate hormone replacement.

For patients with Grade 3 or Grade 4 endocrinopathies that improved to Grade 2 or lower and are
controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered 
after corticosteroid taper, if needed. Otherwise treatment should be discontinued (see sections 4.2 and 
4.8). 

Immune-related skin adverse reactions 
Immune-related severe skin reactions have been reported in patients receiving pembrolizumab (see 
section 4.8). Patients should be monitored for suspected severe skin reactions and other causes should 
be excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld for 
Grade 3 skin reactions until recovery to Grade ≤ 1 or permanently discontinued for Grade 4 skin 
reactions, and corticosteroids should be administered (see section 4.2).

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported
in patients receiving pembrolizumab (see section 4.8). For suspected SJS or TEN, pembrolizumab 
should be withheld and the patient should be referred to a specialised unit for assessment and 
treatment. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued (see 
section 4.2).

Caution should be used when considering the use of pembrolizumab in a patient who has previously 
experienced a severe or life-threatening skin adverse reaction on prior treatment with other 
immune-stimulatory anti-cancer agents.

Other immune-related adverse reactions
The following additional clinically significant, immune-related adverse reactions have been reported 
in clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, 
pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis, 
encephalitis and myelitis (see sections 4.2 and 4.8).

Based on the severity and type of the adverse reaction, pembrolizumab should be withheld for Grade 2 
or Grade 3 events and corticosteroids administered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse 
reaction recovers to Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or 
equivalent per day.

Pembrolizumab must be permanently discontinued for any Grade 3 immune-related adverse reaction 
that recurs and for any Grade 4 immune-related adverse reaction.

For Grades 3 or 4 myocarditis, encephalitis or Guillain-Barré syndrome, pembrolizumab should be 
permanently discontinued (see sections 4.2 and 4.8).

 



75

Transplant-related adverse reactions

Solid organ transplant rejection
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with 
PD-1 inhibitors. Treatment with pembrolizumab may increase the risk of rejection in solid organ 
transplant recipients. The benefit of treatment with pembrolizumab versus the risk of possible organ 
rejection should be considered in these patients.

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT)

Allogeneic HSCT after treatment with pembrolizumab
Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been 
observed in patients with cHL undergoing allogeneic HSCT after previous exposure to 
pembrolizumab. 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).

Allogeneic HSCT prior to treatment with pembrolizumab
In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported 
after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure 
may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of 
treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of 
allogeneic HSCT.

Infusion-related reactions
Severe infusion-related reactions, including hypersensitivity and anaphylaxis, have been reported in 
patients receiving pembrolizumab (see section 4.8). For Grades 3 or 4 infusion reactions, infusion 
should be stopped and pembrolizumab permanently discontinued (see section 4.2). Patients with 
Grades 1 or 2 infusion reaction may continue to receive pembrolizumab with close monitoring; 
premedication with antipyretic and antihistamine may be considered.

Disease-specific precautions

Use of pembrolizumab in urothelial carcinoma patients who have received prior platinum-containing 
chemotherapy
Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in 
patients with poorer prognostic features and/or aggressive disease. In urothelial carcinoma, a higher 
number of deaths within 2 months was observed in pembrolizumab compared to chemotherapy (see 
section 5.1). Factors associated with early deaths were fast progressive disease on prior platinum 
therapy and liver metastases.

Use of pembrolizumab in urothelial carcinoma for patients who are considered ineligible for 
cisplatin-containing chemotherapy and whose tumours express PD-L1 with CPS ≥ 10
The baseline and prognostic disease characteristics of the study population of KEYNOTE-052 
included a proportion of patients eligible for a carboplatin-based combination, for whom the benefit is 
being assessed in a comparative study, and patients eligible for mono-chemotherapy, for whom no 
randomised data are available. In addition, no safety and efficacy data are available in frailer patients 
(e.g. ECOG performance status 3) considered not eligible for chemotherapy. In the absence of these 
data, pembrolizumab should be used with caution in this population after careful consideration of the 
potential risk-benefit on an individual basis.

Use of pembrolizumab for first-line treatment of patients with NSCLC
In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed to 
be higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions of 
each of these components (see sections 4.2 and 4.8). A direct comparison of pembrolizumab when 
used in combination with chemotherapy to pembrolizumab monotherapy is not available.

 



76

Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab 
monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in 
previously untreated patients with NSCLC whose tumours express PD-L1. 

In KEYNOTE-042, a higher number of deaths within 4 months of treatment initiation followed by a 
long-term survival benefit was observed with pembrolizumab monotherapy compared to 
chemotherapy (see section 5.1).

Efficacy and safety data from patients ≥ 75 years are limited. For patients ≥ 75 years, pembrolizumab 
combination therapy should be used with caution after careful consideration of the potential 
benefit/risk on an individual basis (see section 5.1).

Use of pembrolizumab for first-line treatment of patients with HNSCC
In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed to 
be higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions of 
each of these components (see section 4.8). 

Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab 
monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in 
patients with HNSCC whose tumours express PD-L1 (see section 5.1).

Use of pembrolizumab for adjuvant treatment of patients with melanoma
A trend toward increased frequency of severe and serious adverse reactions in patients ≥ 75 years was 
observed. Safety data of pembrolizumab in the adjuvant melanoma setting in patients ≥ 75 years are 
limited.

Use of pembrolizumab in combination with axitinib for first-line treatment of patients with RCC
When pembrolizumab is given with axitinib, higher than expected frequencies of Grades 3 and 4 ALT 
and AST elevations have been reported in patients with advanced RCC (see section 4.8). Liver 
enzymes should be monitored before initiation of and periodically throughout treatment. More 
frequent monitoring of liver enzymes as compared to when the medicines are used in monotherapy 
may be considered. Medical management guidelines for both medicines should be followed (see 
section 4.2 and refer to the SmPC for axitinib). 

Patients excluded from clinical studies
Patients with the following conditions were excluded from clinical studies: active CNS metastases; 
ECOG PS ≥ 2 (except for urothelial carcinoma and RCC); HIV infection, hepatitis B or hepatitis C 
infection; active systemic autoimmune disease; interstitial lung disease; prior pneumonitis requiring 
systemic corticosteroid therapy; a history of severe hypersensitivity to another monoclonal antibody; 
receiving immunosuppressive therapy and a history of severe immune-related adverse reactions from 
treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid 
treatment (> 10 mg/day prednisone or equivalent) for greater than 12 weeks. Patients with active 
infections were excluded from clinical studies and were required to have their infection treated prior to 
receiving pembrolizumab. Patients with active infections occurring during treatment with 
pembrolizumab were managed with appropriate medical therapy. Patients with clinically significant 
renal (creatinine > 1.5 x ULN) or hepatic (bilirubin > 1.5 x ULN, ALT, AST > 2.5 x ULN in the 
absence of liver metastases) abnormalities at baseline were excluded from clinical studies, therefore 
information is limited in patients with severe renal and moderate to severe hepatic impairment.

There are limited data on the safety and efficacy of KEYTRUDA in patients with ocular melanoma 
(see section 5.1).

For subjects with relapsed or refractory cHL, clinical data for the use of pembrolizumab in patients 
ineligible to ASCT due to reasons other than failure to salvage chemotherapy are limited (see 
section 5.1).

 



77

After careful consideration of the potential increased risk, pembrolizumab may be used with
appropriate medical management in these patients. 

Patient alert card
All prescribers of KEYTRUDA must be familiar with the Physician Information and Management 
Guidelines. The prescriber must discuss the risks of KEYTRUDA 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

No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. Since 
pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug 
interactions are expected. 

The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be 
avoided because of their potential interference with the pharmacodynamic activity and efficacy of 
pembrolizumab. However, systemic corticosteroids or other immunosuppressants can be used after 
starting pembrolizumab to treat immune-related adverse reactions (see section 4.4). Corticosteroids 
can also be used as premedication, when pembrolizumab is used in combination with chemotherapy, 
as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
Women of childbearing potential should use effective contraception during treatment with 
pembrolizumab and for at least 4 months after the last dose of pembrolizumab.

Pregnancy
There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have 
not been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1 
signalling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss 
(see section 5.3). These results indicate a potential risk, based on its mechanism of action, that 
administration of pembrolizumab during pregnancy could cause foetal harm, including increased rates 
of abortion or stillbirth. Human immunoglobulins G4 (IgG4) are known to cross the placental barrier; 
therefore, being an IgG4, pembrolizumab has the potential to be transmitted from the mother to the 
developing foetus. Pembrolizumab should not be used during pregnancy unless the clinical condition 
of the woman requires treatment with pembrolizumab.

Breast-feeding
It is unknown whether pembrolizumab is secreted in human milk. Since it is known that antibodies can 
be secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision should be 
made whether to discontinue breast-feeding or to discontinue pembrolizumab, taking into account the 
benefit of breast-feeding for the child and the benefit of pembrolizumab therapy for the woman.

Fertility
No clinical data are available on the possible effects of pembrolizumab on fertility. There were no 
notable effects in the male and female reproductive organs in monkeys based on 1-month and 6-month 
repeat-dose toxicity studies (see section 5.3).

4.7 Effects on ability to drive and use machines

Pembrolizumab has a minor influence on the ability to drive and use machines. In some patients, 
dizziness and fatigue have been reported following administration of pembrolizumab (see section 4.8).

 



78

4.8 Undesirable effects

Summary of the safety profile
Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these, 
including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal 
of pembrolizumab (see “Description of selected adverse reactions” below).

The safety of pembrolizumab as monotherapy has been evaluated in 5,884 patients with advanced 
melanoma, resected Stage III melanoma (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, or 
HNSCC across four doses (2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 
3 weeks) in clinical studies. The frequencies included below and in Table 2 are based on all reported 
adverse drug reactions, regardless of the investigator assessment of causality. In this patient 
population, the median observation time was 7.3 months (range: 1 day to 31 months) and the most 
frequent adverse reactions with pembrolizumab were fatigue (32%), nausea (20%), and 
diarrhoea (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 
severity. The most serious adverse reactions were immune-related adverse reactions and severe 
infusion-related reactions (see section 4.4).

The safety of pembrolizumab in combination with chemotherapy has been evaluated in 1,067 patients 
with NSCLC or HNSCC receiving 200 mg, 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks, in 
clinical studies. The frequencies included below and in Table 2 are based on all reported adverse drug 
reactions, regardless of the investigator assessment of causality. In this patient population, the most 
frequent adverse reactions were anaemia (50%), nausea (50%), fatigue (37%), constipation (35%), 
diarrhoea (30%), neutropaenia (30%), decreased appetite (28%) and vomiting (25%). Incidences of 
Grades 3-5 adverse reactions in patients with NSCLC were 67% for pembrolizumab combination 
therapy and 66% for chemotherapy alone and in patients with HNSCC were 85% for pembrolizumab 
combination therapy and 84% for chemotherapy plus cetuximab.

The safety of pembrolizumab in combination with axitinib has been evaluated in a clinical study of 
429 patients with advanced RCC receiving 200 mg pembrolizumab every 3 weeks and 5 mg axitinib 
twice daily. In this patient population, the most frequent adverse reactions were diarrhoea (54%), 
hypertension (45%), fatigue (38%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar 
erythrodysaesthesia syndrome (28%), nausea (28%), ALT increased (27%), AST increased (26%), 
dysphonia (25%), cough (21%), and constipation (21%). Incidences of Grades 3-5 adverse reactions 
were 76% for pembrolizumab combination therapy and 71% for sunitinib alone.

Tabulated list of adverse reactions
Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination 
with chemotherapy or other anti-tumour medicines or reported from post-marketing use of 
pembrolizumab are listed in Table 2. Adverse reactions known to occur with pembrolizumab or 
chemotherapies given alone may occur during treatment with these medicinal products in 
combination, even if these reactions were not reported in clinical studies with combination therapy. 
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); and not known (cannot be estimated from the 
available data). Within each frequency grouping, adverse reactions are presented in the order of 
decreasing seriousness.

Table 2: Adverse reactions in patients treated with pembrolizumab*

Monotherapy Combination with 
chemotherapy

Combination with 
axitinib

Infections and infestations
Common pneumonia pneumonia pneumonia
Blood and lymphatic system disorders
Very common anaemia anaemia, neutropaenia, 

thrombocytopaenia

 



79

Monotherapy Combination with 
chemotherapy

Combination with 
axitinib

Common thrombocytopaenia, 
lymphopaenia

febrile neutropaenia, 
leukopaenia, 
lymphopaenia

anaemia, neutropaenia, 
leukopaenia, 
thrombocytopaenia

Uncommon neutropaenia, leukopaenia, 
eosinophilia

lymphopaenia, 
eosinophilia

Rare immune thrombocytopenic 
purpura, haemolytic 
anaemia, pure red cell 
aplasia, haemophagocytic 
lymphohistiocytosis

eosinophilia

Immune system disorders
Common infusion-related reactiona infusion-related reactiona infusion-related 

reactiona

Uncommon sarcoidosis
Not known solid organ transplant 

rejection
Endocrine disorders
Very common hypothyroidismb hyperthyroidism, 

hypothyroidismb

Common hyperthyroidism hypothyroidism, 
hyperthyroidism

hypophysitisd, 
thyroiditise, adrenal 
insufficiencyc

Uncommon adrenal insufficiencyc, 
hypophysitisd, thyroiditise

hypophysitisd, 
thyroiditise, adrenal 
insufficiencyc

Metabolism and nutrition disorders
Very common decreased appetite hypokalaemia, decreased 

appetite
decreased appetite

Common hyponatraemia, 
hypokalaemia, 
hypocalcaemia

hyponatraemia, 
hypocalcaemia 

hypokalaemia, 
hyponatraemia, 
hypocalcaemia

Uncommon type 1 diabetes mellitusf type 1 diabetes mellitus type 1 diabetes mellitusf

Psychiatric disorders
Common insomnia insomnia insomnia
Nervous system disorders
Very common headache dizziness, headache, 

neuropathy peripheral, 
dysgeusia

headache, dysgeusia

Common dizziness, neuropathy 
peripheral, lethargy,
dysgeusia

lethargy dizziness, lethargy, 
neuropathy peripheral

Uncommon epilepsy epilepsy myasthenic syndromei

Rare encephalitis, Guillain-Barré 
syndromeg, myelitish, 
myasthenic syndromei, 
meningitis (aseptic)j

Eye disorders 
Common dry eye dry eye dry eye
Uncommon uveitisk uveitisk

Rare Vogt-Koyanagi-Harada 
syndrome

Cardiac disorders

 



80

Monotherapy Combination with 
chemotherapy

Combination with 
axitinib

Common cardiac arrhythmia†

(including atrial 
fibrillation)

cardiac arrhythmia†

(including atrial 
fibrillation)

cardiac arrhythmia†

(including atrial 
fibrillation)

Uncommon pericardial effusion, 
pericarditis

pericardial effusion myocarditisl

Rare myocarditisl myocarditisl, pericarditis
Vascular disorders
Very common hypertension
Common hypertension hypertension
Respiratory, thoracic and mediastinal 
disorders
Very common dyspnoea, cough dyspnoea, cough dyspnoea, cough, 

dysphonia
Common pneumonitism pneumonitism pneumonitism

Gastrointestinal disorders
Very common diarrhoea, abdominal painn, 

nausea, vomiting, 
constipation

diarrhoea, nausea, 
vomiting, constipation, 
abdominal painn

diarrhoea, abdominal 
painn, nausea, vomiting, 
constipation

Common colitiso, dry mouth colitiso, dry mouth colitiso, dry mouth
Uncommon pancreatitisp,

gastrointestinal ulcerationq
pancreatitisp,
gastrointestinal 
ulcerationq

pancreatitisp,
gastrointestinal 
ulcerationq

Rare small intestinal perforation
Hepatobiliary disorders
Common hepatitisr

Uncommon hepatitisr hepatitisr

Skin and subcutaneous tissue disorders
Very common rashs, pruritust rashs, alopecia, pruritust palmar-plantar 

erythrodysaesthesia 
syndrome, rashs, 
pruritust

Common severe skin reactionsu, 
erythema, dry skin, 
vitiligov, eczema, alopecia, 
dermatitis acneiform

severe skin reactionsu, 
erythema, dry skin

severe skin reactionsu, 
dermatitis acneiform, 
dermatitis, dry skin, 
alopecia, eczema, 
erythema 

Uncommon lichenoid keratosisw, 
psoriasis, dermatitis, 
papule, hair colour changes

psoriasis, dermatitis 
acneiform, dermatitis, 
vitiligov, eczema

hair colour changes, 
lichenoid keratosis, 
papule, psoriasis, 
vitiligov

Rare toxic epidermal necrolysis, 
Stevens-Johnson syndrome, 
erythema nodosum

hair colour changes, 
lichenoid keratosis, 
papule

Musculoskeletal and connective tissue 
disorders 
Very common musculoskeletal painx, 

arthralgia
musculoskeletal painx, 
arthralgia

musculoskeletal painx, 
arthralgia, pain in 
extremity

Common pain in extremity, 
myositisy, arthritisz

myositisy, pain in 
extremity, arthritisz

myositisy, arthritisz, 
tenosynovitisaa

Uncommon tenosynovitisaa tenosynovitisaa Sjogren’s syndrome
Rare Sjogren’s syndrome Sjogren’s syndrome

 



81

Monotherapy Combination with 
chemotherapy

Combination with 
axitinib

Renal and urinary disorders
Common nephritisbb, acute kidney 

injury
acute kidney injury,
nephritisbb

Uncommon nephritisbb

General disorders and administration site 
conditions
Very common fatigue, asthenia, oedemacc, 

pyrexia
fatigue, asthenia, pyrexia, 
oedemacc 

fatigue, asthenia, 
pyrexia

Common influenza-like illness, chills chills, influenza-like 
illness

oedemacc, influenza-like 
illness, chills

Investigations 
Very common blood creatinine 

increased
alanine aminotransferase 
increased, aspartate 
aminotransferase 
increased, blood 
creatinine increased

Common aspartate aminotransferase 
increased, alanine 
aminotransferase increased, 
hypercalcaemia, blood 
alkaline phosphatase 
increased, blood bilirubin 
increased, blood creatinine 
increased

hypercalcaemia, alanine 
aminotransferase 
increased, aspartate 
aminotransferase 
increased, blood alkaline 
phosphatase increased

blood alkaline 
phosphatase increased, 
hypercalcaemia, blood 
bilirubin increased

Uncommon amylase increased blood bilirubin increased, 
amylase increased

amylase increased

*Adverse reaction frequencies presented in Table 2 may not be fully attributable to pembrolizumab alone but may contain 
contributions from the underlying disease or from other medicinal products used in a combination.
†Based upon a standard query including bradyarrhythmias and tachyarrhythmias.

 



82

The following terms represent a group of related events that describe a medical condition rather than a single event:
a. infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity and 

cytokine release syndrome)
b. hypothyroidism (myxoedema)
c. adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency)
d. hypophysitis (hypopituitarism) 
e. thyroiditis (autoimmune thyroiditis and thyroid disorder)
f. type 1 diabetes mellitus (diabetic ketoacidosis)
g. Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy)
h. myelitis (including transverse myelitis)
i. myasthenic syndrome (myasthenia gravis, including exacerbation)
j. meningitis aseptic (meningitis, meningitis non-infective)
k. uveitis (iritis and iridocyclitis)
l. myocarditis (autoimmune myocarditis)
m. pneumonitis (interstitial lung disease and organising pneumonia)
n. abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)
o. colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, and autoimmune colitis)
p. pancreatitis (autoimmune pancreatitis and pancreatitis acute)
q. gastrointestinal ulceration (gastric ulcer and duodenal ulcer)
r. hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis)
s. rash (rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash 

pruritic, rash vesicular and genital rash)
t. pruritus (urticaria, urticaria papular, pruritus generalised and pruritus genital) 
u. severe skin reactions (dermatitis bullous, dermatitis exfoliative, dermatitis exfoliative generalised, erythema 

multiforme, exfoliative rash, pemphigus, skin necrosis, toxic skin eruption and Grade ≥ 3 of the following: acute 
febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis psoriasiform, drug eruption, jaundice, 
pemphigoid, pruritus, pruritus generalised, rash, rash erythematous, rash generalised, rash maculo-papular, rash 
pruritic, rash pustular and skin lesion)

v. vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid)
w. lichenoid keratosis (lichen planus and lichen sclerosus)
x. musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain 

and torticollis)
y. myositis (myalgia, myopathy, polymyalgia rheumatica and rhabdomyolysis)
z. arthritis (joint swelling, polyarthritis and joint effusion)
aa. tenosynovitis (tendonitis, synovitis and tendon pain)
bb. nephritis (nephritis autoimmune, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney 

injury with evidence of nephritis, nephrotic syndrome and glomerulonephritis membranous)
cc. oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face 

oedema, localised oedema and periorbital oedema)

Description of selected adverse reactions
Data for the following immune-related adverse reactions are based on patients who received 
pembrolizumab across four doses (2 mg/kg every 3 weeks, 10 mg/kg every 2 or 3 weeks, or 200 mg 
every 3 weeks) in clinical studies (see section 5.1). The management guidelines for these adverse 
reactions are described in section 4.4.

Immune-related adverse reactions (see section 4.4)

Immune-related pneumonitis
Pneumonitis occurred in 253 (4.3%) patients, including Grade 2, 3, 4 or 5 cases in 106 (1.8%), 
69 (1.2%), 13 (0.2%) and 9 (0.2%) patients, respectively, receiving pembrolizumab. The median time
to onset of pneumonitis was 3.3 months (range 2 days to 26.8 months). The median duration was 
1.9 months (range 1 day to 25.3+ months). Pneumonitis occurred more frequently in patients with a 
history of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation 
(3.4%). Pneumonitis led to discontinuation of pembrolizumab in 98 (1.7%) patients. Pneumonitis 
resolved in 138 patients, 2 with sequelae.

In patients with NSCLC, pneumonitis occurred in 160 (5.7%), including Grade 2, 3, 4 or 5 cases in 62 
(2.2%), 47 (1.7%), 14 (0.5%) and 10 (0.4%), respectively. In patients with NSCLC, pneumonitis 
occurred in 8.9% with a history of prior thoracic radiation.

Immune-related colitis
Colitis occurred in 107 (1.8%) patients, including Grade 2, 3 or 4 cases in 31 (0.5%), 62 (1.1%) and 
3 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 

 



83

4.3 months (range 7 days to 24.3 months). The median duration was 0.9 months (range 1 day to 
8.7+ months). Colitis led to discontinuation of pembrolizumab in 29 (0.5%) patients. Colitis resolved 
in 84 patients, 2 with sequelae.

Immune-related hepatitis
Hepatitis occurred in 50 (0.8%) patients, including Grade 2, 3 or 4 cases in 8 (0.1%), 31 (0.5%) and 
8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 
3.6 months (range 8 days to 21.4 months). The median duration was 1.1 months (range 1 day to 
20.9+ months). Hepatitis led to discontinuation of pembrolizumab in 19 (0.3%) patients. Hepatitis 
resolved in 36 patients.

Immune-related nephritis 
Nephritis occurred in 22 (0.4%) patients, including Grade 2, 3 or 4 cases in 5 (0.1%), 14 (0.2%) and 
1 (< 0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset 
of nephritis was 5.0 months (range 12 days to 21.4 months). The median duration was 2.6 months 
(range 6 days to 12.0 months). Nephritis led to discontinuation of pembrolizumab in 10 (0.2%) 
patients. Nephritis resolved in 13 patients, 3 with sequelae. In patients with non-squamous NSCLC 
treated with pembrolizumab in combination with pemetrexed and platinum chemotherapy (n=488), the 
incidence of nephritis was 1.4% (all Grades) with 0.8% Grade 3 and 0.4% Grade 4.

Immune-related endocrinopathies
Adrenal insufficiency occurred in 46 (0.8%) patients, including Grade 2, 3 or 4 cases in 19 (0.3%), 
20 (0.3%) and 3 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of 
adrenal insufficiency was 5.4 months (range 1 day to 17.7 months). The median duration was not 
reached (range 3 days to 26.2+ months). Adrenal insufficiency led to discontinuation of 
pembrolizumab in 4 (0.1%) patients. Adrenal insufficiency resolved in 16 patients, 4 with sequelae.

Hypophysitis occurred in 36 (0.6%) patients, including Grade 2, 3 or 4 cases in 13 (0.2%), 19 (0.3%) 
and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of 
hypophysitis was 5.9 months (range 1 day to 17.7 months). The median duration was 3.3 months 
(range 3 days to 18.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 8 (0.1%) 
patients. Hypophysitis resolved in 17 patients, 8 with sequelae.

Hyperthyroidism occurred in 244 (4.1%) patients, including Grade 2 or 3 cases in 64 (1.1%) and 
7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of 
hyperthyroidism was 1.4 months (range 1 day to 22.5 months). The median duration was 1.8 months 
(range 4 days to 29.2+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 3 (0.1%) 
patients. Hyperthyroidism resolved in 191 (78.3%) patients, 5 with sequelae.

Hypothyroidism occurred in 645 (11.0%) patients, including Grade 2 or 3 cases in 475 (8.1%) and 
8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of 
hypothyroidism was 3.5 months (range 1 day to 19.6 months). The median duration was not reached 
(range 2 days to 32.6+ months). Two patients (< 0.1%) discontinued pembrolizumab due to 
hypothyroidism. Hypothyroidism resolved in 153 (23.7%) patients, 10 with sequelae. In patients with 
cHL (n=241) the incidence of hypothyroidism was 14.1% (all Grades) with 0.4% Grade 3. In patients 
with HNSCC treated with pembrolizumab as monotherapy (n=909), the incidence of hypothyroidism 
was 16.1% (all Grades) with 0.3% Grade 3. In patients with HNSCC treated with pembrolizumab in 
combination with platinum and 5-FU chemotherapy (n=276), the incidence of hypothyroidism 
was 15.2%, all of which were Grade 1 or 2.

Immune-related skin adverse reactions
Immune-related severe skin reactions occurred in 89 (1.5%) patients, including Grade 2, 3 or 5 cases 
in 10 (0.2%), 65 (1.1%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median 
time to onset of severe skin reactions was 3.3 months (range 3 days to 19.4 months). The median 
duration was 1.6 months (range 1 day to 27.3+ months). Severe skin reactions led to discontinuation of 
pembrolizumab in 9 (0.2%) patients. Severe skin reactions resolved in 64 patients.

 



84

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed (see sections 4.2 
and 4.4).

Complications of allogeneic HSCT in cHL
Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with pembrolizumab, 
6 patients (26%) developed GVHD, one of which was fatal, and 2 patients (9%) developed severe 
hepatic VOD after reduced-intensity conditioning, one of which was fatal. The 23 patients had a 
median follow-up from subsequent allogeneic HSCT of 5.1 months (range: 0-26.2 months).

Elevated liver enzymes when pembrolizumab is combined with axitinib in RCC
In a clinical study of previously untreated patients with RCC receiving pembrolizumab in combination 
with axitinib, a higher than expected incidence of Grades 3 and 4 ALT increased (20%) and AST 
increased (13%) were observed. The median time to onset of ALT increased was 2.3 months (range: 
7 days to 19.8 months). In patients with ALT ≥ 3 times ULN (Grades 2-4, n=116), ALT resolved to 
Grades 0-1 in 94%. Fifty-nine percent of the patients with increased ALT received systemic 
corticosteroids. Of the patients who recovered, 92 (84%) were rechallenged with either 
pembrolizumab (3%) or axitinib (31%) monotherapy or with both (50%). Of these patients, 55% had 
no recurrence of ALT > 3 times ULN, and of those patients with recurrence of ALT > 3 times ULN, 
all recovered. There were no Grade 5 hepatic events. 

Laboratory abnormalities 
In patients treated with pembrolizumab monotherapy, the proportion of patients who experienced a 
shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 10.9% for lymphocytes 
decreased, 8.2% for sodium decreased, 6.3% for haemoglobin decreased, 5.2% for phosphate 
decreased, 4.8% for glucose increased, 2.8% for AST increased, 2.7% for alkaline phosphatase 
increased, 2.7% for ALT increased, 2.2% for potassium decreased, 1.8% for calcium increased, 1.8% 
for neutrophils decreased, 1.8% for potassium increased, 1.7% for bilirubin increased, 1.7% for 
platelets decreased, 1.6% for albumin decreased, 1.5% for calcium decreased, 1.3% for creatinine 
increased, 0.8% for leucocytes decreased, 0.7% for magnesium increased, 0.6% for glucose decreased, 
0.2% for magnesium decreased, and 0.2% for sodium increased.

In patients treated with pembrolizumab in combination with chemotherapy, the proportion of patients 
who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 26.7% 
for neutrophils decreased, 23.9% for lymphocytes decreased, 19.1% for haemoglobin decreased, 
17.9% for leucocytes decreased, 12.2% for platelets decreased, 10.2% for sodium decreased, 8.9% for 
phosphate decreased, 7.4% for glucose increased, 6.5% for potassium decreased, 3.3 for creatinine 
increased, 3.1% for ALT increased, 3.1% for AST increased, 3.1% for calcium decreased, 3.0% for 
potassium increased, 2.9% for albumin decreased, 2.3% for calcium increased, 1.2% for alkaline 
phosphatase increased, 0.8% for glucose decreased, 0.7% for bilirubin increased, and 0.3% for sodium 
increased.

In patients treated with pembrolizumab in combination with axitinib, the proportion of patients who 
experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 20.1% for 
ALT increased, 13.2% for AST increased, 10.8% for lymphocytes decreased, 8.9% for glucose 
increased, 7.8% for sodium decreased, 6.4% for phosphate decreased, 6.2% for potassium increased, 
4.3% for creatinine increased, 3.6% for potassium decreased, 2.1% for bilirubin increased, 2.1% for 
haemoglobin decreased, 1.7% for alkaline phosphatase increased, 1.5% for prothrombin INR 
increased, 1.4% for leukocytes decreased, 1.4% for platelets decreased, 1.2% for activated partial 
thromboplastin time prolonged, 1.2% for neutrophils decreased, 1.2% for sodium increased, 0.7% for 
calcium decreased, 0.7% for calcium increased, 0.5% for albumin decreased, and 0.2% for glucose 
decreased.

Immunogenicity
In clinical studies in patients treated with pembrolizumab 2 mg/kg every three weeks, 200 mg every 
three weeks, or 10 mg/kg every two or three weeks as monotherapy, 36 (1.8%) of 2,034 evaluable
patients tested positive for treatment-emergent antibodies to pembrolizumab, of which 9 (0.4%) 
patients had neutralising antibodies against pembrolizumab. There was no evidence of an altered 

 



85

pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody 
development.

Paediatric population
The safety of pembrolizumab as monotherapy has been evaluated in 154 paediatric patients with 
advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours at
2 mg/kg every 3 weeks in the Phase I/II study KEYNOTE-051. The safety profile in these paediatric 
patients was generally similar to that seen in adults treated with pembrolizumab. The most common 
adverse reactions (reported in at least 20% of paediatric patients) were pyrexia (31%), 
vomiting (26%), headache (22%), abdominal pain (21%), anaemia (21%) and constipation (20%). The 
majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. 
Sixty-nine (44.8%) patients had 1 or more Grades 3 to 5 adverse reactions of which 6 (3.9%) patients
had 1 or more adverse reactions that resulted in death. The frequencies are based on all reported 
adverse drug reactions, regardless of the investigator assessment of causality.

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

There is no information on overdose with pembrolizumab. 

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, 
and appropriate symptomatic treatment instituted.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC18

Mechanism of action
KEYTRUDA is a humanised monoclonal antibody which binds to the programmed cell death-1 
(PD-1) receptor and blocks its interaction with ligands 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. KEYTRUDA potentiates T-cell responses, including anti-tumour responses, 
through blockade of PD-1 binding to 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.

Clinical efficacy and safety
Pembrolizumab doses of 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 
2 weeks were evaluated in melanoma or previously treated NSCLC clinical studies. Based on the 
modelling and simulation of dose/exposure relationships for efficacy and safety for pembrolizumab, 
there are no clinically significant differences in efficacy or safety among the doses of 200 mg every 
3 weeks, 2 mg/kg every 3 weeks, and 400 mg every 6 weeks as monotherapy (see section 4.2).

Melanoma
KEYNOTE-006: Controlled study in melanoma patients naïve to treatment with ipilimumab
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-006, a multicentre, 
open-label, controlled, Phase III study for the treatment of advanced melanoma in patients who were 
naïve to ipilimumab. Patients were randomised (1:1:1) to receive pembrolizumab 10 mg/kg every 2 
(n=279) or 3 weeks (n=277) or ipilimumab 3 mg/kg every 3 weeks (n=278). Patients with BRAF 
V600E mutant melanoma were not required to have received prior BRAF inhibitor therapy.

 

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86

Patients were treated with pembrolizumab until disease progression or unacceptable toxicity.
Clinically stable patients with initial evidence of disease progression were permitted to remain on 
treatment until disease progression was confirmed. Assessment of tumour status was performed at 
12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter.

Of the 834 patients, 60% were male, 44% were ≥ 65 years (median age was 62 years [range 18-89]) 
and 98% were white. Sixty-five percent of patients had M1c stage, 9% had a history of brain 
metastases, 66% had no and 34% had one prior therapy. Thirty-one percent had an ECOG 
Performance Status of 1, 69% had ECOG Performance Status of 0 and 32% had elevated LDH. BRAF 
mutations were reported in 302 (36%) patients. Among patients with BRAF mutant tumours, 
139 (46%) were previously treated with a BRAF inhibitor.

The primary efficacy outcome measures were progression free survival (PFS; as assessed by 
Integrated Radiology and Oncology Assessment [IRO] review using Response Evaluation Criteria in 
Solid Tumours [RECIST], version 1.1) and overall survival (OS). Secondary efficacy outcome 
measures were objective response rate (ORR) and response duration. Table 3 summarises key efficacy 
measures in patients naïve to treatment with ipilimumab at the final analysis performed after a 
minimum of 21 months of follow-up. Kaplan-Meier curves for OS and PFS based on the final analysis 
are shown in Figures 1 and 2.

 



87

Table 3: Efficacy results in KEYNOTE-006

Endpoint Pembrolizumab
10 mg/kg every 

3 weeks
n=277

Pembrolizumab
10 mg/kg every 

2 weeks
n=279

Ipilimumab
3 mg/kg every 

3 weeks
n=278

OS
Number (%) of 
patients with event

119 (43%) 122 (44%) 142 (51%)

Hazard ratio*
(95% CI)

0.68 (0.53, 0.86) 0.68 (0.53, 0.87) ---

p-Value† < 0.001 < 0.001 ---
Median in months 
(95% CI)

Not reached
(24, NA)

Not reached
(22, NA)

16
(14, 22)

PFS
Number (%) of 
patients with event

183 (66%) 181 (65%) 202 (73%)

Hazard ratio*
(95% CI)

0.61 (0.50, 0.75) 0.61 (0.50, 0.75) ---

p-Value† < 0.001 < 0.001 ---
Median in months 
(95% CI)

4.1
(2.9, 7.2)

5.6
(3.4, 8.2)

2.8
(2.8, 2.9)

Best objective
response

ORR % (95% CI) 36%
(30, 42)

37%
(31, 43)

13%
(10, 18)

Complete 
response %

13% 12% 5%

Partial response % 23% 25% 8%
Response duration‡

Median in months 
(range)

Not reached
(2.0, 22.8+)

Not reached
(1.8, 22.8+)

Not reached
(1.1+, 23.8+)

% ongoing at 
18 months

68%§ 71%§ 70%§

* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportional 
hazard model

† Based on stratified log-rank test
‡ Based on patients with a best objective response as confirmed complete or partial response
§ Based on Kaplan-Meier estimation
NA = not available

 



88

Figure 1: Kaplan-Meier curve for overall survival by treatment arm in 
KEYNOTE-006 (intent to treat population)

Figure 2: Kaplan-Meier curve for progression-free survival by treatment arm in 
KEYNOTE-006 (intent to treat population)

ipilimumab:

Pembrolizumab 10 mg/kg every 3 weeks:

Pembrolizumab 10 mg/kg every 2 weeks:

278 213 170 145 122 110 28 0

279 249 221 202 176 156 44 0

277 251 215 184 174 156 43 0

Number at Risk

Treatment arm                                           OS rate at 24 months         HR (95% CI)          p-value
Pembrolizumab 10 mg/kg every 2 weeks              55.1%                 0.68 (0.53, 0.87)        0.00085
Pembrolizumab 10 mg/kg every 3 weeks              55.3%                 0.68 (0.53, 0.86)        0.00083
ipilimumab                                                              43.0%                             

0 4 8 12 16 20 24 28

Time in Months

0

10

20

30

40

50

60

70

80

90

100

O
ve

ra
ll 

S
u
rv

iv
a
l (

%
)

ipilimumab:

Pembrolizumab 10 mg/kg every 3 weeks:

Pembrolizumab 10 mg/kg every 2 weeks:

278 88 48 34 29 16 5 0

279 148 116 98 82 52 16 0

277 136 111 91 84 60 13 0

Number at Risk

Treatment arm                                          PFS rate at 18 months          HR (95% CI)           p-value
Pembrolizumab 10 mg/kg every 2 weeks                32.4%                  0.61 (0.50, 0.75)        0.00000
Pembrolizumab 10 mg/kg every 3 weeks                32.9%                  0.61 (0.50, 0.75)        0.00000
ipilimumab                                                                15.2% 

0 4 8 12 16 20 24 28

Time in Months

0

10

20

30

40

50

60

70

80

90

100

P
ro

g
re

ss
io

n
-F

re
e
 S

u
rv

iv
a
l 
(%

)

 



89

KEYNOTE-002: Controlled study in melanoma patients previously treated with ipilimumab
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-002, a multicentre, 
double-blind, controlled study for the treatment of advanced melanoma in patients previously treated 
with ipilimumab and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor. Patients were 
randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=180) or 10 mg/kg (n=181) every 
3 weeks or chemotherapy (n=179; including dacarbazine, temozolomide, carboplatin, paclitaxel, or 
carboplatin+paclitaxel). The study excluded patients with autoimmune disease or those receiving 
immunosuppression; further exclusion criteria were a history of severe or life-threatening 
immune-related adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or 
Grade 3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent dose) for 
greater than 12 weeks; ongoing adverse reactions ≥ Grade 2 from previous treatment with ipilimumab; 
previous severe hypersensitivity to other monoclonal antibodies; a history of pneumonitis or interstitial 
lung disease; HIV, hepatitis B or hepatitis C infection and ECOG Performance Status ≥ 2. 

Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. 
Clinically stable patients with initial evidence of disease progression were permitted to remain on 
treatment until disease progression was confirmed. Assessment of tumour status was performed at 
12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. Patients on 
chemotherapy who experienced independently-verified progression of disease after the first scheduled 
disease assessment were able to crossover and receive 2 mg/kg or 10 mg/kg of pembrolizumab every 
3 weeks in a double-blind fashion.

Of the 540 patients, 61% were male, 43% were ≥ 65 years (median age was 62 years [range 15-89]) 
and 98% were white. Eighty-two percent had M1c stage, 73% had at least two and 32% of patients had 
three or more prior systemic therapies for advanced melanoma. Forty-five percent had an ECOG 
Performance Status of 1, 40% had elevated LDH and 23% had a BRAF mutated tumour. 

The primary efficacy outcome measures were PFS as assessed by IRO using RECIST version 1.1 and 
OS. Secondary efficacy outcome measures were ORR and response duration. Table 4 summarises key 
efficacy measures at the final analysis in patients previously treated with ipilimumab, and the 
Kaplan-Meier curve for PFS is shown in Figure 3. Both pembrolizumab arms were superior to 
chemotherapy for PFS, and there was no difference between pembrolizumab doses. There was no 
statistically significant difference between pembrolizumab and chemotherapy in the final OS analysis 
that was not adjusted for the potentially confounding effects of crossover. Of the patients randomised 
to the chemotherapy arm, 55% crossed over and subsequently received treatment with pembrolizumab.

 



90

Table 4: Efficacy results in KEYNOTE-002

Endpoint Pembrolizumab
2 mg/kg every 

3 weeks
n=180

Pembrolizumab
10 mg/kg every 

3 weeks
n=181

Chemotherapy

n=179
PFS

Number (%) 
of patients 
with event

150 (83%) 144 (80%) 172 (96%)

Hazard ratio* 
(95% CI)

0.58 (0.46, 0.73) 0.47 (0.37, 0.60) ---

p-Value† < 0.001 < 0.001 ---
Median in 
months 
(95% CI)

2.9 (2.8, 3.8) 3.0 (2.8, 5.2) 2.8 (2.6, 2.8)

OS
Number (%) 
of patients 
with event

123 (68%) 117 (65%) 128 (72%)

Hazard ratio* 
(95% CI)

0.86 (0.67, 1.10) 0.74 (0.57, 0.96) ---

p-Value† 0.1173 0.0106‡ ---
Median in 
months 
(95% CI)

13.4 (11.0, 16.4) 14.7 (11.3, 19.5) 11.0 (8.9, 13.8)

Best objective
response

ORR % 
(95% CI)

22% (16, 29) 28% (21, 35) 5% (2, 9)

Complete 
response %

3% 7% 0%

Partial 
response %

19% 20% 5%

Response 
duration§

Median in 
months 
(range)

22.8 
(1.4+, 25.3+)

Not reached 
(1.1+, 28.3+)

6.8
(2.8, 11.3)

% ongoing at 
12 months

73% ¶ 79% ¶ 0% ¶

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox 
proportional hazard model

† Based on stratified log-rank test 
‡ Not statistically significant after adjustment for multiplicity
§ Based on patients with a best objective response as confirmed complete or partial 

response from the final analysis
¶ Based on Kaplan-Meier estimation

 



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Figure 3: Kaplan-Meier curve for progression-free survival by treatment arm in 
KEYNOTE-002 (intent to treat population)

KEYNOTE-001: Open-label study in melanoma patients naïve and previously treated with ipilimumab
The safety and efficacy of pembrolizumab for patients with advanced melanoma were investigated in 
an uncontrolled, open-label study, KEYNOTE-001. Efficacy was evaluated for 276 patients from two 
defined cohorts, one which included patients previously treated with ipilimumab (and if BRAF V600 
mutation-positive, with a BRAF or MEK inhibitor) and the other which included patients naïve to 
treatment with ipilimumab. Patients were randomly assigned to receive pembrolizumab at a dose of 
2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. Patients were treated with pembrolizumab until 
disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease 
progression were permitted to remain on treatment until disease progression was confirmed. Exclusion 
criteria were similar to those of KEYNOTE-002.

Of the 89 patients receiving 2 mg/kg of pembrolizumab who were previously treated with ipilimumab, 
53% were male, 33% were ≥ 65 years of age and the median age was 59 years (range 18-88). All but 
two patients were white. Eighty-four percent had M1c stage and 8% of patients had a history of brain 
metastases. Seventy percent had at least two and 35% of patients had three or more prior systemic 
therapies for advanced melanoma. BRAF mutations were reported in 13% of the study population. All 
patients with BRAF mutant tumours were previously treated with a BRAF inhibitor.

Of the 51 patients receiving 2 mg/kg of pembrolizumab who were naïve to treatment with ipilimumab, 
63% were male, 35% were ≥ 65 years of age and the median age was 60 years (range 35-80). All but 
one patient was white. Sixty-three percent had M1c stage and 2% of patients had a history of brain 
metastases. Forty-five percent had no prior therapies for advanced melanoma. BRAF mutations were 
reported in 20 (39%) patients. Among patients with BRAF mutant tumours, 10 (50%) were previously 
treated with a BRAF inhibitor.

The primary efficacy outcome measure was ORR as assessed by independent review using 
RECIST 1.1. Secondary efficacy outcome measures were disease control rate (DCR; including 
complete response, partial response and stable disease), response duration, PFS and OS. Tumour 

Chemotherapy:

Pembrolizumab 10 mg/kg every 3 weeks:

Pembrolizumab   2 mg/kg every 3 weeks:

179 31 9 2 1 0 0

180 59 36 29 19 1 0

181 69 48 42 30 5 0

Number at Risk

Treatment arm                                          PFS rate at 18 months        HR (95% CI)          p-value
Pembrolizumab   2 mg/kg every 3 weeks                  19.6%               0.58 (0.46, 0.73)      <0.0001
Pembrolizumab 10 mg/kg every 3 weeks                  25.0%               0.47 (0.37, 0.60)      <0.0001
Chemotherapy                                                              1.3% 

0 3 6 9 12 15 18 21 24 27 30 33 36

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response was assessed at 12-week intervals. Table 5 summarises key efficacy measures in patients 
previously treated or naïve to treatment with ipilimumab, receiving pembrolizumab at a dose of 
2 mg/kg based on a minimum follow-up time of 30 months for all patients.

Table 5: Efficacy results in KEYNOTE-001

Endpoint Pembrolizumab 2 mg/kg 
every 3 weeks in patients 
previously treated with 

ipilimumab
n=89

Pembrolizumab 2 mg/kg 
every 3 weeks in patients 
naïve to treatment with 

ipilimumab
n=51

Best objective response* by 
IRO†

ORR %, (95% CI) 26% (17, 36) 35% (22, 50)
Complete response 7% 12%
Partial response 19% 24%

Disease control rate %‡ 48% 49%
Response duration§

Median in months (range) 30.5 (2.8+, 30.6+) 27.4 (1.6+, 31.8+)
% ongoing at 24 months¶ 75% 71%

PFS
Median in months (95% CI) 4.9 (2.8, 8.3) 4.7 (2.8, 13.8)
PFS rate at 12 months 34% 38%

OS
Median in months (95% CI) 18.9 (11, not available) 28.0 (14, not available)
OS rate at 24 months 44% 56%

* Includes patients without measurable disease at baseline by independent radiology
† IRO = Integrated radiology and oncologist assessment using RECIST 1.1
‡ Based on best response of stable disease or better
§ Based on patients with a confirmed response by independent review, starting from the date the response was first 

recorded; n=23 for patients previously treated with ipilimumab; n=18 for patients naïve to treatment with ipilimumab
¶ Based on Kaplan-Meier estimation

Results for patients previously treated with ipilimumab (n=84) and naïve to treatment with ipilimumab 
(n=52) who received 10 mg/kg of pembrolizumab every 3 weeks were similar to those seen in patients 
who received 2 mg/kg of pembrolizumab every 3 weeks. 

Sub-population analyses

BRAF mutation status in melanoma 
A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients who 
were BRAF wild type (n=414; 77%) or BRAF mutant with prior BRAF treatment (n=126; 23%) as 
summarised in Table 6.

 



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Table 6: Efficacy results by BRAF mutation status in KEYNOTE-002

BRAF wild type BRAF mutant with prior BRAF treatment

Endpoint

Pembrolizumab
2 mg/kg every 

3 weeks (n=136)

Chemotherapy
(n=137)

Pembrolizumab
2 mg/kg every 3 weeks 

(n=44)

Chemotherapy 
(n=42)

PFS 
Hazard 
ratio* 
(95% CI)

0.50 (0.39, 0.66) --- 0.79 (0.50, 1.25) ---

OS
Hazard 
ratio* 
(95% CI)

0.78 (0.58, 1.04) --- 1.07 (0.64, 1.78) ---

ORR % 26% 6% 9% 0%
* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who 
were BRAF wild type (n=525; 63%), BRAF mutant without prior BRAF treatment (n=163; 20%) and 
BRAF mutant with prior BRAF treatment (n=139; 17%) as summarised in Table 7.

Table 7: Efficacy results by BRAF mutation status in KEYNOTE-006

BRAF wild type BRAF mutant without prior 
BRAF treatment

BRAF mutant with prior BRAF 
treatment

Endpoint

Pembrolizumab
10 mg/kg every 

2 or 3 weeks 
(pooled)

Ipilimumab 
(n=170)

Pembrolizumab
10 mg/kg every 2 

or 3 weeks 
(pooled)

Ipilimumab 
(n=55)

Pembrolizumab
10 mg/kg every 2 

or 3 weeks 
(pooled)

Ipilimumab 
(n=52)

PFS 
Hazard 
ratio* 
(95% CI)

0.61 (0.49, 0.76) --- 0.52 (0.35, 0.78) --- 0.76 (0.51, 1.14) ---

OS
Hazard 
ratio* 
(95% CI)

0.68 (0.52, 0.88) --- 0.70 (0.40, 1.22) --- 0.66 (0.41, 1.04) ---

ORR % 38% 14% 41% 15% 24% 10%
* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportional hazard model

PD-L1 status in melanoma
A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients who 
were PD-L1 positive (PD-L1 expression in ≥ 1% of tumour and tumour-associated immune cells
relative to all viable tumour cells – MEL score) vs. PD-L1 negative. PD-L1 expression was tested 
retrospectively by immunohistochemistry assay with the 22C3 anti-PD-L1 antibody. Among patients 
who were evaluable for PD-L1 expression (79%), 69% (n=294) were PD-L1 positive and 31% 
(n=134) were PD-L1 negative. Table 8 summarises efficacy results by PD-L1 expression.

 



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Table 8: Efficacy results by PD-L1 expression in KEYNOTE-002

Endpoint Pembrolizumab
2 mg/kg every 

3 weeks

Chemotherapy Pembrolizumab
2 mg/kg every 

3 weeks

Chemotherapy

PD-L1 positive PD-L1 negative
PFS Hazard 
ratio*
(95% CI)

0.55 (0.40, 0.76) --- 0.81 (0.50, 1.31) ---

OS Hazard 
ratio*
(95% CI)

0.90 (0.63, 1.28) --- 1.18 (0.70, 1.99) ---

ORR % 25% 4% 10% 8%
* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional 
hazard model

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who 
were PD-L1 positive (n=671; 80%) vs. PD-L1 negative (n=150; 18%). Among patients who were 
evaluable for PD-L1 expression (98%), 82% were PD-L1 positive and 18% were PD-L1 negative. 
Table 9 summarises efficacy results by PD-L1 expression.

Table 9: Efficacy results by PD-L1 expression in KEYNOTE-006

Endpoint Pembrolizumab
10 mg/kg every 2 or 

3 weeks (pooled) 

Ipilimumab Pembrolizumab
10 mg/kg every 2 or 

3 weeks (pooled)

Ipilimumab

PD-L1 positive PD-L1 negative
PFS Hazard ratio* (95% CI) 0.53 (0.44, 0.65) --- 0.87 (0.58, 1.30) ---
OS Hazard ratio* (95% CI) 0.63 (0.50, 0.80) --- 0.76 (0.48, 1.19) ---
ORR % 40% 14% 24% 13%

* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportional hazard model

Ocular melanoma
In 20 subjects with ocular melanoma included in KEYNOTE-001, no objective responses were 
reported; stable disease was reported in 6 patients.

KEYNOTE-054: Placebo-controlled study for the adjuvant treatment of patients with completely 
resected melanoma
The efficacy of pembrolizumab was evaluated in KEYNOTE-054, a multicentre, randomised, 
double-blind, placebo-controlled study in patients with completely resected stage IIIA (> 1 mm lymph 
node metastasis), IIIB or IIIC melanoma. A total of 1,019 adult patients were randomised (1:1) to 
receive pembrolizumab 200 mg every three weeks (n=514) or placebo (n=505), for up to one year 
until disease recurrence or unacceptable toxicity. Randomisation was stratified by American Joint 
Committee on Cancer (AJCC) 7th edition stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. 
IIIC ≥ 4 positive lymph nodes) and geographic region (North America, European countries, Australia 
and other countries as designated). Patients must have undergone lymph node dissection, and if 
indicated, radiotherapy within 13 weeks prior to starting treatment. Patients with active autoimmune 
disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were 
ineligible. Patients who received prior therapy for melanoma other than surgery or interferon for thick 
primary melanomas without evidence of lymph node involvement were ineligible. Patients underwent 
imaging every 12 weeks after the first dose of pembrolizumab for the first two years, then every 
6 months from year 3 to 5, and then annually.

Among the 1,019 patients, the baseline characteristics were: median age of 54 years (25% age 65 or 
older); 62% male; and ECOG PS of 0 (94%) and 1 (6%). Sixteen percent had stage IIIA; 46% had 
stage IIIB; 18% had stage IIIC (1-3 positive lymph nodes) and 20% had stage IIIC (≥ 4 positive lymph 
nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type. PD-L1 expression 
was tested retrospectively by immunohistochemistry assay with the 22C3 anti-PD-L1 antibody; 84% 

 



95

of patients had PD-L1-positive melanoma (PD-L1 expression in ≥ 1% of tumour and 
tumour-associated immune cells relative to all viable tumour cells). The same scoring system was used 
for metastatic melanoma (MEL score).

The primary efficacy outcome measures were investigator-assessed recurrence-free survival (RFS) in 
the whole population and in the population with PD-L1 positive tumours, where RFS was defined as 
the time between the date of randomisation and the date of first recurrence (local, regional, or distant 
metastasis) or death, whichever occurs first. The study demonstrated a statistically significant 
improvement in RFS for patients randomised to the pembrolizumab arm compared with placebo at the 
pre-specified interim analysis. Efficacy results based on an additional seven months of follow-up are
summarised in Table 10 and Figure 4.

Table 10: Efficacy results in KEYNOTE-054

Endpoint KEYTRUDA
200 mg every 

3 weeks
n=514

Placebo

n=505
Number (%) of patients with 
event 

158 (31%) 246 (49%)

Median in months (95% CI) NR 21.7 (17.1, NR)
Hazard ratio* (98% CI) 0.56 (0.44, 0.72)

p-Value (stratified log-rank) < 0.0001
RFS at 6 months

RFS rate 82% 73%
RFS at 12 months

RFS rate 76% 61%
RFS at 18 months

RFS rate 72% 54%
* Based on the stratified Cox proportional hazard model

NR = not reached

KEYNOTE-054 enrolled patients per AJCC 7th edition and a subgroup analysis of RFS per AJCC 
8th edition was performed after the RFS study results were reported. A statistically significant 
improvement in RFS for patients randomised to the pembrolizumab arm compared with placebo was 
demonstrated in the overall population across resected stage III melanoma per AJCC 7th edition. 
Stage IIIA melanoma according to the AJCC 8th edition identifies a patient population with a better 
prognosis compared to stage IIIA according to AJCC 7th edition. Per the AJCC 8th edition 
classification, a total of 82 subjects were classified as stage IIIA; 42 in the pembrolizumab arm and 40 
in the placebo arm; with a total of 13 RFS events; 6 in the pembrolizumab arm and 7 in the placebo 
arm. There is limited data on subjects with stage IIIA according to AJCC 8th edition at the time of this 
RFS analysis.

 



96

Figure 4: Kaplan-Meier curve for recurrence-free survival by treatment arm in KEYNOTE-054
(intent to treat population)

While the analysis in patients with PD-L1 positive tumours was a co-primary endpoint, pre-defined
subgroup analyses were performed in patients whose tumours were PD-L1 negative, BRAF mutation 
positive or negative. Table 11 summarises efficacy results by PD-L1 expression and BRAF mutation 
status.

Table 11: Efficacy results by PD-L1 expression and BRAF mutation status in KEYNOTE-054

Endpoint Pembrolizumab
200 mg every 3 weeks

Placebo Pembrolizumab
200 mg every 3 weeks

Placebo

PD-L1 positive PD-L1 negative
n=428 n=425 n=59 n=57

RFS Hazard ratio* (95% CI) 0.54 (0.42, 0.69) --- 0.47 (0.26, 0.85) ---
RFS rate at 6 months 84% 75% 81% 64%

BRAF mutation positive BRAF mutation negative
n=245 n=262 n=233 n=214

RFS Hazard ratio* (95% CI) 0.49 (0.36, 0.67) --- 0.64 (0.47, 0.87) ---
RFS rate at 6 months 83% 73% 80% 72%

*Based on the stratified Cox proportional hazard model

NSCLC
KEYNOTE-024: Controlled study of NSCLC patients naïve to treatment
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-024, a multicentre, 
open-label, controlled study for the treatment of previously untreated metastatic NSCLC. Patients had 
PD-L1 expression with a  50% TPS based on the PD-L1 IHC 22C3 pharmDxTM Kit. Patients were 
randomised (1:1) to receive pembrolizumab at a dose of 200 mg every 3 weeks (n=154) or 
investigator’s choice platinum-containing chemotherapy (n=151; including pemetrexed+carboplatin, 
pemetrexed+cisplatin, gemcitabine+cisplatin, gemcitabine+carboplatin, or paclitaxel+carboplatin. 
Patients with non-squamous NSCLC could receive pemetrexed maintenance.). Patients were treated 
with pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue 

 



97

beyond disease progression if the patient was clinically stable and was considered to be deriving 
clinical benefit by the investigator. Patients without disease progression could be treated for up to 
24 months. The study excluded patients with EGFR or ALK genomic tumour aberrations; autoimmune 
disease that required systemic therapy within 2 years of treatment; a medical condition that required 
immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 
26 weeks. Assessment of tumour status was performed every 9 weeks. Patients on chemotherapy who 
experienced independently-verified progression of disease were able to crossover and receive 
pembrolizumab.

Among the 305 patients in KEYNOTE-024, baseline characteristics were: median age 65 years (54% 
age 65 or older); 61% male; 82% White, 15% Asian; and ECOG performance status 0 and 1 in 35% 
and 65%, respectively. Disease characteristics were squamous (18%) and non-squamous (82%); M1 
(99%); and brain metastases (9%).

The primary efficacy outcome measure was PFS as assessed by blinded independent central review
(BICR) using RECIST 1.1. Secondary efficacy outcome measures were OS and ORR (as assessed by 
BICR using RECIST 1.1). Table 12 summarises key efficacy measures for the entire intent to treat 
(ITT) population. PFS and ORR results are reported from an interim analysis at a median follow-up of 
11 months. OS results are reported from the final analysis at a median follow-up of 25 months.

Table 12: Efficacy results in KEYNOTE-024

Endpoint Pembrolizumab
200 mg every 

3 weeks
n=154

Chemotherapy

n=151
PFS

Number (%) of patients with 
event

73 (47%) 116 (77%)

Hazard ratio* (95% CI) 0.50 (0.37, 0.68)
p-Value† < 0.001
Median in months (95% CI) 10.3 (6.7, NA) 6.0 (4.2, 6.2)

OS
Number (%) of patients with 
event

73 (47%) 96 (64%)

Hazard ratio* (95% CI) 0.63 (0.47, 0.86)
p-Value† 0.002
Median in months (95% CI) 30.0

(18.3, NA)
14.2

(9.8, 19.0)
Objective response rate

ORR % (95% CI) 45% (37, 53) 28% (21, 36)
Complete response % 4% 1%
Partial response % 41% 27%

Response duration‡

Median in months (range) Not reached 
(1.9+, 14.5+)

6.3 
(2.1+, 12.6+)

% with duration ≥ 6 months 88%§ 59%¶

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox 
proportional hazard model

† Based on stratified log-rank test
‡ Based on patients with a best objective response as confirmed complete or partial 

response
§ Based on Kaplan-Meier estimates; includes 43 patients with responses of 6 months or 

longer
¶ Based on Kaplan-Meier estimates; includes 16 patients with responses of 6 months or 

longer
NA = not available

 



98

Figure 5: Kaplan-Meier curve for progression-free survival by treatment arm in 
KEYNOTE-024 (intent to treat population)

Figure 6: Kaplan-Meier curve for overall survival by treatment arm in 
KEYNOTE-024 (intent to treat population)

In a subgroup analysis, a reduced survival benefit of pembrolizumab compared to chemotherapy was 
observed in the small number of patients who were never-smokers; however, due to the small number 
of patients, no definitive conclusions can be drawn from these data.

KEYNOTE-042: Controlled study of NSCLC patients naïve to treatment
The safety and efficacy of pembrolizumab were also investigated in KEYNOTE-042, a multicentre, 
controlled study for the treatment of previously untreated locally advanced or metastatic NSCLC. The 

Treatment arm     PFS rate at 6 months    PFS rate at 12 months     HR (95% CI)       p-value
Pembrolizumab                   62%                                 48%                0.50 (0.37, 0.68)    <0.001
Chemotherapy                     50%                                 15% 

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151 99 70 18 9 1 0

Number at Risk

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Chemotherapy:

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Treatment arm     OS rate at 12 months    OS rate at 24 months     HR (95% CI)       p-value
Pembrolizumab                70%                                52%                 0.63 (0.47, 0.86)        0.002
Chemotherapy                  55%                                35%

154 136 121 112 106 96 89 83 52 22 5 0

151 123 107 88 80 70 61 55 31 16 5 0

Number at Risk

Pembrolizumab:

Chemotherapy:

 



99

study design was similar to that of KEYNOTE-024, except that patients had PD-L1 expression with a 
 1% TPS based on the PD-L1 IHC 22C3 pharmDxTM Kit. Patients were randomised (1:1) to receive 
pembrolizumab at a dose of 200 mg every 3 weeks (n=637) or investigator’s choice platinum-
containing chemotherapy (n=637; including pemetrexed+carboplatin or paclitaxel+carboplatin. 
Patients with non-squamous NSCLC could receive pemetrexed maintenance.). Assessment of tumour 
status was performed every 9 weeks for the first 45 weeks, and every 12 weeks thereafter.

Among the 1,274 patients in KEYNOTE-042, 599 (47%) had tumours that expressed PD-L1 with TPS 
≥ 50% based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these 599 
patients included: median age 63 years (45% age 65 or older); 69% male; 63% White and 32% Asian; 
17% Hispanic or Latino; and ECOG performance status 0 and 1 in 31% and 69%, respectively. 
Disease characteristics were squamous (37%) and non-squamous (63%); stage IIIA (0.8%); stage IIIB 
(9%); stage IV (90%); and treated brain metastases (6%).

The primary efficacy outcome measure was OS. Secondary efficacy outcome measures were PFS and 
ORR (as assessed by BICR using RECIST 1.1). The trial demonstrated a statistically significant 
improvement in OS for patients whose tumours expressed PD-L1 TPS ≥ 1% randomised to 
pembrolizumab monotherapy compared to chemotherapy (HR 0.82; 95% CI 0.71, 0.93 at the final 
analysis) and in patients whose tumours expressed PD-L1 TPS ≥ 50% randomised to pembrolizumab 
monotherapy compared to chemotherapy. Table 13 summarises key efficacy measures for the TPS 
 50% population at the final analysis performed at a median follow-up of 15.4 months. The Kaplan-
Meier curve for OS for the TPS ≥ 50% population based on the final analysis is shown in Figure 7.

Table 13: Efficacy results (PD-L1 TPS  50%) in KEYNOTE-042

Endpoint Pembrolizumab
200 mg every 

3 weeks
n=299

Chemotherapy

n=300
OS

Number (%) of patients with 
event

180 (60%) 220 (73%)

Hazard ratio* (95% CI) 0.70 (0.58, 0.86)
p-Value† 0.0003
Median in months (95% CI) 20.0 (15.9, 24.2) 12.2 (10.4, 14.6)

PFS
Number (%) of patients with 
event

238 (80%) 250 (83%)

Hazard ratio* (95% CI) 0.84 (0.70, 1.01)
Median in months (95% CI) 6.5 (5.9, 8.5) 6.4 (6.2, 7.2)

Objective response rate
ORR % (95% CI) 39% (34, 45) 32% (27, 38)

Complete response % 1% 0.3%
Partial response % 38% 32%

Response duration‡

Median in months (range) 22.0
(2.1+, 36.5+)

10.8
(1.8+, 30.4+)

% with duration ≥ 18 months 57% 34%
* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox 

proportional hazard model
† Based on stratified log-rank test
‡ Based on patients with a best objective response as confirmed complete or partial 

response

 



100

Figure 7: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-042 (patients 
with PD-L1 expression TPS ≥ 50%, intent to treat population)

The results of a post-hoc exploratory subgroup analysis indicated a trend towards reduced survival 
benefit of pembrolizumab compared to chemotherapy, during both the first 4 months and throughout 
the entire duration of treatment, in patients who were never-smokers. However, due to the exploratory 
nature of this subgroup analysis, no definitive conclusions can be drawn.

KEYNOTE-189: Controlled study of combination therapy in non-squamous NSCLC patients naïve to 
treatment
The efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy was 
investigated in a multicentre, randomised, active-controlled, double-blind study, KEYNOTE-189. Key 
eligibility criteria were metastatic non-squamous NSCLC, no prior systemic treatment for metastatic 
NSCLC, and no EGFR or ALK genomic tumour aberrations. Patients with autoimmune disease that 
required systemic therapy within 2 years of treatment; a medical condition that required 
immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 
26 weeks were ineligible. Patients were randomised (2:1) to receive one of the following regimens:

 Pembrolizumab 200 mg with pemetrexed 500 mg/m2 and investigator’s choice of 
cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 
4 cycles followed by pembrolizumab 200 mg and pemetrexed 500 mg/m2 intravenously 
every 3 weeks (n=410)

 Placebo with pemetrexed 500 mg/m2 and investigator’s choice of cisplatin 75 mg/m2 or 
carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by 
placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks (n=206)

Treatment with pembrolizumab continued until RECIST 1.1-defined progression of disease as 
determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of 
pembrolizumab was permitted beyond RECIST-defined disease progression by BICR or beyond 
discontinuation of pemetrexed if the patient was clinically stable and deriving clinical benefit as 

 



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determined by the investigator. For patients who completed 24 months of therapy or had a complete 
response, treatment with pembrolizumab could be reinitiated for disease progression and administered 
for up to 1 additional year. Assessment of tumour status was performed at Week 6 and Week 12, 
followed by every 9 weeks thereafter. Patients receiving placebo plus chemotherapy who experienced 
independently-verified progression of disease were offered pembrolizumab as monotherapy.

Among the 616 patients in KEYNOTE-189, baseline characteristics were: median age of 64 years 
(49% age 65 or older); 59% male; 94% White and 3% Asian; 43% and 56% ECOG performance status 
of 0 or 1 respectively; 31% PD-L1 negative (TPS < 1%); and 18% with treated or untreated brain 
metastases at baseline.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). 
Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using 
RECIST 1.1. Table 14 summarises key efficacy measures and Figures 8 and 9 show the Kaplan-Meier 
curves for OS and PFS based on the final analysis with a median follow-up of 18.8 months.

Table 14: Efficacy results in KEYNOTE-189

Endpoint Pembrolizumab + 
Pemetrexed + 

Platinum 
Chemotherapy

n=410

Placebo + 
Pemetrexed + 

Platinum 
Chemotherapy

n=206
OS*

Number (%) of patients with 
event

258 (63%) 163 (79%)

Hazard ratio† (95% CI) 0.56 (0.46, 0.69)
p-Value‡ < 0.00001
Median in months (95% CI) 22.0

(19.5, 24.5)
10.6

(8.7, 13.6)
PFS

Number (%) of patients with 
event

337 (82%) 197 (96%)

Hazard ratio† (95% CI) 0.49 (0.41, 0.59)
p-Value‡ < 0.00001
Median in months (95% CI) 9.0 (8.1, 10.4) 4.9 (4.7, 5.5)

Objective response rate
ORR§ % (95% CI) 48% (43, 53) 20% (15, 26)

Complete response % 1.2% 0.5%
Partial response % 47% 19%

p-Value¶ < 0.0001
Response duration

Median in months (range) 12.5
(1.1+, 34.9+)

7.1
(2.4, 27.8+)

% with duration ≥ 12 months# 53% 27%
* A total of 113 patients (57%) who discontinued study treatment in the placebo plus 

chemotherapy arm crossed over to receive monotherapy pembrolizumab or received a 
checkpoint inhibitor as subsequent therapy

† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test
§ Based on patients with a best objective response as confirmed complete or partial 

response
¶ Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum 

chemotherapy and smoking status 
# Based on Kaplan-Meier estimation

 



102

Figure 8: Kaplan-Meier curve for overall survival by treatment arm in
KEYNOTE-189 (intent to treat population)

Treatment arm     OS rate at 12 months      OS rate at 24 months     HR (95% CI)      p-value
Pembrolizumab                    70%                                 46%                 0.56 (0.46, 0.69) < 0.00001
Control                                  48%                               27%

O
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Figure 9: Kaplan-Meier curve for progression-free survival by treatment arm in
KEYNOTE-189 (intent to treat population)

An analysis was performed in KEYNOTE-189 in patients who had PD-L1 TPS < 1% [pembrolizumab 
combination: n=127 (31%) vs. chemotherapy: n=63 (31%)], TPS 1-49% [pembrolizumab 
combination: n=128 (31%) vs. chemotherapy: n=58 (28%)] or ≥ 50% [pembrolizumab combination: 
n=132 (32%) vs. chemotherapy: n=70 (34%)] (see Table 15).

Table 15: Efficacy results by PD-L1 Expression in KEYNOTE-189*

Endpoint Pembrolizumab 
combination 

therapy

Chemotherapy Pembrolizumab 
combination 

therapy

Chemotherapy Pembrolizumab 
combination 

therapy

Chemotherapy

TPS < 1% TPS 1 to 49% TPS ≥ 50%
OS Hazard 
ratio†

(95% CI)
0.51 (0.36, 0.71) 0.66 (0.46, 0.96) 0.59 (0.40, 0.86)

PFS Hazard 
ratio†

(95% CI)
0.67 (0.49, 0.93) 0.53 (0.38, 0.74) 0.35 (0.25, 0.49)

ORR % 33% 14% 50% 21% 62% 26%
* Based on final analysis
† Hazard ratio (pembrolizumab combination therapy compared to chemotherapy) based on the stratified Cox proportional hazard 

model

At final analysis, a total of 57 NSCLC patients aged ≥ 75 years were enrolled in study KEYNOTE-189 
(35 in the pembrolizumab combination and 22 in the control). A HR=1.54 [95% CI 0.76, 3.14] in OS 
and HR=1.12 [95% CI 0.56, 2.22] in PFS for pembrolizumab combination vs. chemotherapy was 
reported within this study subgroup. Data about efficacy and safety of pembrolizumab in combination 
with platinum chemotherapy are limited in this patient population.

KEYNOTE-407: Controlled study of combination therapy in squamous NSCLC patients naïve to 
treatment

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Pembrolizumab                     39%                                   22%                 0.49 (0.41, 0.59) < 0.00001
Control                                   18%                                    3%

 



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The efficacy of pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel 
was investigated in Study KEYNOTE-407, a randomised, double-blind, multicentre, 
placebo-controlled study. The key eligibility criteria for this study were metastatic squamous NSCLC, 
regardless of tumour PD-L1 expression status, and no prior systemic treatment for metastatic disease. 
Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a 
medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic 
radiation within the prior 26 weeks were ineligible. Randomisation was stratified by tumour PD-L1 
expression (TPS < 1% [negative] vs. TPS ≥ 1%), investigator’s choice of paclitaxel or nab-paclitaxel, 
and geographic region (East Asia vs. non-East Asia). Patients were randomised (1:1) to one of the 
following treatment arms via intravenous infusion:

 Pembrolizumab 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day 
cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 
4 cycles or nab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 
4 cycles, followed by pembrolizumab 200 mg every 3 weeks. Pembrolizumab was 
administered prior to chemotherapy on Day 1.

 Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 
4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or 
nab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, 
followed by placebo every 3 weeks.

Treatment with pembrolizumab or placebo continued until RECIST 1.1-defined progression of disease 
as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of 
pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was 
clinically stable and deriving clinical benefit as determined by the investigator. 

Patients in the placebo arm were offered pembrolizumab as a single agent at the time of disease 
progression.

Assessment of tumour status was performed every 6 weeks through Week 18, every 9 weeks through 
Week 45 and every 12 weeks thereafter. 

A total of 559 patients were randomised. The study population characteristics were: median age of 
65 years (range: 29 to 88); 55% age 65 or older; 81% male; 77% White; ECOG performance status of 
0 (29%) and 1 (71%); and 8% with treated brain metastases at baseline. Thirty-five percent had 
tumour PD-L1 expression TPS < 1% [negative]; 19% were East Asian; and 60% received paclitaxel.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). 
Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using 
RECIST 1.1. Table 16 summarises key efficacy measures and Figures 10 and 11 show the 
Kaplan-Meier curves for OS and PFS based on the final analysis with a median follow-up of 
14.3 months. 

 



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Table 16: Efficacy Results in KEYNOTE-407

Endpoint Pembrolizumab
Carboplatin

Paclitaxel/Nab-paclitaxel
n=278

Placebo
Carboplatin

Paclitaxel/Nab-paclitaxel
n=281

OS*
Number of events (%) 168 (60%) 197 (70%)
Median in months (95% CI) 17.1 (14.4, 19.9) 11.6 (10.1, 13.7)
Hazard ratio† (95% CI) 0.71 (0.58, 0.88)
p-Value‡ 0.0006

PFS
Number of events (%) 217 (78%) 252 (90%)
Median in months (95% CI) 8.0 (6.3, 8.4) 5.1 (4.3, 6.0)
Hazard ratio† (95% CI) 0.57 (0.47, 0.69)
p-Value‡ < 0.0001

Objective response rate
ORR % (95% CI) 63% (57, 68) 38% (33, 44)

Complete response % 2.2% 3.2%
Partial response % 60% 35%

p-Value§ < 0.0001
Response duration

Median duration of response in 
months (range)

8.8 (1.3+, 28.4+) 4.9 (1.3+, 28.3+)

% with duration ≥ 12 months¶ 38% 25%
* A total of 138 patients (51%) who discontinued study treatment in the placebo plus chemotherapy arm 

crossed over to receive monotherapy pembrolizumab or received a checkpoint inhibitor as subsequent 
therapy

† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test 
§ Based on method by Miettinen and Nurminen
¶ Based on Kaplan-Meier estimation

 



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Figure 10: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407

Treatment arm     OS rate at 12 months      OS rate at 18 months     HR (95% CI)      p-value
Pembrolizumab                    65%                                 48%                 0.71 (0.58, 0.88) 0.0006
Control                                  50%                               37%

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Figure 11: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-407

An analysis was performed in KEYNOTE-407 in patients who had PD-L1 TPS < 1% [pembrolizumab 
plus chemotherapy arm: n=95 (34%) vs. placebo plus chemotherapy arm: n=99 (35%)], TPS 1% to 
49% [pembrolizumab plus chemotherapy arm: n=103 (37%) vs. placebo plus chemotherapy arm: 
n=104 (37%)] or TPS ≥ 50% [pembrolizumab plus chemotherapy arm: n=73 (26%) vs. placebo plus 
chemotherapy arm: n=73 (26%)] (see Table 17).

Table 17: Efficacy results by PD-L1 Expression in KEYNOTE-407*

Endpoint Pembrolizumab 
combination 

therapy

Chemotherapy Pembrolizumab 
combination 

therapy

Chemotherapy Pembrolizumab 
combination 

therapy

Chemotherapy

TPS < 1% TPS 1 to 49% TPS ≥ 50%
OS Hazard 
ratio†

(95% CI)
0.79 (0.56, 1.11) 0.59 (0.42, 0.84) 0.79 (0.52, 1.21)

PFS Hazard 
ratio†

(95% CI)
0.67 (0.49, 0.91) 0.52 (0.38, 0.71) 0.43 (0.29, 0.63)

ORR % 67% 41% 55% 42% 64% 30%
* Based on final analysis
† Hazard ratio (pembrolizumab combination therapy compared to chemotherapy) based on the stratified Cox proportional hazard 

model

At final analysis, a total of 65 NSCLC patients aged ≥ 75 years were enrolled in study KEYNOTE-407 
(34 in the pembrolizumab combination and 31 in the control). An HR=0.81 [95% CI 0.43, 1.55] in OS, 
an HR=0.61 [95% CI 0.34, 1.09] in PFS, and an ORR of 62% and 45% for pembrolizumab 
combination vs. chemotherapy was reported within this study subgroup. Data about efficacy and 
safety of pembrolizumab in combination with platinum chemotherapy are limited in this patient 
population.

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Pembrolizumab                     36%                                   26%                 0.57 (0.47, 0.69) < 0.0001
Control                                   18%                                   11%

Time in MonthsNumber at Risk
Pembrolizumab:

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KEYNOTE-010: Controlled study of NSCLC patients previously treated with chemotherapy
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-010, a multicentre, 
open-label, controlled study for the treatment of advanced NSCLC in patients previously treated with 
platinum-containing chemotherapy. Patients had PD-L1 expression with a  1% TPS based on the 
PD-L1 IHC 22C3 pharmDxTM Kit. Patients with EGFR activation mutation or ALK translocation also 
had disease progression on approved therapy for these mutations prior to receiving pembrolizumab. 
Patients were randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=344) or 10 mg/kg 
(n=346) every 3 weeks or docetaxel at a dose of 75 mg/m2 every 3 weeks (n=343) until disease 
progression or unacceptable toxicity. The study excluded patients with autoimmune disease; a medical 
condition that required immunosuppression; or who had received more than 30 Gy of thoracic 
radiation within the prior 26 weeks. Assessment of tumour status was performed every 9 weeks.

The baseline characteristics for this population included: median age 63 years (42% age 65 or older); 
61% male; 72% White and 21% Asian and 34% and 66% with an ECOG performance status 0 and 1, 
respectively. Disease characteristics were squamous (21%) and non-squamous (70%); stage IIIA (2%); 
stage IIIB (7%); stage IV (91%); stable brain metastases (15%) and the incidence of mutations was 
EGFR (8%) or ALK (1%). Prior therapy included platinum-doublet regimen (100%); patients received 
one (69%) or two or more (29%) treatment lines.

The primary efficacy outcome measures were OS and PFS as assessed by BICR using RECIST 1.1. 
Secondary efficacy outcome measures were ORR and response duration. Table 18 summarises key 
efficacy measures for the entire population (TPS  1%) and for the patients with TPS  50%, and 
Figure 12 shows the Kaplan-Meier curve for OS (TPS  1%), based on a final analysis with median 
follow up of 42.6 months.

 



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Table 18: Response to pembrolizumab 2 or 10 mg/kg every 3 weeks in previously treated 
patients with NSCLC in KEYNOTE-010

Endpoint Pembrolizumab 
2 mg/kg every 

3 weeks

Pembrolizumab 
10 mg/kg every 

3 weeks

Docetaxel
75 mg/m2 every 

3 weeks

TPS ≥ 1%
Number of patients 344 346 343

OS
Number (%) of patients with event 284 (83%) 264 (76%) 295 (86%)
Hazard ratio* (95% CI) 0.77 (0.66, 0.91) 0.61 (0.52, 0.73) ---
p-Value† 0.00128 < 0.001 ---
Median in months (95% CI) 10.4 (9.5, 11.9) 13.2 (11.2, 16.7) 8.4 (7.6, 9.5)

PFS‡

Number (%) of patients with event 305 (89%) 292 (84%) 314 (92%)
Hazard ratio* (95% CI) 0.88 (0.75, 1.04) 0.75 (0.63, 0.89) ---
p-Value† 0.065 < 0.001 ---
Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.7, 4.5) 4.1 (3.8, 4.5)

Objective response rate‡

ORR % (95% CI) 20% (16, 25) 21% (17, 26) 9% (6, 13)
Complete response % 2% 3% 0%
Partial response % 18% 18% 9%

Response duration‡,§

Median in months (range) Not reached
(2.8, 46.2+)

37.8
(2.0+, 49.3+)

7.1
(1.4+, 16.8)

% ongoing¶ 42% 43% 6%

TPS  50%
Number of patients 139 151 152

OS
Number (%) of patients with event 97 (70%) 102 (68%) 127 (84%)
Hazard ratio* (95% CI) 0.56 (0.43, 0.74) 0.50 (0.38, 0.65) ---
p-Value† < 0.001 < 0.001 ---
Median in months (95% CI) 15.8 (10.8, 22.5) 18.7 (12.1, 25.3) 8.2 (6.4, 9.8)

PFS‡

Number (%) of patients with event 107 (77%) 115 (76%) 138 (91%)
Hazard ratio* (95% CI) 0.59 (0.45, 0.77) 0.53 (0.41, 0.70) ---
p-Value† < 0.001 < 0.001 ---
Median in months (95% CI) 5.3 (4.1, 7.9) 5.2 (4.1, 8.1) 4.2 (3.8, 4.7)

Objective response rate‡

ORR % (95% CI) 32% (24, 40) 32% (25, 41) 9% (5, 14)
Complete response % 4% 4% 0%
Partial response % 27% 28% 9%

Response duration‡,§

Median in months (range) Not reached
(2.8, 44.0+)

37.5
(2.0+, 49.3+)

8.1
(2.6, 16.8)

% ongoing¶ 55% 47% 8%
* Hazard ratio (pembrolizumab compared to docetaxel) based on the stratified Cox proportional hazard model
† Based on stratified log-rank test
‡ Assessed by BICR using RECIST 1.1
§ Based on patients with a best objective response as confirmed complete or partial response
¶ Ongoing response includes all responders who at the time of analysis were alive, progression free, did not initiate new 

anti-cancer therapies and had not been determined to be lost to follow-up

 



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Figure 12: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-010
(patients with PD-L1 expression TPS  1%, intent to treat population)

Efficacy results were similar for the 2 mg/kg and 10 mg/kg pembrolizumab arms. Efficacy results for 
OS were consistent regardless of the age of tumour specimen (new vs. archival) based on an 
intergroup comparison.

In subgroup analyses, a reduced survival benefit of pembrolizumab compared to docetaxel was 
observed for patients who were never-smokers or patients with tumours harbouring EGFR activating 
mutations who received at least platinum-based chemotherapy and a tyrosine kinase inhibitor; 
however, due to the small numbers of patients, no definitive conclusions can be drawn from these 
data.

The efficacy and safety of pembrolizumab in patients with tumours that do not express PD-L1 have
not been established.

Classical Hodgkin lymphoma
KEYNOTE-087 and KEYNOTE-013: Open-label studies in patients with relapsed or refractory cHL
The efficacy of pembrolizumab was investigated in KEYNOTE-087 and KEYNOTE-013, two 
multicentre, open-label studies for the treatment of 241 patients with cHL. These studies enrolled 
patients who failed ASCT and BV, who were ineligible for ASCT because they were unable to 
achieve a complete or partial remission to salvage chemotherapy and failed BV, or who failed ASCT 
and did not receive BV. Five study subjects were ineligible to ASCT due to reasons other than failure 
to salvage chemotherapy. Both studies included patients regardless of PD-L1 expression. Patients with 
active, non-infectious pneumonitis, an allogeneic transplant within the past 5 years (or > 5 years but 
with GVHD), active autoimmune disease or a medical condition that required immunosuppression 
were ineligible for either study. Patients received pembrolizumab 200 mg every 3 weeks (n=210; 
KEYNOTE-087) or 10 mg/kg every 2 weeks (n=31; KEYNOTE-013) until unacceptable toxicity or 
documented disease progression.

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Pembrolizumab 2 mg/kg               28%                               20%                  0.77 (0.66, 0.91)        0.00128
Pembrolizumab 10 mg/kg             36%                               26%                  0.61 (0.52, 0.73)        0.00001
Docetaxel                                        14%                               11%

343 226 135 90 57 44 40 35 20 13 2 0 0

344 261 177 136 111 91 72 67 36 17 2 0 0
346 262 197 159 137 120 99 84 50 28 3 0 0

Number at Risk

Pembrolizumab 2 mg/kg:
Pembrolizumab 10 mg/kg:
Docetaxel:

 



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Among KEYNOTE-087 patients, the baseline characteristics were median age 35 years (9% age 65 or 
older); 54% male; 88% White; and 49% and 51% had an ECOG performance status 0 and 1, 
respectively. The median number of prior lines of therapy administered for the treatment of cHL was 4 
(range 1 to 12). Eighty-one percent were refractory to at least one prior therapy, including 35% who 
were refractory to first line therapy. Sixty-one percent of patients had received Auto-SCT, 38% were 
transplant ineligible; 17% had no prior brentuximab vedotin use; and 36% of patients had prior 
radiation therapy. Disease subtypes were 80% nodular sclerosis, 11% mixed cellularity, 4% 
lymphocyte-rich and 2% lymphocyte-depleted. 

Among KEYNOTE-013 patients, the baseline characteristics were median age 32 years (7% age 65 or 
older), 58% male, 94% White; and 45% and 55% had an ECOG performance status 0 and 1, 
respectively. The median number of prior lines of therapy administered for the treatment of cHL was 5 
(range 2 to 15). Eighty-four percent were refractory to at least one prior therapy, including 35% who 
were refractory to first line therapy. Seventy-four percent of patients had received Auto-SCT, 26% 
were transplant ineligible, and 45% of patients had prior radiation therapy. Disease subtypes were 97% 
nodular sclerosis and 3% mixed cellularity.

The major efficacy outcome measures (ORR and CRR) were assessed by BICR according to the 2007 
revised International Working Group (IWG) criteria. Secondary efficacy outcome measures were 
duration of response, PFS and OS. Response was assessed in KEYNOTE-087 and KEYNOTE-013 
every 12 and 8 weeks, respectively, with the first planned post-baseline assessment at Week 12. 
Efficacy results are summarised in Table 19. 

 



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Table 19: Efficacy results in KEYNOTE-087 and KEYNOTE-013

KEYNOTE-087a KEYNOTE-013b

Endpoint Pembrolizumab
200 mg every 3 weeks

n=210

Pembrolizumab
10 mg/kg every 2 weeks

n=31
Objective response ratec

ORR % (95% CI) 69% (62.3, 75.2) 58% (39.1, 75.5)
Complete remission 22% 19%
Partial remission 47% 39%

Response durationc

Median in months (range) 11.1 (0.0+, 11.1)d Not reached (0.0+, 45.6+)e

% with duration ≥ 6-months 76%f 80%g

% with duration ≥ 12-months --- 70%h

Time to response
Median in months (range) 2.8 (2.1, 8.8)d 2.8 (2.4, 8.6)e

PFSc

Number (%) of patients with event 70 (33%) 19 (61%)
Median in months (95% CI) 11.3 (10.8, Not reached) 11.4 (4.9, 27.8)
6-month PFS rate 72% 66%
9-month PFS rate 62% ---
12-month PFS rate --- 48%

OS
Number (%) of patients with event 4 (2%) 6 (19%)
6-month OS rate 99.5% 100%
12-month OS rate 97.6% 87.1%

a Median follow-up time of 10.1 months
b Median follow-up time of 52.8 months
c Assessed by BICR according to the 2007 revised International Working Group (IWG) criteria by PET CT 

scans
d Based on patients (n=145) with a response by independent review
e Based on patients (n=18) with a response by independent review
f Based on Kaplan-Meier estimation; includes 31 patients with responses of 6 months or longer
g Based on Kaplan-Meier estimation; includes 9 patients with responses of 6 months or longer
h Based on Kaplan-Meier estimation; includes 7 patients with responses of 12 months or longer

Safety and efficacy in elderly patients 
Overall, 20 cHL patients ≥ 65 years were treated with pembrolizumab in studies KEYNOTE-087 and 
KEYNOTE-013. Data from these patients are too limited to draw any conclusion on safety or efficacy 
in this population.

Urothelial Carcinoma
KEYNOTE-045: Controlled study in urothelial carcinoma patients who have received prior 
platinum-containing chemotherapy
The safety and efficacy of pembrolizumab were evaluated in KEYNOTE-045, a multicentre, 
open-label, randomised (1:1), controlled study for the treatment of locally advanced or metastatic 
urothelial carcinoma in patients with disease progression on or after platinum-containing 
chemotherapy. Patients must have received first line platinum-containing regimen for locally 
advanced/metastatic disease or as neoadjuvant/adjuvant treatment, with recurrence/progression 
≤ 12 months following completion of therapy. Patients were randomised (1:1) to receive either 
pembrolizumab 200 mg every 3 weeks (n=270) or investigator’s choice of any of the following 
chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=84), 
docetaxel 75 mg/m2 (n=84), or vinflunine 320 mg/m2 (n=87). Patients were treated with 
pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyond 
progression if the patient was clinically stable and was considered to be deriving clinical benefit by the 
investigator. Patients without disease progression could be treated for up to 24 months. The study 
excluded patients with autoimmune disease, a medical condition that required immunosuppression and 

 



113

patients with more than 2 prior lines of systemic chemotherapy for metastatic urothelial carcinoma. 
Patients with an ECOG performance status of 2 had to have a haemoglobin ≥ 10 g/dL, could not have 
liver metastases, and must have received the last dose of their last prior chemotherapy regimen 
≥ 3 months prior to enrolment. Assessment of tumour status was performed at 9 weeks after the first 
dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter. 

Among the 542 randomised patients in KEYNOTE-045, baseline characteristics were: median age 
66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 56% ECOG 
performance status of 1 and 1% ECOG performance status of 2; and 96% M1 disease and 4% M0 
disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. 
Eighty-six percent had a primary tumour in the lower tract and 14% had a primary tumour in the upper
tract. Fifteen percent of patients had disease progression following prior platinum-containing 
neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 prior systemic regimens in 
the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior 
carboplatin, and 1% was treated with other platinum-based regimens.

The primary efficacy outcomes were OS and PFS as assessed by BICR using RECIST v1.1. 
Secondary outcome measures were ORR (as assessed by BICR using RECIST v1.1) and duration of 
response. Table 20 summarises the key efficacy measures for the ITT population at the final analysis. 
The Kaplan-Meier curve based on the final analysis for OS is shown in Figure 13. The study 
demonstrated statistically significant improvements in OS and ORR for patients randomised to 
pembrolizumab as compared to chemotherapy. There was no statistically significant difference 
between pembrolizumab and chemotherapy with respect to PFS. 

 



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Table 20: Response to pembrolizumab 200 mg every 3 weeks in patients with urothelial 
carcinoma previously treated with chemotherapy in KEYNOTE-045

Endpoint Pembrolizumab
200 mg every 

3 weeks
n=270

Chemotherapy

n=272

OS
Number (%) of patients with event 200 (74%) 219 (81%)
Hazard ratio* (95% CI) 0.70 (0.57, 0.85)
p-Value† < 0.001
Median in months (95% CI) 10.1 (8.0, 12.3) 7.3 (6.1, 8.1)

PFS‡

Number (%) of patients with event 233 (86%) 237 (87%)
Hazard ratio* (95% CI) 0.96 (0.79, 1.16)
p-Value† 0.313
Median in months (95% CI) 2.1 (2.0, 2.2) 3.3 (2.4, 3.6)

Objective response rate‡

ORR % (95% CI) 21% (16, 27) 11% (8, 15)
p-Value§ < 0.001

Complete response 9% 3%
Partial response 12% 8%
Stable disease 17% 34%

Response duration‡,¶

Median in months (range) Not reached
(1.6+, 30.0+)

4.4
(1.4+, 29.9+)

Number (%#) of patients with duration ≥ 6 months 46 (84%) 8 (47%)
Number (%#) of patients with duration ≥ 12 
months

35 (68%) 5 (35%)

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model
† Based on stratified log-rank test
‡ Assessed by BICR using RECIST 1.1
§ Based on method by Miettinen and Nurminen
¶ Based on patients with a best objective response as confirmed complete or partial response
# Based on Kaplan-Meier estimation

 



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Figure 13: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-045 (intent 
to treat population)

An analysis was performed in KEYNOTE-045 in patients who had PD-L1 CPS < 10 [pembrolizumab: 
n=186 (69%) vs. chemotherapy: n= 176 (65%)] or ≥ 10 [pembrolizumab: n=74 (27%) vs. 
chemotherapy: n= 90 (33%)] in both pembrolizumab- and chemotherapy-treated arms (see Table 21).

Table 21: OS by PD-L1 Expression

PD-L1 Expression Pembrolizumab Chemotherapy
OS by PD-L1 Expression

Number (%) of patients with event*
Hazard

Ratio† (95% CI)
CPS < 10 140 (75%) 144 (82%) 0.75 (0.59, 0.95)
CPS ≥ 10 53 (72%) 72 (80%) 0.55 (0.37, 0.81)

* Based on final analysis
† Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model

Patient-reported outcomes (PROs) were assessed using EORTC QLQ-C30. A prolonged time to 
deterioration in EORTC QLQ-C30 global health status/QoL was observed for patients treated with 
pembrolizumab compared to investigator’s choice chemotherapy (HR 0.70; 95% CI 0.55-0.90). Over 
15 weeks of follow-up, patients treated with pembrolizumab had stable global health status/QoL, 
while those treated with investigator’s choice chemotherapy had a decline in global health status/QoL. 
These results should be interpreted in the context of the open-label study design and therefore taken 
cautiously.

KEYNOTE-052: Open-label study in urothelial carcinoma patients ineligible for cisplatin-containing 
chemotherapy
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-052, a multicentre, 
open-label study for the treatment of locally advanced or metastatic urothelial carcinoma in patients 

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Treatment arm     OS rate at 6 months    OS rate at 12 months     HR (95% CI)       p-value
Pembrolizumab                64%                              44%                  0.70 (0.57, 0.85)   0.00015
Control                             57%                               30%

272 234 173 140 109 91 73 62 59 47 42 35 34 24 18 10 4 0 0 0 0

270 226 195 170 148 132 116 105 98 86 80 76 67 52 33 14 7 0 0 0 0

Number at Risk

Pembrolizumab:

Control:

 



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who were not eligible for cisplatin-containing chemotherapy. Patients received pembrolizumab at a 
dose of 200 mg every 3 weeks until unacceptable toxicity or disease progression. Treatment could 
continue beyond progression if the patient was clinically stable and was considered to be deriving 
clinical benefit by the investigator. Patients without disease progression could be treated for up to 
24 months. The study excluded patients with autoimmune disease or a medical condition that required 
immunosuppression. Assessment of tumour status was performed at 9 weeks after the first dose, then 
every 6 weeks through the first year, followed by every 12 weeks thereafter.

Among 370 patients with urothelial carcinoma who were not eligible for cisplatin-containing 
chemotherapy baseline characteristics were: median age 74 years (82% age 65 or older); 77% male; 
and 89% White and 7% Asian. Eighty-eight percent had M1 disease and 12% had M0 disease. 
Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons 
for cisplatin ineligibility included: baseline creatinine clearance of < 60 mL/min (50%), ECOG 
performance status of 2 (32%), ECOG performance status of 2 and baseline creatinine clearance of 
< 60 mL/min (9%), and other (Class III heart failure, Grade 2 or greater peripheral neuropathy, and 
Grade 2 or greater hearing loss; 9%). Ninety percent of patients were treatment naïve, and 10%
received prior adjuvant or neoadjuvant platinum-based chemotherapy. Eighty-one percent had a 
primary tumour in the lower tract, and 19% of patients had a primary tumour in the upper tract. 

The primary efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Secondary 
efficacy outcome measures were duration of response, PFS, and OS. Table 22 summarises the key 
efficacy measures for the study population at the final analysis based on a median follow-up time of 
11.4 months (range: 0.1, 41.2 months) for all patients.

Table 22: Response to pembrolizumab 200 mg every 3 weeks in patients with urothelial 
carcinoma ineligible for cisplatin-containing chemotherapy in KEYNOTE-052

Endpoint n=370

Objective response rate*

ORR %, (95% CI) 29% (24, 34)

Disease control rate† 47%

Complete response 9%

Partial response 20%

Stable disease 18%

Response duration

Median in months (range) 30.1
(1.4+, 35.9+)

% with duration ≥ 6-months 81%‡

Time to response

Median in months (range) 2.1 (1.3, 9.0)

PFS*

Median in months (95% CI) 2.2 (2.1, 3.4)

6-month PFS rate 33%

12-month PFS rate 22%

OS

Median in months (95% CI) 11.3 (9.7, 13.1)

6-month OS rate 67%

12-month OS rate 47%
* Assessed by BICR using RECIST 1.1
† Based on best response of stable disease or better 
‡ Based on Kaplan-Meier estimates; includes 84 patients with response of 6 months or longer

 



117

An analysis was performed in KEYNOTE-052 in patients who had tumours that expressed PD-L1 
with a CPS < 10 (n=251; 68%) or ≥ 10 (n=110; 30%) based on the PD-L1 IHC 22C3 pharmDxTM Kit
(see Table 23).

Table 23: ORR and OS by PD-L1 Expression

Endpoint CPS < 10
N=251

CPS ≥ 10
N=110

Objective response rate*

ORR %, (95% CI) 20% (16, 26) 47% (38, 57)

OS

Median in months (95% CI) 10 (8, 12) 19 (12, 29)

12-month OS rate 41% 61% 
* BICR using RECIST 1.1

KEYNOTE-361 is an ongoing Phase III, randomised, controlled, open-label clinical study of 
pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy as 
first-line treatment in subjects with advanced or metastatic urothelial carcinoma. Preliminary data 
from an early review showed a reduced survival with pembrolizumab monotherapy in patients whose 
tumours express PD-L1 with a CPS < 10 compared with standard chemotherapy.

Based on a recommendation by an external Data Monitoring Committee, the accrual in the 
pembrolizumab monotherapy arm was stopped for patients whose tumours express PD-L1 with a 
CPS < 10. The pembrolizumab monotherapy arm remains open only to patients whose tumours 
express PD-L1 with a CPS ≥ 10. Subjects whose tumours express PD-L1 CPS < 10 already enrolled 
into the pembrolizumab monotherapy arm can continue treatment. Randomisation to the chemotherapy 
and the chemotherapy-pembrolizumab arms remains open.

Head and Neck Squamous Cell Carcinoma
KEYNOTE-048: Controlled study of monotherapy and combination therapy in HNSCC patients naïve 
to treatment in the recurrent or metastatic setting
The efficacy of pembrolizumab was investigated in KEYNOTE-048, a multicentre, randomised, 
open-label, active-controlled study in patients with histologically confirmed metastatic or recurrent 
HNSCC of the oral cavity, pharynx or larynx, who had not previously received systemic therapy for 
recurrent or metastatic disease and who were considered incurable by local therapies. Patients with 
nasopharyngeal carcinoma, active autoimmune disease that required systemic therapy within two years 
of treatment or a medical condition that required immunosuppression were ineligible for the study. 
Randomisation was stratified by tumour PD-L1 expression (TPS ≥ 50% or < 50%), HPV status 
(positive or negative), and ECOG PS (0 vs. 1). Patients were randomised 1:1:1 to one of the following 
treatment arms:

 Pembrolizumab 200 mg every 3 weeks
 Pembrolizumab 200 mg every 3 weeks, carboplatin AUC 5 mg/mL/min every 3 weeks or 

cisplatin 100 mg/m2 every 3 weeks, and 5-FU 1,000 mg/m2/d 4 days continuous every 
3 weeks (maximum of 6 cycles of platinum and 5-FU)

 Cetuximab 400 mg/m2 load then 250 mg/m2 once weekly, carboplatin AUC 5 mg/mL/min 
every 3 weeks or cisplatin 100 mg/m2 every 3 weeks, and 5-FU 1,000 mg/m2/d 4 days 
continuous every 3 weeks (maximum of 6 cycles of platinum and 5-FU)

Treatment with pembrolizumab continued until RECIST 1.1-defined progression of disease as 
determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of 
pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was 
clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of 
tumour status was performed at Week 9 and then every 6 weeks for the first year, followed by every 
9 weeks through 24 months. 

 



118

Among the 882 patients in KEYNOTE-048, 754 (85%) had tumours that expressed PD-L1 with a 
CPS ≥ 1 based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these 
754 patients included: median age of 61 years (range: 20 to 94); 36% age 65 or older; 82% male; 74% 
White and 19% Asian; 61% ECOG performance status of 1; and 77% former/current smokers. Disease 
characteristics were: 21% HPV positive and 95% had stage IV disease (stage IVa 21%, stage IVb 6%, 
and stage IVc 69%).

The primary efficacy outcome measures were OS and PFS (assessed by BICR according to 
RECIST 1.1). The study demonstrated a statistically significant improvement in OS for all patients 
randomised to pembrolizumab in combination with chemotherapy compared to standard treatment 
(HR 0.72; 95% CI 0.60-0.87) and in patients whose tumours expressed PD-L1 CPS ≥ 1 randomised to 
pembrolizumab monotherapy compared to standard treatment. Tables 24 and 25 summarise key 
efficacy results for pembrolizumab in patients whose tumours expressed PD-L1 with a CPS ≥ 1 in 
KEYNOTE-048 at the final analysis performed at a median follow-up of 13 months for 
pembrolizumab in combination with chemotherapy and at a median follow-up of 11.5 months for 
pembrolizumab monotherapy. Kaplan-Meier curves for OS based on the final analysis are shown in 
Figures 14 and 15.

Table 24: Efficacy results for pembrolizumab plus chemotherapy in KEYNOTE-048 with PD-L1 
expression (CPS ≥ 1)

Endpoint Pembrolizumab +
Platinum 

Chemotherapy +
5-FU
n=242

Standard
Treatment*

n=235

OS
Number (%) of patients with event 177 (73%) 213 (91%)
Median in months (95% CI) 13.6 (10.7, 15.5) 10.4 (9.1, 11.7)
Hazard ratio† (95% CI) 0.65 (0.53, 0.80)
p-Value‡ 0.00002
PFS
Number (%) of patients with event 212 (88%) 221 (94%)
Median in months (95% CI) 5.1 (4.7, 6.2) 5.0 (4.8, 6.0)
Hazard ratio† (95% CI) 0.84 (0.69, 1.02)
p-Value‡ 0.03697
Objective response rate
ORR§ % (95% CI) 36% (30.3, 42.8) 36% (29.6, 42.2)
Complete response 7% 3%
Partial response 30% 33%
p-Value¶ 0.4586
Response duration
Median in months (range) 6.7 (1.6+, 39.0+) 4.3 (1.2+, 31.5+)
% with duration ≥ 6 months 54% 34%
* Cetuximab, platinum, and 5-FU
† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test
§ Response: Best objective response as confirmed complete response or partial response
¶ Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positive vs. 

negative) and PD-L1 status (strongly positive vs. not strongly positive)

 



119

Figure 14: Kaplan-Meier curve for overall survival for pembrolizumab plus chemotherapy in 
KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

Treatment arm                    OS rate at 12 months    OS rate at 24 months     HR (95% CI)      p-value
Pembrolizumab + Chemo                   55%                                31%             0.65 (0.53, 0.80)    0.00002
Standard                                              44%                                17%

0 5 10 15 20 25 30 35 40 45 50

Time in Months

0

10

20

30

40

50

60

70

80

90

100

O
v
e

ra
ll 

S
u

rv
iv

a
l 
(%

)

242 197 144 109 84 70 52 29 5 0 0

235 191 122 83 54 35 17 5 1 0 0

Number at Risk

Pembrolizumab + Chemo:

Standard:

 



120

Table 25: Efficacy results for pembrolizumab as monotherapy in KEYNOTE-048 with PD-L1 
expression (CPS ≥ 1)

Endpoint Pembrolizumab
n=257

Standard
Treatment*

n=255
OS
Number (%) of patients with event 197 (77%) 229 (90%)
Median in months (95% CI) 12.3 (10.8, 14.3) 10.3 (9.0, 11.5)
Hazard ratio† (95% CI) 0.74 (0.61, 0.90)
p-Value‡ 0.00133
PFS
Number (%) of patients with event 228 (89%) 237 (93%)
Median in months (95% CI) 3.2 (2.2, 3.4) 5.0 (4.8, 6.0)
Hazard ratio† (95% CI) 1.13 (0.94, 1.36)
p-Value‡ 0.89580
Objective response rate
ORR§ % (95% CI) 19.1% (14.5, 24.4) 35% (29.1, 41.1)
Complete response 5% 3%
Partial response 14% 32%
p-Value¶ 1.0000
Response duration
Median in months (range) 23.4 (1.5+, 43.0+) 4.5 (1.2+, 38.7+)
% with duration ≥ 6 months 81% 36%
* Cetuximab, platinum, and 5-FU
† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test
§ Response: Best objective response as confirmed complete response or partial response
¶ Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positive 

vs. negative) and PD-L1 status (strongly positive vs. not strongly positive)

 



121

Figure 15: Kaplan-Meier curve for overall survival for pembrolizumab as monotherapy in 
KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

An analysis was performed in KEYNOTE-048 in patients whose tumours expressed PD-L1 CPS ≥ 20 
[pembrolizumab plus chemotherapy: n=126 (49%) vs. standard treatment: n=110 (43%) and 
pembrolizumab monotherapy: n=133 (52%) vs. standard treatment: n=122 (48%)] (see Table 26).

Table 26: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab as 
monotherapy by PD-L1 Expression in KEYNOTE-048 (CPS ≥ 20)

Endpoint Pembrolizumab +
Platinum 

Chemotherapy +
5-FU
n=126

Standard
Treatment*

n=110

Pembrolizumab 
Monotherapy

n=133

Standard
Treatment*

n=122

OS

Number (%) of patients with 
event

84 (66.7) 98 (89.1) 94 (70.7) 108 (88.5)

Median in months (95% CI) 14.7 (10.3, 19.3) 11.0 (9.2, 13.0) 14.8 (11.5, 20.6) 10.7 (8.8, 12.8)

Hazard ratio† (95% CI) 0.60 (0.45, 0.82) 0.58 (0.44, 0.78)

p-Value‡ 0.00044 0.00010

OS rate at 6 months (95% CI) 74.6 (66.0, 81.3) 80.0 (71.2, 86.3) 74.4 (66.1, 81.0) 79.5 (71.2, 85.7)

OS rate at 12 months (95% CI) 57.1 (48.0, 65.2) 46.1 (36.6, 55.1) 56.4 (47.5, 64.3) 44.9 (35.9, 53.4)

OS rate at 24 months (95% CI) 35.4 (27.2, 43.8) 19.4 (12.6, 27.3) 35.3 (27.3, 43.4) 19.1 (12.7, 26.6)

Treatment arm   OS rate at 12 months    OS rate at 24 months     HR (95% CI)      p-value
Pembrolizumab                50%                                29%                0.74 (0.61, 0.90)   0.00133
Standard                           44%                                17%

0 5 10 15 20 25 30 35 40 45 50

Time in Months

0

10

20

30

40

50

60

70

80

90

100

O
v
e
ra

ll 
S

u
rv

iv
a
l 
(%

)

257 197 152 110 91 70 43 21 13 1 0

255 207 131 89 59 40 21 9 5 0 0

Number at Risk

Pembrolizumab:

Standard:

 



122

Endpoint Pembrolizumab +
Platinum 

Chemotherapy +
5-FU
n=126

Standard
Treatment*

n=110

Pembrolizumab 
Monotherapy

n=133

Standard
Treatment*

n=122

PFS

Number (%) of patients with 
event

106 (84.1) 104 (94.5) 115 (86.5) 114 (93.4)

Median in months (95% CI) 5.8 (4.7, 7.6) 5.3 (4.9, 6.3) 3.4 (3.2, 3.8) 5.3 (4.8, 6.3)

Hazard ratio† (95% CI) 0.76 (0.58, 1.01) 0.99 (0.76, 1.29)

p-Value‡ 0.02951 0.46791

PFS rate at 6 months (95% CI) 49.4 (40.3, 57.9) 47.2 (37.5, 56.2) 33.0 (25.2, 41.0) 46.6 (37.5, 55.2)

PFS rate at 12 months (95% CI) 23.9 (16.7, 31.7) 14.0 (8.2, 21.3) 23.5 (16.6, 31.1) 15.1 (9.3, 22.2)

PFS rate at 24 months (95% CI) 14.6 (8.9, 21.5) 5.0 (1.9, 10.5) 16.8 (10.9, 23.8) 6.1 (2.7, 11.6)
Objective response rate

ORR§ % (95% CI) 42.9 (34.1, 52.0) 38.2 (29.1, 47.9) 23.3 (16.4, 31.4) 36.1 (27.6, 45.3)
Response duration

Number of responders 54 42 31 44

Median in months (range) 7.1 (2.1+, 39.0+) 4.2 (1.2+, 31.5+) 22.6 (2.7+, 43.0+) 4.2 (1.2+, 31.5+)
* Cetuximab, platinum, and 5-FU
† Based on the stratified Cox proportional hazard model
‡ Based on stratified log-rank test
§ Response: Best objective response as confirmed complete response or partial response

An exploratory subgroup analysis was performed in KEYNOTE-048 in patients whose tumours 
expressed PD-L1 CPS ≥ 1 to < 20 [pembrolizumab plus chemotherapy: n=116 (45%) vs. standard 
treatment: n=125 (49%) and pembrolizumab monotherapy: n=124 (48%) vs. standard treatment: 
n=133 (52%)] (see Table 27).

Table 27: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab as 
monotherapy by PD-L1 Expression in KEYNOTE-048 (CPS ≥ 1 to < 20)

Endpoint Pembrolizumab +
Platinum 

Chemotherapy +
5-FU
n=116

Standard
Treatment*

n=125

Pembrolizumab 
Monotherapy

n=124

Standard
Treatment*

n=133

OS

Number (%) of patients with event 93 (80.2) 115 (92.0) 103 (83.1) 121 (91.0)

Median in months (95% CI) 12.7 (9.4, 15.3) 9.9 (8.6, 11.5) 10.8 (9.0, 12.6) 10.1 (8.7, 12.1)

Hazard ratio† (95% CI) 0.71 (0.54, 0.94) 0.86 (0.66, 1.12)

OS rate at 6 months (95% CI) 76.7 (67.9, 83.4) 77.4 (69.0, 83.8) 67.6 (58.6, 75.1) 78.0 (70.0, 84.2)

OS rate at 12 months (95% CI) 52.6 (43.1, 61.2) 41.1 (32.4, 49.6) 44.0 (35.1, 52.5) 42.4 (33.9, 50.7)

OS rate at 24 months (95% CI) 25.9 (18.3, 34.1) 14.5 (9.0, 21.3) 22.0 (15.1, 29.6) 15.9 (10.3, 22.6)
PFS

Number (%) of patients with event 106 (91.4) 117 (93.6) 113 (91.1) 123 (92.5)

Median in months (95% CI) 4.9 (4.2, 5.3) 4.9 (3.7, 6.0) 2.2 (2.1, 2.9) 4.9 (3.8, 6.0)

Hazard ratio† (95% CI) 0.93 (0.71, 1.21) 1.25 (0.96, 1.61)

PFS rate at 6 months (95% CI) 40.1 (31.0, 49.0) 40.0 (31.2, 48.5) 24.2 (17.1, 32.0) 41.4 (32.8, 49.7)

PFS rate at 12 months (95% CI) 15.1 (9.1, 22.4) 11.3 (6.4, 17.7) 17.5 (11.4, 24.7) 12.1 (7.2, 18.5)

PFS rate at 24 months (95% CI) 8.5 (4.2, 14.7) 5.0 (1.9, 10.1) 8.3 (4.3, 14.1) 6.3 (2.9, 11.5)
Objective response rate

ORR‡ % (95% CI) 29.3 (21.2, 38.5) 33.6 (25.4, 42.6) 14.5 (8.8, 22.0) 33.8 (25.9,42.5)
Response duration

 



123

Number of responders 34 42 18 45

Median in months (range) 5.6 (1.6+, 25.6+) 4.6 (1.4+, 31.4+) NR (1.5+, 38.9+) 5.0 (1.4+, 38.7+)
* Cetuximab, platinum, and 5-FU
† Based on the stratified Cox proportional hazard model
‡ Response: Best objective response as confirmed complete response or partial response

KEYNOTE-040: Controlled study in HNSCC patients previously treated with platinum-containing 
chemotherapy
The safety and efficacy of pembrolizumab were investigated in KEYNOTE-040, a multicentre, 
open-label, randomised, controlled study for the treatment of histologically confirmed recurrent or 
metastatic HNSCC of the oral cavity, pharynx or larynx in patients who had disease progression on or 
after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following 
platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy, 
and were not amenable to local therapy with curative intent. Patients were stratified by PD-L1 
expression (TPS ≥ 50%), HPV status and ECOG performance status and then randomised (1:1) to 
receive either pembrolizumab 200 mg every 3 weeks (n=247) or one of three standard treatments
(n=248): methotrexate 40 mg/m2 once weekly (n=64), docetaxel 75 mg/m2 once every 3 weeks (n=99), 
or cetuximab 400 mg/m2 loading dose and then 250 mg/m2 once weekly (n=71). Treatment could 
continue beyond progression if the patient was clinically stable and was considered to be deriving 
clinical benefit by the investigator. The study excluded patients with nasopharyngeal carcinoma, active 
autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition 
that required immunosuppression, or who were previously treated with 3 or more systemic regimens 
for recurrent and/or metastatic HNSCC. Assessment of tumour status was performed at 9 weeks, then 
every 6 weeks through Week 52, followed by every 9 weeks through 24 months.

Among the 495 patients in KEYNOTE-040, 129 (26%) had tumours that expressed PD-L1 with a 
TPS ≥ 50% based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these 
129 patients included: median age 62 years (40% age 65 or older); 81% male; 78% White, 11% Asian, 
and 2% Black; 23% and 77% with an ECOG performance status 0 or 1, respectively; and 19% with 
HPV positive tumours. Sixty-seven percent (67%) of patients had M1 disease and the majority had 
stage IV disease (stage IV 32%, stage IVa 14%, stage IVb 4%, and stage IVc 44%). Sixteen
percent (16%) had disease progression following platinum-containing neoadjuvant or adjuvant 
chemotherapy, and 84% had received 1-2 prior systemic regimens for metastatic disease.

The primary efficacy outcome was OS in the ITT population. The initial analysis resulted in a HR for 
OS of 0.82 (95% CI: 0.67, 1.01) with a one-sided p-value of 0.0316. The median OS was 8.4 months 
for pembrolizumab compared to 7.1 months for standard treatment. Table 28 summarises the key 
efficacy measures for the TPS ≥ 50% population. The Kaplan-Meier curve for OS for the TPS ≥ 50% 
population is shown in Figure 16.

 



124

Table 28: Efficacy of pembrolizumab 200 mg every 3 weeks in HNSCC patients with TPS ≥ 50% 
who were previously treated with platinum chemotherapy in KEYNOTE-040

Endpoint Pembrolizumab
200 mg every 3 weeks

n=64

Standard Treatment*
n=65

OS
   Number (%) of patients with event 41 (64) 56 (86)
   Hazard ratio† (95% CI) 0.53 (0.35, 0.81)
   p-Value‡ 0.001
   Median in months (95% CI) 11.6 (8.3, 19.5) 6.6 (4.8, 9.2)
PFS§

   Number (%) of patients with event 52 (81) 58 (89)
   Hazard ratio† (95% CI) 0.58 (0.39, 0.86)
   p-Value‡ 0.003
   Median in months (95% CI) 3.5 (2.1, 6.3) 2.1 (2.0, 2.4)
   Rate (%) at 6 months (95% CI) 40.1 (28.1, 51.9) 17.1 (8.8, 27.7)
Objective response rate§

ORR % (95% CI) 26.6 (16.3, 39.1) 9.2 (3.5, 19.0)
p-Value¶ 0.0009
          Complete response 5% 2%
          Partial response 22% 8%
          Stable disease 23% 23%
Response duration§,#

   Median in months (range) Not reached (2.7, 13.8+) 6.9 (4.2, 18.8)
Number (%Þ) of patients with duration 
≥ 6 months

9 (66) 2 (50)
* Methotrexate, docetaxel, or cetuximab
† Hazard ratio (pembrolizumab compared to standard treatment) based on the stratified Cox proportional hazard 

model
‡ One-sided p-Value based on log-rank test
§ Assessed by BICR using RECIST 1.1
¶ Based on method by Miettinen and Nurminen
# Based on patients with a best objective response as confirmed complete or partial response
Þ Based on Kaplan-Meier estimation 

 



125

Figure 16: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-040
patients with PD-L1 expression (TPS ≥ 50%)

Renal cell carcinoma
KEYNOTE-426: Controlled study of combination therapy in RCC patients naïve to treatment
The efficacy of pembrolizumab in combination with axitinib was investigated in KEYNOTE-426, 
a randomised, multicentre, open-label, active-controlled study conducted in patients with advanced 
RCC with clear cell component, regardless of PD-L1 tumour expression status and International 
Metastatic RCC Database Consortium (IMDC) risk group categories. The study excluded patients with 
autoimmune disease or a medical condition that required immunosuppression. Randomisation was 
stratified by risk categories (favourable versus intermediate versus poor) and geographic region (North 
America versus Western Europe versus “Rest of the World”). Patients were randomised (1:1) to one of 
the following treatment arms:

 pembrolizumab 200 mg intravenously every 3 weeks in combination with axitinib 5 mg 
orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive 
treatment cycles (i.e. 6 weeks) with no > Grade 2 treatment-related adverse events to 
axitinib and with blood pressure well controlled to ≤ 150/90 mm Hg were permitted 
dose escalation of axitinib to 7 mg twice daily. Dose escalation of axitinib to 10 mg 
twice daily was permitted using the same criteria. Axitinib could be interrupted or 
reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.

 sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.

Treatment with pembrolizumab and axitinib continued until RECIST v1.1-defined progression of 
disease as verified by BICR or confirmed by the investigator, unacceptable toxicity, or for 
pembrolizumab, a maximum of 24 months. Administration of pembrolizumab and axitinib was 
permitted beyond RECIST-defined disease progression if the patient was clinically stable and 
considered to be deriving clinical benefit by the investigator. Assessment of tumour status was 
performed at baseline, after randomisation at Week 12, then every 6 weeks thereafter until Week 54, 

Treatment arm          OS rate at 12 months        HR (95% CI)       p-value
Pembrolizumab                          47%                0.53 (0.35, 0.81)    0.00136
Standard Treatment                   25%

0 5 10 15 20 25

Time in Months

0

10

20

30

40

50

60

70

80

90

100

O
v
e
ra

ll 
S

u
rv

iv
a
l 
(%

)

64 49 35 19 7 1

65 38 22 9 2 0

Number at Risk

Pembrolizumab:

Standard Treatment:

 



126

and then every 12 weeks thereafter. Chemistry and haematology laboratory tests were performed at 
each cycle.

A total of 861 patients were randomised. The study population characteristics were: median age of 
62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 80% had a 
Karnofsky Performance Score (KPS) 90-100 and 20% had KPS 70-80; patient distribution by IMDC 
risk categories was 31% favourable, 56% intermediate and 13% poor.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). 
Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using 
RECIST 1.1. The median follow-up time was 12.8 months (range: 0.1 to 21.5 months). Table 29
summarises key efficacy measures from the pre-specified interim analysis. The Kaplan-Meier curves 
for OS and PFS based on an additional four months of follow up are shown in Figures 17 and 18.

Table 29: Efficacy Results in KEYNOTE-426

Endpoint Pembrolizumab
Axitinib
n=432

Sunitinib
n=429

OS
Number of events (%) 59 (14%) 97 (23%)
Median in months (95% CI) Not reached (NA, NA) Not reached (NA, NA)
Hazard ratio* (95% CI) 0.53 (0.38, 0.74)
p-Value† 0.00005

PFS‡

Number of events (%) 183 (42%) 213 (50%)
Median in months (95% CI) 15.1 (12.6, 17.7) 11.0 (8.7, 12.5)
Hazard ratio* (95% CI) 0.69 (0.56, 0.84)
p-Value† 0.00012

Objective response rate
ORR§ % (95% CI) 59 (54, 64) 36 (31, 40)
          Complete response 6% 2%
          Partial response 53% 34%
p-Value¶ < 0.0001

Response duration
Median in months (range) Not reached (1.4+, 18.2+) 15.2 (1.1+, 15.4+)
Number (%#) of patients with 
duration ≥ 6 months

161 (88%) 84 (81%)

Number (%#) of patients with 
duration ≥ 12 months

58 (71%) 26 (62%)

* Based on the stratified Cox proportional hazard model
† Based on stratified log-rank test 
‡ Assessed by BICR using RECIST 1.1
§ Based on patients with a best objective response as confirmed complete or partial response
¶ Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region
# Based on Kaplan-Meier estimation
NA = not available

 



127

Figure 17: Kaplan-Meier curve for overall survival by treatment arm in
KEYNOTE-426 (intent to treat population)*

*p-Value is nominal. See Table 29 for p-Value for inferential test of OS based on the pre-specified 
interim analysis, where statistical significance has been reached.

Treatment arm                OS rate at 12 months    OS rate at 18 months     HR (95% CI)      p-value
Pembrolizumab + Axitinib            90%                                 81%              0.59 (0.45, 0.78)   0.00010
Sunitinib                                        79%                                 71%

0 5 10 15 20 25 30

Time in Months

0

10

20

30

40

50

60

70

80

90

100

O
ve

ra
ll 

S
u

rv
iv

a
l 
(%

)

432 411 392 275 133 9 0

429 389 346 230 111 6 0

Number at Risk

Pembrolizumab + Axitinib:

Sunitinib:

 



128

Figure 18: Kaplan-Meier curve for progression-free survival by treatment arm in
KEYNOTE-426 (intent to treat population)*

*p-Value is nominal. See Table 29 for p-Value for inferential test of PFS based on the pre-specified 
interim analysis, where statistical significance has been reached.

Subgroup analyses by enrolment were performed in KEYNOTE-426 in patients with PD-L1 CPS ≥ 1 
[pembrolizumab/axitinib combination: n=243 (56%) vs. sunitinib: n=254 (59%)]; CPS < 1 
[pembrolizumab/axitinib combination: n=167 (39%) vs. sunitinib: n=158 (37%)], and in patients with 
IMDC risk categories of favourable [pembrolizumab/axitinib combination: n=138 (32%) vs. sunitinib: 
n=131 (31%)]; intermediate [pembrolizumab/axitinib combination: n=238 (55%) vs. sunitinib: n=246 
(57%)]; and poor [pembrolizumab/axitinib combination: n=56 (13%) vs. sunitinib: n=52 (12%)]. OS 
and PFS benefits were observed regardless of PD-L1 expression level. 

The KEYNOTE-426 study was not powered to evaluate efficacy of individual subgroups. Table 30
summarises the efficacy measures by IMDC risk category from the pre-specified interim analysis.

Table 30: Efficacy Results in KEYNOTE-426 by IMDC Risk Category

Endpoint Pembrolizumab + 
Axitinib
N = 432

Sunitinib
N = 429

Pembrolizumab + Axitinib 
vs. Sunitinib

OS 12-month OS rate, % (95% CI) OS HR (95% CI)

  Favourable 95.2 (89.6, 97.9) 93.8 (87.4, 97.0) 0.64 (0.24, 1.68)

  Intermediate 92.1 (84.7, 96.0) 76.7 (70.6, 81.8) 0.53 (0.35, 0.82)

  Poor 70.3 (56.1, 80.7) 45.2 (30.0, 59.3) 0.43 (0.23, 0.81)

PFS Median (95% CI), months PFS HR (95% CI)

Treatment arm              PFS rate at 12 months    PFS rate at 18 months    HR (95% CI)     p-value
Pembrolizumab + Axitinib         60%                                 48%                  0.69 (0.57, 0.83)  0.00005
Sunitinib                                     48%                                 36%

0 5 10 15 20 25 30

Time in Months

0

10

20

30

40

50

60

70

80

90

100

P
ro

g
re

s
si

o
n
-F

re
e
 S

u
rv

iv
a
l 
(%

)

432 324 247 145 51 0 0

429 277 175 90 32 0 0

Number at Risk

Pembrolizumab + Axitinib:

Sunitinib:

 



129

Endpoint Pembrolizumab + 
Axitinib
N = 432

Sunitinib
N = 429

Pembrolizumab + Axitinib 
vs. Sunitinib

  Favourable 17.7 (15.2, NA) 12.7 (11.5, NA) 0.81 (0.53, 1.24)

  Intermediate 14.5 (12.4, 18.0) 9.5 (8.0, 12.5) 0.69 (0.53, 0.90)

  Poor 4.9 (2.9, 12.4) 2.9 (2.7, 4.2) 0.58 (0.35, 0.94)

Confirmed ORR % (95% CI) ORR difference, 
% (95% CI)

  Favourable 66.7 (58.1, 74.5) 49.6 (40.8, 58.5) 17.0 (5.3, 28.4)

  Intermediate 59.2 (52.7, 65.5) 33.7 (27.9, 40.0) 25.5 (16.7, 33.9)

  Poor 41.1 (28.1, 55.0) 9.6 (3.2, 21.0) 31.5 (15.7, 46.2)

NA = not available

An updated OS analysis was performed when patients had a median follow-up of 16.6 months (range: 
0.1 to 26.3 months). At the time of this analysis, the hazard ratio in the overall population (95% CI) 
was 0.59 (0.45, 0.78) with 84/432 (19.4%) events in the combination arm and 122/429 (28.4%) events 
in the sunitinib arm. The 12-month OS rate was 89.5% (95% CI 86.2, 92.1) for pembrolizumab in 
combination with axitinib and 78.8% (95% CI 74.7, 82.4) for sunitinib. The 18-month OS rate was 
81.0% (95% CI 76.7, 84.6) for pembrolizumab in combination with axitinib and 70.7% (95% CI 65.8, 
75.1) for sunitinib. For the IMDC risk category, the OS hazard ratio for the favourable risk group was 
0.94 (95% CI 0.43, 2.07), for the intermediate risk group the OS hazard ratio was 0.52 (95% CI 0.36, 
0.75), and for the poor risk group the OS hazard ratio was 0.50 (95% CI 0.29, 0.87).

Paediatric population
In KEYNOTE-051, 154 paediatric patients (60 children aged 6 months to less than 12 years and
94 adolescents aged 12 years to 18 years) with advanced melanoma or PD-L1 positive advanced, 
relapsed, or refractory solid tumours or lymphoma were administered pembrolizumab 2 mg/kg every 
3 weeks. All patients received pembrolizumab for a median of 3 doses (range 1-35 doses), with 
130 patients (84.4%) receiving pembrolizumab for 2 doses or more. Participants were enrolled across 
28 tumour types by primary diagnosis. The most common tumour types by histology were Hodgkin 
lymphoma (11.7%), glioblastoma multiforme (9.1%), neuroblastoma (6.5%), osteosarcoma (6.5%) and 
melanoma (5.2%). Of the 154 patients, 134 were enrolled with solid tumours, 18 with Hodgkin 
lymphoma, and 2 with other lymphomas. In patients with solid tumours and other lymphomas, the 
ORR was 5.9%, no patient had a complete response and 8 patients (5.9%) had a partial response. In 
the Hodgkin lymphoma population, the ORR was 50.0%, 2 patients (11.1%) had a complete response 
and 7 patients (38.9%) had a partial response.

The European Medicines Agency has deferred the obligation to submit the results of studies with 
pembrolizumab in one or more subsets of the paediatric population in treatment of Hodgkin lymphoma 
(see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of pembrolizumab was studied in 2,993 patients with metastatic or unresectable 
melanoma, NSCLC, or carcinoma who received doses in the range of 1 to 10 mg/kg every 2 weeks, 
2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks.

Absorption
Pembrolizumab is administered via the intravenous route and therefore is immediately and completely 
bioavailable.

Distribution
Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab at 
steady-state is small (~6.0 L; CV: 20%). As expected for an antibody, pembrolizumab does not bind to 
plasma proteins in a specific manner.

 



130

Biotransformation
Pembrolizumab is catabolised through non-specific pathways; metabolism does not contribute to its 
clearance.

Elimination
Pembrolizumab CL is approximately 23% lower (geometric mean, 195 mL/day [CV%: 40%]) after 
achieving maximal change at steady-state compared with the first dose (252 mL/day [CV%: 37%]); 
this decrease in CL with time is not considered clinically meaningful. The geometric mean value 
(CV%) for the terminal half-life is 22 days (32%) at steady-state.

Linearity/non-linearity
Exposure to pembrolizumab as expressed by peak concentration (Cmax) or area under the plasma 
concentration time curve (AUC) increased dose proportionally within the dose range for efficacy. 
Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an 
every 3 week regimen and the systemic accumulation was 2.1-fold. The median trough concentrations 
(Cmin) at steady-state were approximately 22 mcg/mL at a dose of 2 mg/kg every 3 weeks and 
29 mcg/mL at a dose of 200 mg every 3 weeks. The median area under the concentration time curve at 
steady-state over 3 weeks (AUC0-3weeks) was 794 mcg∙day/mL at a dose of 2 mg/kg every 3 weeks and 
1,053 mcg∙day/mL at a dose of 200 mg every 3 weeks.

Following administration of pembrolizumab 200 mg every 3 weeks in patients with cHL, the observed 
median Cmin at steady-state was up to 40% higher than that in other tumour types treated with the same 
dosage; however, the range of trough concentrations is similar. There are no notable differences in 
median Cmax between cHL and other tumour types. Based on available safety data in cHL and other 
tumour types, these differences are not clinically meaningful.

Special populations
The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in 
population pharmacokinetic analyses. The following factors had no clinically important effect on the 
clearance of pembrolizumab: age (range 15-94 years), gender, race, mild or moderate renal 
impairment, mild hepatic impairment and tumour burden. The relationship between body weight and 
clearance supports the use of either fixed dose or body weight-based dosing to provide adequate and 
similar control of exposure. Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 
3 weeks in paediatric patients (2 to 17 years) are comparable to those of adults at the same dose.

Renal impairment
The effect of renal impairment on the clearance of pembrolizumab was evaluated by population 
pharmacokinetic analyses in patients with mild or moderate renal impairment compared to patients 
with normal renal function. No clinically important differences in the clearance of pembrolizumab 
were found between patients with mild or moderate renal impairment and patients with normal renal 
function. Pembrolizumab has not been studied in patients with severe renal impairment. 

Hepatic impairment
The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by population 
pharmacokinetic analyses in patients with mild hepatic impairment (as defined using the US National 
Cancer Institute criteria of hepatic dysfunction) compared to patients with normal hepatic function. No 
clinically important differences in the clearance of pembrolizumab were found between patients with 
mild hepatic impairment and normal hepatic function. Pembrolizumab has not been studied in patients 
with moderate or severe hepatic impairment (see section 4.2).

5.3 Preclinical safety data

The safety of pembrolizumab was evaluated in a 1-month and a 6-month repeat-dose toxicity study in 
Cynomolgus monkeys administered intravenous doses of 6, 40 or 200 mg/kg once a week in the 
1-month study and once every two weeks in the 6-month study, followed by a 4-month treatment-free 
period. No findings of toxicological significance were observed and the no observed adverse effect 

 



131

level (NOAEL) in both studies was ≥ 200 mg/kg, which produced exposure multiples of 19 and 
94 times the exposure in humans at doses of 10 and 2 mg/kg, respectively. The exposure multiple 
between the NOAEL and a human dose of 200 mg was 74.

Animal reproduction studies have not been conducted with pembrolizumab. The PD-1/PD-L1 pathway 
is thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of 
PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and 
to result in an increase in foetal loss. 

Animal fertility studies have not been conducted with pembrolizumab. In 1 month and 6 month 
repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female 
reproductive organs; however, many animals in these studies were not sexually mature.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

L-histidine
L-histidine hydrochloride monohydrate
Sucrose
Polysorbate 80
Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial
2 years.

After preparation of infusion
From a microbiological point of view, the product, once diluted, should be used immediately. The 
diluted solution must not be frozen. If not used immediately, chemical and physical in-use stability of 
KEYTRUDA has been demonstrated for 96 hours at 2ºC to 8ºC. This 96-hour hold may include up to 
6 hours at room temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must 
be allowed to come to room temperature prior to use.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

4 mL of concentrate in a 10 mL Type I clear glass vial, with a coated grey chlorobutyl or bromobutyl
stopper and an aluminium seal with a dark blue coloured flip-off cap, containing 100 mg 
pembrolizumab.

Each carton contains one vial.

 



132

6.6 Special precautions for disposal and other handling

Preparation and administration of the infusion
 Do not shake the vial.
 Equilibrate the vial to room temperature (at or below 25°C).
 Prior to dilution, the vial of liquid can be out of refrigeration (temperatures at or below 25°C) 

for up to 24 hours.
 Parenteral medicinal products should be inspected visually for particulate matter and 

discolouration prior to administration. The concentrate is a clear to slightly opalescent, 
colourless to slightly yellow solution. Discard the vial if visible particles are observed.

 Withdraw the required volume up to 4 mL (100 mg) of concentrate and transfer into an 
intravenous bag containing sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) to 
prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Each vial 
contains an excess fill of 0.25 mL (total content per vial 4.25 mL) to ensure the recovery of 
4 mL of concentrate. Mix diluted solution by gentle inversion.

 From a microbiological point of view, the product, once diluted, should be used immediately. 
The diluted solution must not be frozen. If not used immediately, chemical and physical in-use 
stability of KEYTRUDA has been demonstrated for 96 hours at 2ºC to 8ºC. This 96-hour hold 
may include up to 6 hours at room temperature (at or below 25°C). If refrigerated, the vials 
and/or intravenous bags must be allowed to come to room temperature prior to use. Translucent 
to white proteinaceous particles may be seen in diluted solution. Administer the infusion 
solution intravenously over 30 minutes using a sterile, non-pyrogenic, low-protein binding 0.2 
to 5 µm in-line or add-on filter.

 Do not co-administer other medicinal products through the same infusion line.
 KEYTRUDA is for single use only. Discard any unused portion left in the vial. 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1024/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 July 2015
Date of latest renewal: 24 March 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.

 

http://www.ema.europa.eu/


133

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

 



134

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

Name and address of the manufacturers of the biological active substance

AstraZeneca Pharmaceuticals LP
Frederick Manufacturing Center (FMC) 
633 Research Court 
Frederick, Maryland 21703 
U.S.

Boehringer Ingelheim (BIB)
Pharma GmbH & Co. KG
Birkendorfer Straße 65
88397 Biberach an der Riss
Germany

MSD Biotech B.V.
Vollenhovermeer 2
5347 JV Oss
The Netherlands

Boehringer Ingelheim Fremont, Inc. (BIF)
6701 Kaiser Drive
Fremont, California 94555
U.S.

Name and address of the manufacturers responsible for batch release

Schering-Plough Labo NV
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

Merck Sharp & Dohme B.V. 
Waarderweg 39
2031 BN Haarlem
The Netherlands 

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.

 



135

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 

Prior to launch of KEYTRUDA in each Member State the MAH must agree about the content and 
format of the educational programme, including communication media, distribution modalities, and 
any other aspects of the programme, with the National Competent Authority.

The educational programme is aimed at increasing the awareness of patients and/or their caregivers on 
the signs and symptoms relevant to the early recognition/identification of the potential immune-related 
adverse reactions (irARs).

The MAH shall ensure that in each Member State where KEYTRUDA is marketed, all healthcare 
professionals and patients/caregivers who are expected to prescribe and use KEYTRUDA have access 
to/are provided with the patient educational material.

The patient educational material should contain:
 Patient Information Brochure
 The patient alert card 

The Patient Information Brochure and patient alert card shall contain the following key elements:
 Description of the main signs or symptoms of the irARs and the importance of notifying their 

treating physician immediately if symptoms occur 
 The importance of not attempting to self-treat any symptoms without consulting their healthcare 

professional first
 The importance of carrying the patient alert card at all times and to show it at all medical visits 

to healthcare professionals other than the prescriber (e.g. emergency healthcare professionals).

The card reminds patients about key symptoms that need to be reported immediately to the 
physician/nurse. It also contains prompts to enter contact details of the physician and to alert other 
physicians that the patient is treated with KEYTRUDA.

 



136

 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 final 
study report for study P087, A Phase II Clinical Trial of MK-3475 
(Pembrolizumab) in Subjects with Relapsed or Refractory (R/R) Classical 
Hodgkin Lymphoma (cHL) – Final Study Report

3Q 2021

2. Post-authorisation efficacy study (PAES): The MAH should submit the final 
study report for study P204: A Phase III, Randomised, Open-label, Clinical Trial 
to Compare Pembrolizumab with Brentuximab Vedotin in Subjects with 
Relapsed or Refractory Classical Hodgkin Lymphoma – Final Study Report

2Q 2021

3. The value of biomarkers to predict the efficacy of pembrolizumab should be 
further explored, specifically:

Additional biomarkers other than PD-L1 expression status by 
Immunohistochemistry (IHC) (e.g. PD-L2, RNA signature, etc.) predictive of 
pembrolizumab efficacy should be investigated together with more information 
regarding the pattern of expression of PD-L1 obtained in the ongoing NSCLC 
studies (P001, P010, P024 and P042) 
and urothelial carcinoma studies (KN045, KN052),
HNSCC study (KN040) and
resected Stage II melanoma adjuvant study (KN716):

 Genomic analyses using whole exome sequencing and/or RNAseq (e.g. 
Nanostring RNA gene signature)

 IHC staining for PD-L2 
 Data on RNA and proteomic serum profiling

2Q 2020
2Q 2019
4Q 2021
4Q 2024

4. Post-authorisation efficacy study (PAES): The MAH should provide the study 
report for study P361: A Phase III Randomised, Controlled Clinical Trial of 
Pembrolizumab with or without Platinum-Based Combination Chemotherapy 
versus Chemotherapy in Subjects with Advanced or Metastatic Urothelial 
Carcinoma – Study Report

4Q 2020

5. Post-authorisation efficacy study (PAES) the MAH should submit the final study 
report of RFS/DMFS and OS data for study KN054: a Phase III Clinical Trial of 
Pembrolizumab (MK-3475) in Subjects with complete resection of high-risk 
Stage III melanoma – Final Study Report

4Q 2023  

6. Post-authorisation efficacy study (PAES): The MAH should submit the final 
study report for study P426: A Phase III Randomised, Open-label Study to 
Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in combination with 
Axitinib versus Sunitinib Monotherapy as a First-line Treatment for Locally 
Advanced or Metastatic Renal Cell Carcinoma (mRCC)

1Q 2021

 



137

ANNEX III

LABELLING AND PACKAGE LEAFLET

 



138

A. LABELLING

 



139

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

KEYTRUDA 50 mg powder for concentrate for solution for infusion 
pembrolizumab

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One vial of powder contains 50 mg of pembrolizumab. After reconstitution, 1 mL of concentrate 
contains 25 mg of pembrolizumab.

3. LIST OF EXCIPIENTS

Excipients: L-histidine, L-histidine hydrochloride monohydrate, sucrose, polysorbate 80.

4. PHARMACEUTICAL FORM AND CONTENTS

powder for concentrate for solution for infusion
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Intravenous use.
For single use only.
Read the package leaflet before use.

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

The reconstituted vials and/or diluted intravenous bags may be stored for a cumulative time of up to
96 hours in a refrigerator (2°C – 8°C).

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2°C – 8°C).

 



140

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

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1024/001 (1 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.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN

 



141

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

KEYTRUDA 50 mg powder for concentrate for solution for infusion
pembrolizumab
Intravenous use
IV

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

 



142

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

KEYTRUDA 25 mg/mL concentrate for solution for infusion 
pembrolizumab
100 mg/4 mL

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One vial of 4 mL contains 100 mg of pembrolizumab. Each mL of concentrate contains 25 mg of 
pembrolizumab.

3. LIST OF EXCIPIENTS

Excipients: L-histidine, L-histidine hydrochloride monohydrate, sucrose, polysorbate 80, water for 
injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Intravenous use after dilution.
For single use only.
Read the package leaflet before use.

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

Do not shake.

8. EXPIRY DATE

EXP

The diluted solution may be stored for up to 96 hours in a refrigerator (2°C – 8°C).

 



143

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator (2°C – 8°C).
Do not Freeze.
Store in the original carton 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

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/15/1024/002 (1 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.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN

 



144

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

KEYTRUDA 25 mg/mL concentrate for solution for infusion
pembrolizumab
100 mg/4 mL
IV

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

 



145

B. PACKAGE LEAFLET

 



146

Package leaflet: Information for the patient

KEYTRUDA 50 mg powder for concentrate for solution for infusion
pembrolizumab

Read all of this leaflet carefully before you are given 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 KEYTRUDA is and what it is used for 
2. What you need to know before you are given KEYTRUDA
3. How you are given KEYTRUDA
4. Possible side effects 
5. How to store KEYTRUDA
6. Contents of the pack and other information

1. What KEYTRUDA is and what it is used for

KEYTRUDA contains the active substance pembrolizumab, which is a monoclonal antibody. 
KEYTRUDA works by helping your immune system fight your cancer.

KEYTRUDA is used in adults to treat:
 a kind of skin cancer called melanoma
 a kind of lung cancer called non-small cell lung cancer
 a kind of cancer called classical Hodgkin lymphoma
 a kind of cancer called bladder cancer (urothelial carcinoma)
 a kind of head and neck cancer called head and neck squamous cell carcinoma
 a kind of kidney cancer called renal cell carcinoma.

People get KEYTRUDA when their cancer has spread or cannot be taken out by surgery.

People get KEYTRUDA after they have had surgery to remove melanoma to help prevent their cancer 
from coming back (adjuvant therapy).

KEYTRUDA may be given in combination with other anti-cancer medicines. It is important that you 
also read the package leaflets for these other medicines. If you have any questions about these 
medicines, ask your doctor.

2. What you need to know before you are given KEYTRUDA

You should not be given KEYTRUDA
- if you are allergic to pembrolizumab 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.

Warnings and precautions 
Talk to your doctor or nurse before receiving KEYTRUDA.

Before you get KEYTRUDA, tell your doctor if you:
- have an autoimmune disease (a condition where the body attacks its own cells)

 



147

- have pneumonia or inflammation of your lungs (called pneumonitis)
- were previously given ipilimumab, another medicine for treating melanoma, and experienced 

serious side effects because of that medicine
- had an allergic reaction to other monoclonal antibody therapies
- have or have had chronic viral infection of the liver, including hepatitis B (HBV) or hepatitis C 

(HCV)
- have human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome 

(AIDS)
- have liver damage
- have kidney damage
- have had a solid organ transplant or a bone marrow (stem cell) transplant that used donor stem 

cells (allogeneic)

When you get KEYTRUDA, you can have some serious side effects. These side effects can sometimes 
become life-threatening and can lead to death. These side effects may happen anytime during 
treatment or even after your treatment has ended. You may experience more than one side effect at the 
same time.

If you have any of the following conditions, call or see your doctor right away. Your doctor may give 
you other medicines in order to prevent more severe complications and reduce your symptoms. Your 
doctor may withhold the next dose of KEYTRUDA or stop your treatment with KEYTRUDA.
- inflammation of the lungs, which may include shortness of breath, chest pain or coughing
- inflammation of the intestines, which may include diarrhoea or more bowel movements than 

usual, black, tarry, sticky stools or stools with blood or mucus, severe stomach pain or 
tenderness, nausea, vomiting

- inflammation of the liver, which may include nausea or vomiting, feeling less hungry, pain on 
the right side of stomach, yellowing of skin or whites of eyes, dark urine or bleeding or bruising 
more easily than normal

- inflammation of the kidneys, which may include changes in the amount or colour of your urine
- inflammation of hormone glands (especially the thyroid, pituitary and adrenal glands), which 

may include rapid heartbeat, weight loss, increased sweating, weight gain, hair loss, feeling 
cold, constipation, deeper voice, muscle aches, dizziness or fainting, headaches that will not go 
away or unusual headache

- type 1 diabetes, which may include feeling more hungry or thirsty than usual, need to urinate 
more often or weight loss

- inflammation of the eyes, which may include changes in eyesight
- inflammation in the muscles, which may include muscle pain or weakness
- inflammation of the heart muscle, which may include shortness of breath, irregular heartbeat, 

feeling tired, or chest pain
- inflammation of the pancreas, which may include abdominal pain, nausea and vomiting
- inflammation of the skin, which may include rash, itching, skin blistering, peeling or sores,

and/or ulcers in mouth or in lining of nose, throat, or genital area 
- an immune disorder that can affect the lungs, skin, eyes and/or lymph nodes (sarcoidosis)
- inflammation of the brain, which may include confusion, fever, memory problems or seizures 

(encephalitis)
- pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems including 

needing to urinate more frequently, urinary incontinence, difficulty urinating and constipation 
(myelitis)

- infusion reactions, which may include shortness of breath, itching or rash, dizziness or fever

Complications, including graft-versus-host-disease (GVHD), in people with bone marrow (stem 
cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can 
lead to death. They may occur if you had this kind of transplant in the past or if you get it in the future. 
Your doctor will monitor you for signs and symptoms, which may include skin rash, liver 
inflammation, abdominal pain, or diarrhoea.

 



148

Children and adolescents
KEYTRUDA should not be used in children and adolescents below 18 years of age.

Other medicines and KEYTRUDA
Tell your doctor 
- If you are taking other medicines that make your immune system weak. Examples of these may 

include corticosteroids, such as prednisone. These medicines may interfere with the effect of 
KEYTRUDA. However, once you are treated with KEYTRUDA, your doctor may give you 
corticosteroids to reduce the side-effects that you may have with KEYTRUDA. Corticosteroids 
may also be given to you before receiving KEYTRUDA in combination with chemotherapy to 
prevent and/or treat nausea, vomiting, and other side effects caused by chemotherapy.

- If you are taking, have recently taken or might take any other medicines.

Pregnancy
- You must not use KEYTRUDA if you are pregnant unless your doctor specifically recommends 

it.
- If you are pregnant, think you may be pregnant or are planning to have a baby, tell your doctor.
- KEYTRUDA can cause harm or death to your unborn baby.
- If you are a woman who could become pregnant, you must use adequate birth control while you 

are being treated with KEYTRUDA and for at least 4 months after your last dose.

Breast-feeding
- If you are breast-feeding, tell your doctor.
- Do not breast-feed while taking KEYTRUDA.
- It is not known if KEYTRUDA passes into your breast milk.

Driving and using machines
KEYTRUDA has a minor effect on your ability to drive or use machines. Feeling dizzy, tired or weak 
are possible side effects of KEYTRUDA. Do not drive or use machines after you have been given 
KEYTRUDA unless you are sure you are feeling well.

3. How you are given KEYTRUDA

KEYTRUDA will be given to you in a hospital or clinic under the supervision of a doctor experienced 
in cancer treatment.
- The recommended dose of KEYTRUDA is either 200 mg every 3 weeks or 400 mg every 

6 weeks.
- Your doctor will give you KEYTRUDA through an infusion into your vein (intravenous) for 

about 30 minutes.
- Your doctor will decide how many treatments you need.

If you miss an appointment to get KEYTRUDA
- Call your doctor right away to reschedule your appointment.
- It is very important that you do not miss a dose of this medicine.

If you stop receiving KEYTRUDA
Stopping your treatment may stop the effect of the medicine. Do not stop treatment with KEYTRUDA 
unless you have discussed this with your doctor.

If you have any further questions about your treatment, ask your doctor.

You will also find this information in the patient alert card you have been given by your doctor. It is 
important that you keep this alert card and show it to your partner or caregivers.

 



149

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

When you get KEYTRUDA, you can have some serious side effects. See section 2.

The following side effects have been reported with pembrolizumab alone:

Very common (may affect more than 1 in 10 people)
- decrease in the number of red blood cells
- reduced thyroid gland activity
- feeling less hungry
- headache
- shortness of breath; cough
- diarrhoea; stomach pain; nausea; vomiting; constipation
- itching; skin rash
- pain in muscle and bones; joint pain
- feeling tired; unusual tiredness or weakness; swelling; fever

Common (may affect up to 1 in 10 people)
- lung infection
- decrease in the number of platelets (bruising or bleeding more easily); decrease in the number of 

white blood cell (lymphocytes)
- reactions related to the infusion of the medicine
- overactive thyroid gland activity; hot flush
- decreased sodium, potassium, or calcium in the blood
- trouble sleeping
- dizziness; inflammation of the nerves causing numbness, weakness, tingling or burning pain of 

the arms and legs; lack of energy; change in your sense of taste
- dry eye
- abnormal heart rhythm
- high blood pressure
- inflammation of the lungs
- inflammation of the intestines; dry mouth
- red raised rash sometimes with blisters; patches of skin which have lost colour; dry, itchy skin; 

hair loss; acne-like skin problem
- muscle pain, aches or tenderness; pain in arms or legs; joint pain with swelling
- chills; flu-like illness
- increased liver enzyme levels in the blood; increased calcium in the blood; abnormal kidney 

function test

Uncommon (may affect up to 1 in 100 people)
- a decreased number of white blood cells (neutrophils, leukocytes, and eosinophils)
- an immune disorder that can affect the lungs, skin, eyes and/or lymph nodes (sarcoidosis)
- inflammation of the pituitary gland situated at the base of the brain; decreased secretion of 

hormones produced by the adrenal glands; inflammation of the thyroid
- type 1 diabetes
- seizure
- inflammation of the eyes; eye pain, irritation, itchiness or redness; uncomfortable sensitivity to 

light; seeing spots
- inflammation of the covering of the heart; accumulation of fluid around the heart
- inflammation of the pancreas
- a sore that develops on the inside lining of your stomach or upper part of your small intestine
- inflammation of the liver
- thickened, sometimes scaly, skin growth; inflammation of the skin; hair colour changes; small 

skin bumps, lumps or sores
- inflammation of the sheath that surrounds tendons

 



150

- inflammation of the kidneys
- increased level of amylase, an enzyme that breaks down starch

Rare (may affect up to 1 in 1,000 people)
- inflammation response against platelets or red blood cells; feeling weak, lightheaded, short of 

breath or if your skin looks pale (signs of low level of red blood cells, possibly due to a type of 
anaemia called pure red cell aplasia); a condition called haemophagocytic lymphohistiocytosis, 
where the immune system makes too many infection fighting cells called histiocytes and 
lymphocytes that may cause various symptoms

- inflammation of the brain, which may present as confusion, fever, memory problems or seizures 
(encephalitis)

- a temporary inflammation of the nerves that causes pain, weakness, and paralysis in the 
extremities; a condition in which the muscles become weak and tire easily

- pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems including 
needing to urinate more frequently, urinary incontinence, difficulty urinating and constipation 
(myelitis)

- inflammation of the membrane around the spinal cord and brain, which may present as neck 
stiffness, headache, fever, eye sensitivity to light, nausea or vomiting (meningitis) 

- inflammation of the heart muscle, which may present as shortness of breath, irregular heartbeat, 
feeling tired, or chest pain

- a hole in the small intestines
- tender red bumps under the skin
- itching, skin blistering, peeling or sores, and/or ulcers in mouth or in lining of nose, throat, or 

genital area (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)

The following side effects have been reported in clinical studies with pembrolizumab in combination
with chemotherapy:

Very common (may affect more than 1 in 10 people)
- decrease in the number of red blood cells
- decreased number of white blood cells; decrease in the number of platelets (bruising or bleeding 

more easily)
- decreased potassium in the blood; feeling less hungry 
- dizziness; headache; inflammation of the nerves causing numbness, weakness, tingling or 

burning pain of the arms and legs; change in your sense of taste 
- shortness of breath; cough
- diarrhoea; nausea; vomiting; constipation; stomach pain
- skin rash; itching; hair loss 
- pain in the muscles and bones; joint pain
- unusual tiredness or weakness; swelling; fever
- abnormal kidney function test

Common (may affect up to 1 in 10 people)
- lung infection
- decreased number of white blood cells (neutrophils) with a fever
- reaction related to the infusion of the medicine
- thyroid gland problems 
- decreased sodium or calcium in the blood
- trouble sleeping
- dry eye
- abnormal heart rhythm
- high blood pressure
- inflammation of the lungs
- inflammation of the intestines; dry mouth
- red raised rash, sometimes with blisters

 



151

- muscle pain, aches or tenderness; joint pain with swelling; pain in arms or legs
- inflammation of the kidneys; sudden kidney damage
- chills; flu-like illness
- increased calcium in the blood; increased liver enzyme levels in the blood

Uncommon (may affect up to 1 in 100 people)
- inflammation of the pituitary gland situated at the base of the brain; inflammation of the thyroid; 

decreased secretion of hormones produced by the adrenal glands
- type 1 diabetes
- seizure
- accumulation of fluid around the heart
- inflammation of the pancreas
- a sore that develops on the inside lining of your stomach or upper part of your small intestine
- inflammation of the liver
- thickened, sometimes scaly, skin growth; acne-like skin problem; inflammation of the skin; 

patches of skin that have lost colour
- inflammation of the sheath that surrounds tendons
- increased level of amylase, an enzyme that breaks down starch; increased bilirubin in the blood

Rare (may affect up to 1 in 1,000 people)
- a decreased number of white blood cells (eosinophils)
- inflammation of the heart muscle, which may present as shortness of breath, irregular heartbeat, 

feeling tired, or chest pain; inflammation of the covering of the heart
- hair colour changes; dry, itchy skin; small skin bumps, lumps or sores
- disease in which the immune system attacks the glands that make moisture for the body, such as 

tears and saliva (Sjogren’s syndrome)

The following side effects have been reported in clinical studies with pembrolizumab in combination
with axitinib:

Very common (may affect more than 1 in 10 people)
- thyroid gland problems 
- feeling less hungry
- headache; change in your sense of taste
- high blood pressure
- shortness of breath; cough; hoarseness
- diarrhoea; stomach pain; nausea; vomiting; constipation
- blisters or rash on palms of hands or soles of feet; skin rash; itching
- feeling tired; unusual tiredness or weakness; fever
- increased liver enzyme levels in the blood; abnormal kidney function test
- pain in the muscles and bones; joint or muscle pain, aches or tenderness; pain in arms or legs

Common (may affect up to 1 in 10 people)
- lung infection
- decrease in the number of red blood cells; decreased number of white blood cells (neutrophils, 

leukocytes); decrease in the number of platelets (bruising or bleeding more easily)
- reaction related to the infusion of the medicine
- inflammation of the pituitary gland situated at the base of the brain; inflammation of the thyroid; 

decreased secretion of hormones produced by the adrenal glands 
- decreased potassium, sodium or calcium in the blood
- trouble sleeping
- dizziness; lack of energy; inflammation of the nerves causing numbness, weakness, tingling or 

burning pain of the arms and legs 
- dry eye
- abnormal heart rhythm
- inflammation of the lungs
- inflammation of the intestines; dry mouth

 



152

- red raised rash, sometimes with blisters; acne-like skin problem; inflammation of the skin; dry, 
itchy skin; hair loss 

- inflammation of the liver
- muscle pain, aches or tenderness; joint or muscle pain with swelling; inflammation of the sheath 

that surrounds tendons
- sudden kidney damage; inflammation of the kidneys
- swelling; flu-like illness; chills
- increased calcium in the blood; increased liver enzyme levels in the blood

Uncommon (may affect up to 1 in 100 people)
- decreased number of white blood cells (lymphocytes and eosinophils)
- type 1 diabetes
- a condition in which the muscles become weak and tire easily
- inflammation of the heart muscle, which may present as shortness of breath, irregular heartbeat, 

feeling tired, or chest pain
- inflammation of the eyes; eye pain, irritation, itchiness or redness; uncomfortable sensitivity to 

light; seeing spots
- inflammation of the pancreas
- a sore that develops on the inside lining of your stomach or upper part of your small intestine
- hair colour changes; thickened, sometimes scaly, skin growth; small skin bumps, lumps or 

sores; patches of skin that have lost colour
- increased level of amylase, an enzyme that breaks down starch
- disease in which the immune system attacks the glands that make moisture for the body, such as 

tears and saliva (Sjogren’s syndrome)

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 KEYTRUDA

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 vial label after EXP. 
The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C). 

From a microbiological point of view, the reconstituted or diluted solution should be used 
immediately. The reconstituted or diluted solution must not be frozen. If not used immediately, 
chemical and physical in-use stability of KEYTRUDA has been demonstrated for 96 hours at 2°C to 
8°C. This 96-hour total hold from reconstitution may include up to 6 hours at room temperature (at or 
below 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to come to room 
temperature prior to use.

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 KEYTRUDA contains
The active substance is pembrolizumab. One vial contains 50 mg of pembrolizumab.

After reconstitution, 1 mL of concentrate contains 25 mg of pembrolizumab.

 

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153

The other ingredients are L-histidine, L-histidine hydrochloride monohydrate, sucrose and
polysorbate 80.

What KEYTRUDA looks like and contents of the pack
KEYTRUDA is a white to off-white lyophilised powder.
It is available in cartons containing one glass vial. 

Marketing Authorisation Holder
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

Manufacturer
Schering-Plough Labo NV
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel. + 370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel: +420 233 010 111 
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 
(+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

 



154

Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: +386 1 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

Italia
MSD Italia S.r.l. 
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: + 371 67364224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in 

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

 

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155

The following information is intended for healthcare professionals only:

Preparation and administration
• Prior to reconstitution, the vial of lyophilised powder can be out of refrigeration (temperatures 

at or below 25°C) for up to 24 hours.
• Aseptically add 2.3 mL of water for injections to yield a 25 mg/mL (pH 5.2-5.8) solution of 

KEYTRUDA. Each vial contains an excess fill of 10 mg (0.4 mL) to ensure the recovery of 
50 mg of KEYTRUDA per vial. After reconstitution, 1 mL of concentrate contains 25 mg of 
pembrolizumab.

• To avoid foaming, deliver the water along the walls of the vial and not directly on the 
lyophilised powder.

• Slowly swirl the vial to allow reconstitution of the lyophilised powder. Allow up to 5 minutes 
for the bubbles to clear. Do not shake the vial.

• Parenteral medicinal products should be inspected visually for particulate matter and 
discolouration prior to administration. Reconstituted KEYTRUDA is a clear to slightly 
opalescent, colourless to slightly yellow solution. Discard the vial if visible particles are 
observed.

• Withdraw the required volume up to 2 mL (50 mg) of KEYTRUDA and transfer into an 
intravenous bag containing sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) to 
prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted 
solution by gentle inversion.

• From a microbiological point of view, the reconstituted or diluted solution should be used 
immediately. The reconstituted or diluted solution must not be frozen. If not used immediately, 
chemical and physical in-use stability of KEYTRUDA has been demonstrated for 96 hours at 
2°C to 8°C. This 96-hour total hold from reconstitution may include up to 6 hours at room 
temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must be 
allowed to come to room temperature prior to use. Translucent to white proteinaceous particles 
may be seen in diluted solution. Administer the infusion solution intravenously over 30 minutes 
using a sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line or add-on filter.

• Do not co-administer other medicinal products through the same infusion line.
• KEYTRUDA is for single use only. Discard any unused portion left in the vial.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

 



156

Package leaflet: Information for the patient

KEYTRUDA 25 mg/mL concentrate for solution for infusion
pembrolizumab

Read all of this leaflet carefully before you are given 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 KEYTRUDA is and what it is used for 
2. What you need to know before you are given KEYTRUDA
3. How you are given KEYTRUDA
4. Possible side effects 
5. How to store KEYTRUDA
6. Contents of the pack and other information

1. What KEYTRUDA is and what it is used for

KEYTRUDA contains the active substance pembrolizumab, which is a monoclonal antibody. 
KEYTRUDA works by helping your immune system fight your cancer.

KEYTRUDA is used in adults to treat:
 a kind of skin cancer called melanoma
 a kind of lung cancer called non-small cell lung cancer
 a kind of cancer called classical Hodgkin lymphoma
 a kind of cancer called bladder cancer (urothelial carcinoma)
 a kind of head and neck cancer called head and neck squamous cell carcinoma.
 a kind of kidney cancer called renal cell carcinoma.

People get KEYTRUDA when their cancer has spread or cannot be taken out by surgery.

People get KEYTRUDA after they have had surgery to remove melanoma to help prevent their cancer 
from coming back (adjuvant therapy).

KEYTRUDA may be given in combination with other anti-cancer medicines. It is important that you 
also read the package leaflets for these other medicines. If you have any questions about these 
medicines, ask your doctor.

2. What you need to know before you are given KEYTRUDA

You should not be given KEYTRUDA
- if you are allergic to pembrolizumab 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.

Warnings and precautions 
Talk to your doctor or nurse before receiving KEYTRUDA.

Before you get KEYTRUDA, tell your doctor if you:
- have an autoimmune disease (a condition where the body attacks its own cells)

 



157

- have pneumonia or inflammation of your lungs (called pneumonitis)
- were previously given ipilimumab, another medicine for treating melanoma, and experienced 

serious side effects because of that medicine
- had an allergic reaction to other monoclonal antibody therapies
- have or have had chronic viral infection of the liver, including hepatitis B (HBV) or hepatitis C 

(HCV)
- have human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome 

(AIDS)
- have liver damage
- have kidney damage
- have had a solid organ transplant or a bone marrow (stem cell) transplant that used donor stem 

cells (allogeneic)
-
When you get KEYTRUDA, you can have some serious side effects. These side effects can sometimes 
become life-threatening and can lead to death. These side effects may happen anytime during 
treatment or even after your treatment has ended. You may experience more than one side effect at the 
same time.

If you have any of the following conditions, call or see your doctor right away. Your doctor may give 
you other medicines in order to prevent more severe complications and reduce your symptoms. Your 
doctor may withhold the next dose of KEYTRUDA or stop your treatment with KEYTRUDA.
- inflammation of the lungs, which may include shortness of breath, chest pain or coughing
- inflammation of the intestines, which may include diarrhoea or more bowel movements than 

usual, black, tarry, sticky stools or stools with blood or mucus, severe stomach pain or 
tenderness, nausea, vomiting

- inflammation of the liver, which may include nausea or vomiting, feeling less hungry, pain on 
the right side of stomach, yellowing of skin or whites of eyes, dark urine or bleeding or bruising 
more easily than normal

- inflammation of the kidneys, which may include changes in the amount or colour of your urine
- inflammation of hormone glands (especially the thyroid, pituitary and adrenal glands), which 

may include rapid heartbeat, weight loss, increased sweating, weight gain, hair loss, feeling 
cold, constipation, deeper voice, muscle aches, dizziness or fainting, headaches that will not go 
away or unusual headache

- type 1 diabetes, which may include feeling more hungry or thirsty than usual, need to urinate 
more often or weight loss

- inflammation of the eyes, which may include changes in eyesight
- inflammation in the muscles, which may include muscle pain or weakness
- inflammation of the heart muscle, which may include shortness of breath, irregular heartbeat, 

feeling tired, or chest pain
- inflammation of the pancreas, which may include abdominal pain, nausea and vomiting
- inflammation of the skin, which may include rash, itching, skin blistering, peeling or sores, 

and/or ulcers in mouth or in lining of nose, throat, or genital area 
- an immune disorder that can affect the lungs, skin, eyes and/or lymph nodes (sarcoidosis)
- inflammation of the brain, which may include confusion, fever, memory problems or seizures 

(encephalitis)
- pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems including 

needing to urinate more frequently, urinary incontinence, difficulty urinating and constipation 
(myelitis)

- infusion reactions, which may include shortness of breath, itching or rash, dizziness or fever

Complications, including graft-versus-host-disease (GVHD), in people with bone marrow (stem 
cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can 
lead to death. They may occur if you had this kind of transplant in the past or if you get it in the future. 
Your doctor will monitor you for signs and symptoms, which may include skin rash, liver 
inflammation, abdominal pain, or diarrhoea.

 



158

Children and adolescents
KEYTRUDA should not be used in children and adolescents below 18 years of age.

Other medicines and KEYTRUDA
Tell your doctor 
- If you are taking other medicines that make your immune system weak. Examples of these may 

include corticosteroids, such as prednisone. These medicines may interfere with the effect of 
KEYTRUDA. However, once you are treated with KEYTRUDA, your doctor may give you 
corticosteroids to reduce the side-effects that you may have with KEYTRUDA. Corticosteroids 
may also be given to you before receiving KEYTRUDA in combination with chemotherapy to 
prevent and/or treat nausea, vomiting, and other side effects caused by chemotherapy.

- If you are taking, have recently taken or might take any other medicines.

Pregnancy
- You must not use KEYTRUDA if you are pregnant unless your doctor specifically recommends 

it.
- If you are pregnant, think you may be pregnant or are planning to have a baby, tell your doctor.
- KEYTRUDA can cause harm or death to your unborn baby.
- If you are a woman who could become pregnant, you must use adequate birth control while you 

are being treated with KEYTRUDA and for at least 4 months after your last dose.

Breast-feeding
- If you are breast-feeding, tell your doctor.
- Do not breast-feed while taking KEYTRUDA.
- It is not known if KEYTRUDA passes into your breast milk.

Driving and using machines
KEYTRUDA has a minor effect on your ability to drive or use machines. Feeling dizzy, tired or weak 
are possible side effects of KEYTRUDA. Do not drive or use machines after you have been given 
KEYTRUDA unless you are sure you are feeling well.

3. How you are given KEYTRUDA

KEYTRUDA will be given to you in a hospital or clinic under the supervision of a doctor experienced 
in cancer treatment.
- The recommended dose of KEYTRUDA is either 200 mg every 3 weeks or 400 mg every 

6 weeks.
- Your doctor will give you KEYTRUDA through an infusion into your vein (intravenous) for 

about 30 minutes.
- Your doctor will decide how many treatments you need.

If you miss an appointment to get KEYTRUDA
- Call your doctor right away to reschedule your appointment.
- It is very important that you do not miss a dose of this medicine.

If you stop receiving KEYTRUDA
Stopping your treatment may stop the effect of the medicine. Do not stop treatment with KEYTRUDA 
unless you have discussed this with your doctor.

If you have any further questions about your treatment, ask your doctor.

You will also find this information in the patient alert card you have been given by your doctor. It is 
important that you keep this alert card and show it to your partner or caregivers.

 



159

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

When you get KEYTRUDA, you can have some serious side effects. See section 2.

The following side effects have been reported with pembrolizumab alone:

Very common (may affect more than 1 in 10 people)
- decrease in the number of red blood cells
- reduced thyroid gland activity
- feeling less hungry
- headache
- shortness of breath; cough
- diarrhoea; stomach pain; nausea; vomiting; constipation
- itching; skin rash
- pain in muscle and bones; joint pain
- feeling tired; unusual tiredness or weakness; swelling; fever

Common (may affect up to 1 in 10 people)
- lung infection
- decrease in the number of platelets (bruising or bleeding more easily); decrease in the number of 

white blood cell (lymphocytes)
- reactions related to the infusion of the medicine
- overactive thyroid gland activity; hot flush
- decreased sodium, potassium, or calcium in the blood
- trouble sleeping
- dizziness; inflammation of the nerves causing numbness, weakness, tingling or burning pain of 

the arms and legs; lack of energy; change in your sense of taste
- dry eye
- abnormal heart rhythm
- high blood pressure
- inflammation of the lungs
- inflammation of the intestines; dry mouth
- red raised rash sometimes with blisters; patches of skin which have lost colour; dry, itchy skin; 

hair loss; acne-like skin problem
- muscle pain, aches or tenderness; pain in arms or legs; joint pain with swelling
- chills; flu-like illness
- increased liver enzyme levels in the blood; increased calcium in the blood; abnormal kidney 

function test

Uncommon (may affect up to 1 in 100 people)
- a decreased number of white blood cells (neutrophils, leukocytes, and eosinophils)
- an immune disorder that can affect the lungs, skin, eyes and/or lymph nodes (sarcoidosis)
- inflammation of the pituitary gland situated at the base of the brain; decreased secretion of 

hormones produced by the adrenal glands; inflammation of the thyroid
- type 1 diabetes
- seizure
- inflammation of the eyes; eye pain, irritation, itchiness or redness; uncomfortable sensitivity to 

light; seeing spots
- inflammation of the covering of the heart; accumulation of fluid around the heart
- inflammation of the pancreas
- a sore that develops on the inside lining of your stomach or upper part of your small intestine
- inflammation of the liver
- thickened, sometimes scaly, skin growth; inflammation of the skin; hair colour changes; small 

skin bumps, lumps or sores
- inflammation of the sheath that surrounds tendons

 



160

- inflammation of the kidneys
- increased level of amylase, an enzyme that breaks down starch

Rare (may affect up to 1 in 1,000 people)
- inflammation response against platelets or red blood cells; feeling weak, lightheaded, short of 

breath or if your skin looks pale (signs of low level of red blood cells, possibly due to a type of 
anaemia called pure red cell aplasia); a condition called haemophagocytic lymphohistiocytosis, 
where the immune system makes too many infection fighting cells called histiocytes and 
lymphocytes that may cause various symptoms

- inflammation of the brain, which may present as confusion, fever, memory problems or seizures 
(encephalitis)

- a temporary inflammation of the nerves that causes pain, weakness, and paralysis in the 
extremities; a condition in which the muscles become weak and tire easily

- pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems including 
needing to urinate more frequently, urinary incontinence, difficulty urinating and constipation 
(myelitis)

- inflammation of the membrane around the spinal cord and brain, which may present as neck 
stiffness, headache, fever, eye sensitivity to light, nausea or vomiting (meningitis) 

- inflammation of the heart muscle, which may present as shortness of breath, irregular heartbeat, 
feeling tired, or chest pain

- a hole in the small intestines
- tender red bumps under the skin
- itching, skin blistering, peeling or sores, and/or ulcers in mouth or in lining of nose, throat, or 

genital area (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)

The following side effects have been reported in clinical studies with pembrolizumab in combination
with chemotherapy:

Very common (may affect more than 1 in 10 people)
- decrease in the number of red blood cells
- decreased number of white blood cells; decrease in the number of platelets (bruising or bleeding 

more easily)
- decreased potassium in the blood; feeling less hungry 
- dizziness; headache; inflammation of the nerves causing numbness, weakness, tingling or 

burning pain of the arms and legs; change in your sense of taste 
- shortness of breath; cough
- diarrhoea; nausea; vomiting; constipation; stomach pain
- skin rash; itching; hair loss 
- pain in the muscles and bones; joint pain
- unusual tiredness or weakness; swelling; fever
- abnormal kidney function test

Common (may affect up to 1 in 10 people)
- lung infection
- decreased number of white blood cells (neutrophils) with a fever
- reaction related to the infusion of the medicine
- thyroid gland problems 
- decreased sodium or calcium in the blood
- trouble sleeping
- dry eye
- abnormal heart rhythm
- high blood pressure
- inflammation of the lungs
- inflammation of the intestines; dry mouth
- red raised rash, sometimes with blisters

 



161

- muscle pain, aches or tenderness; joint pain with swelling; pain in arms or legs
- inflammation of the kidneys; sudden kidney damage
- chills; flu-like illness
- increased calcium in the blood; increased liver enzyme levels in the blood

Uncommon (may affect up to 1 in 100 people)
- inflammation of the pituitary gland situated at the base of the brain; inflammation of the thyroid; 

decreased secretion of hormones produced by the adrenal glands
- type 1 diabetes
- seizure
- accumulation of fluid around the heart
- inflammation of the pancreas
- a sore that develops on the inside lining of your stomach or upper part of your small intestine
- inflammation of the liver
- thickened, sometimes scaly, skin growth; acne-like skin problem; inflammation of the skin; 

patches of skin that have lost colour
- inflammation of the sheath that surrounds tendons
- increased level of amylase, an enzyme that breaks down starch; increased bilirubin in the blood

Rare (may affect up to 1 in 1,000 people)
- a decreased number of white blood cells (eosinophils)
- inflammation of the heart muscle, which may present as shortness of breath, irregular heartbeat, 

feeling tired, or chest pain; inflammation of the covering of the heart
- hair colour changes; dry, itchy skin; small skin bumps, lumps or sores
- disease in which the immune system attacks the glands that make moisture for the body, such as 

tears and saliva (Sjogren’s syndrome)

The following side effects have been reported in clinical studies with pembrolizumab in combination
with axitinib:

Very common (may affect more than 1 in 10 people)
- thyroid gland problems 
- feeling less hungry
- headache; change in your sense of taste
- high blood pressure
- shortness of breath; cough; hoarseness
- diarrhoea; stomach pain; nausea; vomiting; constipation
- blisters or rash on palms of hands or soles of feet; skin rash; itching
- feeling tired; unusual tiredness or weakness; fever
- increased liver enzyme levels in the blood; abnormal kidney function test
- pain in the muscles and bones; joint or muscle pain, aches or tenderness; pain in arms or legs

Common (may affect up to 1 in 10 people)
- lung infection
- decrease in the number of red blood cells; decreased number of white blood cells (neutrophils, 

leukocytes); decrease in the number of platelets (bruising or bleeding more easily)
- reaction related to the infusion of the medicine
- inflammation of the pituitary gland situated at the base of the brain; inflammation of the thyroid; 

decreased secretion of hormones produced by the adrenal glands 
- decreased potassium, sodium or calcium in the blood
- trouble sleeping
- dizziness; lack of energy; inflammation of the nerves causing numbness, weakness, tingling or 

burning pain of the arms and legs 
- dry eye
- abnormal heart rhythm
- inflammation of the lungs
- inflammation of the intestines; dry mouth

 



162

- red raised rash, sometimes with blisters; acne-like skin problem; inflammation of the skin; dry, 
itchy skin; hair loss

- inflammation of the liver
- muscle pain, aches or tenderness; joint or muscle pain with swelling; inflammation of the sheath 

that surrounds tendons
- sudden kidney damage; inflammation of the kidneys
- swelling; flu-like illness; chills
- increased calcium in the blood; increased liver enzyme levels in the blood

Uncommon (may affect up to 1 in 100 people)
- decreased number of white blood cells (lymphocytes and eosinophils)
- type 1 diabetes
- a condition in which the muscles become weak and tire easily
- inflammation of the heart muscle, which may present as shortness of breath, irregular heartbeat, 

feeling tired, or chest pain
- inflammation of the eyes; eye pain, irritation, itchiness or redness; uncomfortable sensitivity to 

light; seeing spots
- inflammation of the pancreas
- a sore that develops on the inside lining of your stomach or upper part of your small intestine
- hair colour changes; thickened, sometimes scaly, skin growth; small skin bumps, lumps or 

sores; patches of skin that have lost colour
- increased level of amylase, an enzyme that breaks down starch
- disease in which the immune system attacks the glands that make moisture for the body, such as 

tears and saliva (Sjogren’s syndrome)

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 KEYTRUDA

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 vial label after EXP. 
The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original carton in order to protect from light.

From a microbiological point of view, the product, once diluted, should be used immediately. The 
diluted solution must not be frozen. If not used immediately, chemical and physical in-use stability of 
KEYTRUDA has been demonstrated for 96 hours at 2ºC to 8ºC. This 96-hour hold may include up to 
6 hours at room temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must 
be allowed to come to room temperature prior to use.

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 KEYTRUDA contains
The active substance is pembrolizumab. 

 

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163

One vial of 4 mL contains 100 mg of pembrolizumab.
Each mL of concentrate contains 25 mg of pembrolizumab.

The other ingredients are L-histidine, L-histidine hydrochloride monohydrate, sucrose, polysorbate 80
and water for injections.

What KEYTRUDA looks like and contents of the pack
KEYTRUDA is a clear to slightly opalescent, colourless to slightly yellow solution, pH 5.2 – 5.8.
It is available in cartons containing one glass vial. 

Marketing Authorisation Holder
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

Manufacturer
Schering-Plough Labo NV
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

Merck Sharp & Dohme B.V. 
Waarderweg 39
2031 BN Haarlem
The Netherlands

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel. + 370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel: +420 233 010 111 
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 
(+31 23 5153153)
medicalinfo.nl@merck.com

 



164

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: +386 1 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

Italia
MSD Italia S.r.l. 
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: + 371 67364224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in 

 



165

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

 

http://www.ema.europa.eu/


166

The following information is intended for healthcare professionals only:

Preparation and administration of the infusion
• Do not shake the vial. 
• Equilibrate the vial to room temperature (at or below 25°C).
• Prior to dilution, the vial of liquid can be out of refrigeration (temperatures at or below 25°C) 

for up to 24 hours.
• Parenteral medicinal products should be inspected visually for particulate matter and 

discolouration prior to administration. The concentrate is a clear to slightly opalescent, 
colourless to slightly yellow solution. Discard the vial if visible particles are observed.

• Withdraw the required volume up to 4 mL (100 mg) of concentrate and transfer into an 
intravenous bag containing sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) to 
prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Each vial 
contains an excess fill of 0.25 mL (total content per vial 4.25 mL) to ensure the recovery of 
4 mL of concentrate. Mix diluted solution by gentle inversion.

• From a microbiological point of view, the product, once diluted, should be used immediately. 
The diluted solution must not be frozen. If not used immediately, chemical and physical in-use 
stability of KEYTRUDA has been demonstrated for 96 hours at 2ºC to 8ºC. This 96-hour hold 
may include up to 6 hours at room temperature (at or below 25°C). If refrigerated, the vials 
and/or intravenous bags must be allowed to come to room temperature prior to use. Translucent 
to white proteinaceous particles may be seen in diluted solution. Administer the infusion 
solution intravenously over 30 minutes using a sterile, non-pyrogenic, low-protein binding 0.2 
to 5 µm in-line or add-on filter.

• Do not co-administer other medicinal products through the same infusion line.
• KEYTRUDA is for single use only. Discard any unused portion left in the vial.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	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
	A. LABELLING
	B. PACKAGE LEAFLET