Click on one of the following links to immediately go to the full article: article in NL, article in FR.
The new 5-year data from the KEYNOTE-024 study demonstrate unequivocally that immunotherapy with pembrolizumab is superior to platinum-based chemotherapy in patients with metastatic NSCLC who have a PD-L1 TPS of 50% or greater and no EGFR/ALK alterations. These results are likely to change the way we treat patients: they entail almost double the overall survival rate, significant improved progression-free survival, a response period almost 5 times as long with a favorable safety profile and a maintained quality of life. These data enable us to look 5 years back in time, which is unseen before in NSCLC. Prof. Dr. Johan Vansteenkiste explains that “we are now seeing results in KEYNOTE-024 that nobody could have imagined in 2014. That’s how impressive they are. It is unprecedented, to have one third of the patients still alive after five years.”
Figure 1. Kaplan-Meier estimates of 5-year OS in the pembrolizumab group vs. the chemotherapy group.
During this interview, Prof. Dr. Johan Vansteenkiste is looking five years back in time to explain the rationale behind KEYNOTE-024 and how this study started to change the survival outcomes for metastatic NSCLC patients who have a PD-L1 TPS ≥ 50% and no EGFR/ALK alterations. Next to highlighting the most important long-term survival data from this study, he also explains how these data change the communication with the patients and that new perspectives can be offered.
Continue reading: the full article in NL or the full article in FR.
Reference: Reck M, et al. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021 Jul 20;39(21):2339-2349.
Abbreviations: ALK = Anaplastic Lymphoma Kinase; CI = Confidence Interval; EGFR = Epithelial Growth Factor Receptor; HR = Hazard Ratio; mo = months; n = number; NSCLC = Non-Small Cell Lung Cancer; OS = Overall Survival; PD-L1 TPS = Programmed Death Ligand 1 Tumor Proportion Score
BE-LAM-00089 | Date of last revision: 11/2021.
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 and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option. 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). Colorectal cancer (CRC) KEYTRUDA as monotherapy is indicated for the first‑line treatment of metastatic microsatellite instability‑high (MSI‑H) or mismatch repair deficient (dMMR) colorectal cancer in adults. Oesophageal carcinoma KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a CPS ≥ 10 (see section 5.1). Triple‑negative breast cancer (TNBC) KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple‑negative breast cancer in adults whose tumours express PD‑L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease (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 If specified in the indication, patient selection for treatment with KEYTRUDA based on the tumour expression of PD-L1 should be confirmed by a validated test (see sections 4.1, 4.4, 4.8, and 5.1). MSI‑H/dMMR testing for patients with CRC For treatment with KEYTRUDA as monotherapy, testing for MSI‑H/dMMR tumour status using a validated test is recommended to select patients with CRC (see sections 4.1 and 5.1). Posology The recommended dose of KEYTRUDA in adults 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 monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (bw) (up to a maximum of 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. 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); Other immune-related adverse reactions: Based on severity and type of reaction (Grade 2 or Grade 3) (Withhold until adverse reactions recover to Grades 0-1*), Grades 3 or 4 myocarditis or Grades 3 or 4 encephalitis or Grades 3 or 4 Guillain-Barré syndrome (Permanently discontinue), Grade 4 or recurrent Grade 3 (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 sections 4.4 and 5.1). 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 been established except in paediatric patients with cHL. Currently available data are described in sections 4.8, 5.1 and 5.2. Method of administrationKEYTRUDA 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. 4.8 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 6,185 patients with advanced melanoma, resected Stage III melanoma (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, HNSCC, or CRC across four doses (2 mg/kg bw every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg bw 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 7.6 months (range: 1 day to 47 months) and the most frequent adverse reactions with pembrolizumab were fatigue (32%), nausea (21%), and diarrhoea (21%). 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 2,033 patients with NSCLC, HNSCC, oesophageal carcinoma or TNBC receiving 200mg, 2mg/kg bw or 10mg/kg bw 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 (52%), nausea (52%), fatigue (37%), constipation (34%), neutropenia (33%), diarrhoea (32%), decreased appetite (30%), and vomiting (28%). Incidences of Grades 3‑5 adverse reactions in patients with NSCLC were 67% for pembrolizumab combination therapy and 66% for chemotherapy alone, in patients with HNSCC were 85% for pembrolizumab combination therapy and 84% for chemotherapy plus cetuximab, and in patients with oesophageal carcinoma were 86% for pembrolizumab combination therapy and 83% for chemotherapy alone, and in patients with TNBC were 78% for pembrolizumab combination therapy and 74% for chemotherapy alone. 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*: Infections and infestationsMonotherapy:Common: pneumonia, Combination with chemotherapy:Very Common: pneumonia, Combination with axitinib: Common: pneumonia. Blood and lymphatic system disorders Monotherapy:Very Common: anaemia; Common: thrombocytopenia, neutropenia, lymphopenia; Uncommon: leukopenia, eosinophilia; Rare: immune thrombocytopenia, haemolytic anaemia, pure red cell aplasia, haemophagocytic lymphohistiocytosis, Combination with chemotherapy:Very Common:neutropenia, anaemia,thrombocytopenia, leukopenia; Common: febrile neutropenia, lymphopenia; Uncommon: eosinophilia, Combination with axitinib: Common: anaemia, neutropenia, leukopenia, thrombocytopenia; Uncommon: lymphopenia, eosinophilia. Immune system disorders Monotherapy:Common: infusion-related reactiona; Uncommon: sarcoidosis; Not known: solid organ transplant rejection, Combination with chemotherapy:Common: infusion-related reactiona, Combination with axitinib: Common: infusion-related reactiona. Endocrine disorders Monotherapy: Very Common: hypothyroidismb; Common: hyperthyroidism, thyroiditisc; Uncommon: adrenal insufficiencye, hypophysitisf, Combination with chemotherapy:Very Common: hypothyroidism, Common:hyperthyroidismd; Uncommon: adrenal insufficiencye, hypophysitisf, thyroiditisc, Combination with axitinib: Very common: hyperthyroidism, hypothyroidismb; Common: hypophysitisf, thyroiditisc, adrenal insufficiencye. Metabolism and nutrition disorders Monotherapy: Very Common: decreased appetite; Common: hyponatraemia, hypokalaemia, hypocalcaemia; Uncommon: type 1 diabetes mellitusg, Combination with chemotherapy:Very common: hypokalaemia, decreased appetite; Common: hyponatraemia, hypocalcaemia; Uncommon: type 1 diabetes mellitus, Combination with axitinib: Very common: decreased appetite; Common: hypokalaemia, hyponatraemia, hypocalcaemia; Uncommon: type 1 diabetes mellitusg. Psychiatric disorders Monotherapy: Common: insomnia, Combination with chemotherapy:Very Common: insomnia, Combination with axitinib: Common: insomnia. Nervous system disorders Monotherapy: Very Common: headache; Common: dizziness, neuropathy peripheral, lethargy, dysgeusia; Uncommon: epilepsy; Rare: encephalitish, Guillain-Barré syndromei, myelitisj, myasthenic syndromek, meningitis (aseptic)l, Combination with chemotherapy:Very common: neuropathy peripheral, headache, dizziness; Common: lethargy, dysgeusia; Uncommon: epilepsy; Rare: encephalitis, Guillain-Barré Syndromei, Combination with axitinib: Very common: headache, dysgeusia; Common: dizziness, lethargy, neuropathy peripheral; Uncommon: myasthenic syndromek. Eye disorders Monotherapy: Common: dry eye; Uncommon: uveitism; Rare: Vogt-Koyanagi-Harada syndrome, Combination with chemotherapy:Common: dry eye;Rare: uveitism, Combination with axitinib: Common: dry eye; Uncommon: uveitism. Cardiac disorders Monotherapy:Common:cardiac arrhythmia† (including atrial fibrillation); Uncommon: myocarditis, pericardial effusion, pericarditis, Combination with chemotherapy:Common:cardiac arrhythmia† (including atrial fibrillation); Uncommon: myocarditisn, pericardial effusion, pericarditis, Combination with axitinib: Common: cardiac arrhythmia† (including atrial fibrillation); Uncommon: myocarditis. Vascular disorders Monotherapy: Common: hypertension; Rare: vasculitis, Combination with chemotherapy:Common: hypertension; Uncommon: vasculitiso, Combination with axitinib: Very common: hypertension. Respiratory, thoracic and mediastinal disorders Monotherapy: Very Common: dyspnoea, cough; Common: pneumonitisp, Combination with chemotherapy:Very common: dyspnoea, cough;Common: pneumonitisp, Combination with axitinib: Very common: dyspnoea, cough, dysphonia; Common: pneumonitisp. Gastrointestinal disorders Monotherapy: Very common: diarrhoea, abdominal painq, nausea, vomiting, constipation; Common: colitisr, dry mouth; Uncommon: pancreatitiss, gastritis, gastrointestinal ulcerationr; Rare: small intestinal perforation, Combination with chemotherapy: Very common: nausea, vomiting, diarrhoea, abdominal painq, constipation; Common: colitisr, dry mouth, gastritis; Uncommon: pancreatitiss, gastrointestinal ulcerationt, Combination with axitinib: Very Common: diarrhoea, abdominal painq, nausea, vomiting, constipation; Common: colitisr, dry mouth, gastritis;Uncommon: pancreatitiss, gastrointestinal ulcerationt. Hepatobiliary disorders Monotherapy: Uncommon: hepatitisu; Rare: cholangitis sclerosing, Combination with chemotherapy: Uncommon: hepatitisu, Rare: cholangitis sclerosing,Combination with axitinib: Common: hepatitisu. Skin and subcutaneous tissue disorders Monotherapy: Very common: rashv, pruritusw; Common: severe skin reactionsx, erythema, dermatitis, dry skin, vitiligoy, eczema, alopecia, dermatitis acneiform; Uncommon: psoriasis, lichenoid keratosisz, papule, hair colour changes; Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema nodosum, Combination with chemotherapy: Very common: alopecia, rashv, pruritusw; Common: severe skin reactionsx, erythema, dermatitis, dry skin; Uncommon: psoriasis, eczema, lichenoid keratosis, dermatitis acneiform, vitiligoy; Rare: erythema nodosum, papule, hair colour changes, Combination with axitinib: Very common: palmar-plantar erythrodysaesthesia syndrome, rashv, pruritusw; Common: severe skin reactionsx, dermatitis acneiform, dermatitis, dry skin, alopecia, eczema, erythema; Uncommon: hair colour changes, lichenoid keratosis, papule, psoriasis, vitiligoy. Musculoskeletal and connective tissue disorders Monotherapy: Very Common: musculoskeletal painaa, arthralgia; Common: pain in extremity, myositisbb, arthritiscc Uncommon: tenosynovitisdd; Rare: Sjogren’s syndrome, Combination with chemotherapy:Very Common: musculoskeletal painaa, arthralgia;Common: myositisbb, pain in extremity, arthritiscc; Uncommon: tenosynovitisdd; Rare: Sjogren’s syndrome, Combination with axitinib: Very common: musculoskeletal painaa, arthralgia, pain in extremity; Common: myositisbb, arthritiscc, tenosynovitisdd; Uncommon: Sjogren’s syndrome. Renal and urinary disorders Monotherapy: Uncommon: nephritisee; Rare: cystitis noninfective, Combination with chemotherapy: Common: acute kidney injury; Uncommon: nephritiscc, Combination with axitinib: Common: acute kidney injury, nephritisee. General disorders and administration site conditions Monotherapy:Very common: fatigue, asthenia, oedemaff, pyrexia; Common: influenza like illness, chills, Combination with chemotherapy:Very common: fatigue, asthenia, pyrexia, oedemaff; Common: influenza like illness, chills, Combination with axitinib: Very common: fatigue, asthenia, pyrexia, Common: oedemaff, influenza like illness, chills. Investigations Monotherapy:Common: aspartate aminotransferase increased, alanine aminotransferase increased, hypercalcaemia, blood alkaline phosphatase increased, blood bilirubin increased, blood creatinine increased; Uncommon: amylase increased, Combination with chemotherapy:Very common: alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased; Common: hypercalcaemia, blood alkaline phosphatase increased, blood bilirubin increased; Uncommon: amylase increased, Combination with axitinib: Very common: alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased; Common: blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased;Uncommon: 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. 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. thyroiditis (autoimmune thyroiditis, thyroid disorder and thyroiditis acute); d. hyperthyroidism (Basedow’s disease); e. adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency); f. hypophysitis (hypopituitarism); g. type 1 diabetes mellitus (diabetic ketoacidosis); h. encephalitis (autoimmune encephalitis); i. Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy); j. myelitis (including transverse myelitis); k. myasthenic syndrome (myasthenia gravis, including exacerbation); l. meningitis aseptic (meningitis, meningitis non-infective); m. uveitis (chorioretinitis, iritis and iridocyclitis); n. myocarditis (autoimmune myocarditis); o. vasculitis (central nervous system vasculitis); p. pneumonitis (interstitial lung disease and organising pneumonia); q. abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower); r. colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, autoimmune colitis, and immune-mediated enterocolitis); s. pancreatitis (autoimmune pancreatitis and pancreatitis acute); t. gastrointestinal ulceration (gastric ulcer and duodenal ulcer); u. hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis); v. rash (rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash); w. pruritus (urticaria, urticaria papular and pruritus genital); x. severe skin reactions (dermatitis bullous, dermatitis exfoliative generalised, exfoliative rash, pemphigus, and Grade ≥ 3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis exfoliative, dermatitis psoriasiform, drug eruption, erythema multiforme, jaundice, lichen planus, oral lichen planus, pemphigoid, pruritus, pruritus genital, rash, rash erythematous, rash maculo‑papular, rash pruritic, rash pustular, skin lesion, skin necrosis and toxic skin eruption); y. vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid); z. lichenoid keratosis (lichen planus and lichen sclerosus); aa. musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis); bb. myositis (myalgia, myopathy, necrotising myositis, polymyalgia rheumatica and rhabdomyolysis); cc. arthritis (joint swelling, polyarthritis and joint effusion); dd. tenosynovitis (tendonitis, synovitis and tendon pain); ee. nephritis (autoimmune nephritis, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis and glomerulonephritis membranous); ff. 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 bw every 3 weeks, 10 mg/kg bw 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 286 (4.6%) patients, including Grade 2, 3, 4 or 5 cases in 128 (2.1%), 73 (1.2%), 17 (0.3%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.5 months (range 2 days to 26.7 months). The median duration was 2.0 months (range 1 day to 33.0+ months). Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.2%) than in patients who did not receive prior thoracic radiation (4.2%). Pneumonitis led to discontinuation of pembrolizumab in 117 (1.9%) patients. Pneumonitis resolved in 166 patients, 4 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. In patients with cHL, the incidence of pneumonitis (all Grades) ranged from 5.2% to 10.8% for cHL patients in KEYNOTE-087 (n=210) and KEYNOTE-204 (n=148), respectively. Immune-related colitis Colitis occurred in 121 (2.0%) patients, including Grade 2, 3 or 4 cases in 35 (0.6%), 67 (1.1%) and 5 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 4.7 months (range 7 days to 24.3 months). The median duration was 1.0 month (range 1 day to 12.4 months). Colitis led to discontinuation of pembrolizumab in 34 (0.5%) patients. Colitis resolved in 99 patients, 2 with sequelae.In patients with CRC treated with pembrolizumab as monotherapy (n=153), the incidence of colitis was 6.5% (all Grades) with 2.0% Grade 3 and 1.3% Grade 4. Immune-related hepatitisHepatitis occurred in 61 (1.0%) patients, including Grade 2, 3 or 4 cases in 8 (0.1%), 41 (0.7%) and 8 ( 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 3.8 months (range 8 days to 26.3 months). The median duration was 1.1 months (range 1 day to 20.9+ months). Hepatitis led to discontinuation of pembrolizumab in 24 (0.4%) patients. Hepatitis resolved in 46 patients.Immune-related nephritis Nephritis occurred in 25 (0.4%) patients, including Grade 2, 3 or 4 cases in 5 (0.1%), 15 (0.2%) and 2 (< 0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset of nephritis was 5.1 months (range 12 days to 21.4 months). The median duration was 3.3 months (range 6 days to 19.6 months). Nephritis led to discontinuation of pembrolizumab in 10 (0.2%) patients. Nephritis resolved in 15 patients, 4 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 endocrinopathiesAdrenal insufficiency occurred in 52 (0.8%) patients, including Grade 2, 3 or 4 cases in 23 (0.4%), 21 (0.3%) and 4 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of adrenal insufficiency was 5.5 months (range 1 day to 23.7 months). The median duration was not reached (range 3 days to 32.4+ months). Adrenal insufficiency led to discontinuation of pembrolizumab in 5 (0.1%) patients. Adrenal insufficiency resolved in 18 patients, 5 with sequelae. Hypophysitis occurred in 38 (0.6%) patients, including Grade 2, 3 or 4 cases in 15 (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 3.6 months (range 3 days to 30.4+ months). Hypophysitis led to discontinuation of pembrolizumab in 9 (0.1%) patients. Hypophysitis resolved in 17 patients, 8 with sequelae. Hyperthyroidism occurred in 261 (4.2%) patients, including Grade 2 or 3 cases in 64 (1.0%) and 7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 23.2 months). The median duration was 1.8 months (range 4 days to 27.6+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 3 (<0.1%) patients. Hyperthyroidism resolved in 207 (79.3%) patients, 5 with sequelae. Hypothyroidism occurred in 699 (11.3%) patients, including Grade 2 or 3 cases in 510 (8.2%) and 7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.4 months (range 1 day to 25.9 months). The median duration was not reached (range 2 days to 53.9+ months). Two patients (< 0.1%) discontinued pembrolizumab due to hypothyroidism. Hypothyroidism resolved in 171 (24.5%) patients, 14 with sequelae. In patients with cHL (n=389) the incidence of hypothyroidism was 17%, all of which were Grade 1 or 2. 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 102 (1.6%) patients, including Grade 2, 3 or 5 cases in 11 (0.2%), 77 (1.2%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin reactions was 3.5 months (range 3 days to 25.5 months). The median duration was 1.9 months (range 1 day to 33.0+ months). Severe skin reactions led to discontinuation of pembrolizumab in 13 (0.2%) patients. Severe skin reactions resolved in 71 patients, 1 with sequelae. 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 14 patients in KEYNOTE‑013 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 6 patients reported acute GVHD and 1 patient reported chronic GVHD, none of which were fatal. Two patients experienced hepatic VOD, one of which was fatal. One patient experienced engraftment syndrome post-transplant. Of 32 patients in KEYNOTE‑087 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 16 patients reported acute GVHD and 7 patients reported chronic GVHD, two of which were fatal. No patients experienced hepatic VOD. No patients experienced engraftment syndrome post-transplant. Of 14 patients in KEYNOTE‑204 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 8 patients reported acute GVHD and 3 patients reported chronic GVHD, none of which were fatal. No patients experienced hepatic VOD. One patient experienced engraftment syndrome post-transplant. 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: 10.8% for lymphocytes decreased, 8.3% for sodium decreased, 6.4% for haemoglobin decreased, 5.4% for phosphate decreased, 5.0% for glucose increased, 3.1% for AST increased, 3.0% for ALT increased, 2.7% for alkaline phosphatase increased, 2.4% for potassium decreased, 2.1% for neutrophils decreased, 2.0% for platelets decreased, 1.9% for calcium increased, 1.9% for potassium increased, 1.9% for bilirubin increased, 1.6% for albumin decreased, 1.5% for calcium decreased, 1.5% for creatinine increased, 0.9% 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: 37.7% for neutrophils decreased, 25.8% for lymphocytes decreased, 25.2% for leucocytes decreased, 20.3% for haemoglobin decreased, 13.3% for platelets decreased, 11.3% for sodium decreased, 8.9% for phosphate decreased, 7.2% for potassium decreased, 6.7% for glucose increased, 5.8% for ALT increased, 5.4% for AST increased, 3.6% for calcium decreased, 3.4% for potassium increased, 2.8% for albumin decreased, 2.7% for creatinine increased, 2.3% for alkaline phosphatase increased, 1.9% for bilirubin increased, 1.7% for calcium increased, 1.0% for glucose decreased, and 0.6% for sodium increased, and 0.1% for haemoglobin 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 bw every three weeks, 200 mg every three weeks, or 10 mg/kg bw 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 pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody development. Paediatric population The safety of pembrolizumab as monotherapy has been evaluated in 161 paediatric patients aged 9 months to 17 years with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours at 2 mg/kg bw every 3 weeks in the Phase I/II study KEYNOTE-051. The cHL population (n=22) included patients 11 to 17 years of age. The safety profile in 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 (33%), vomiting (30%), headache (26%), abdominal pain (22%), anaemia (21%), cough (21%) and constipation (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. Seventy-six (47.2%) patients had 1 or more Grades 3 to 5 adverse reactions of which 5 (3.1%) 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: in Belgium: Agence Fédérale des Médicaments et des Produits de Santé. Division Vigilance. Boîte Postale 97, B-1000 Brussels Madou. Website: www.notifieruneffetindesirable.be, e-mail: adr@afmps.be, in Luxembourg: Centre Régional de Pharmacovigilance de Nancy -Bâtiment de Biologie Moléculaire et de Biopathologie (BBB) – CHRU de Nancy – Hôpitaux de Brabois, Rue du Morvan 54, 511 VANDOEUVRE LES NANCY CEDEX, Tél : (+33) 3 83 65 60 85 / 87, E-mail : crpv@chru-nancy.fr ou Direction de la Santé – Division de la Pharmacie et des Médicaments, 20, rue de Bitbourg. L-1273 Luxembourg-Hamm, Tél. : (+352) 2478 5592, E-mail : pharmacovigilance@ms.etat.lu Lien pour le formulaire https://guichet.public.lu/fr/entreprises/sectoriel/sante/medecins/notification-effets-indesirables-medicaments.html. 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 10/2021. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. DELIVERY: on medical prescription.
