Active Ingredient: Pembrolizumab
Pembrolizumab as monotherapy is indicated for the treatment of adults and adolescents aged 12 years and older with advanced (unresectable or metastatic) melanoma.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Regimen A: Intravenous, 200 milligrams pembrolizumab, once every 3 weeks.
Regimen B: Intravenous, 400 milligrams pembrolizumab, once every 6 weeks.
The recommended dose of pembrolizumab in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes.
Patients should be treated with pembrolizumab until disease progression or unacceptable toxicity (and up to maximum duration of therapy if specified for an indication). 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 trea tment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.
No dose adjustment is necessary in patients ≥65 years.
No dose reductions of pembrolizumab are recommended. Pembrolizumab should be withheld or discontinued to manage adverse reactions as described in Table 1.
Table 1. Recommended treatment modifications for pembrolizumab:
| Immune-mediated 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. | 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-mediated 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 Grades 3 or 4 encephalitis 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 pembrolizumab, or if corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks, pembrolizumab should be permanently discontinued.
The safety of re-initiating pembrolizumab therapy in patients previously experiencing immune-mediated myocarditis is not known.
Pembrolizumab, as monotherapy or as combination therapy, should be permanently discontinued for Grade 4 or recurrent Grade 3 immune-mediated adverse reactions, unless otherwise specified in Table 1.
For Grade 4 haematological toxicity, only in patients with cHL, pembrolizumab should be withheld until adverse reactions recover to Grades 0-1.
Intravenous infusion over 30 minutes.
For:
Intravenous, 2 milligrams pembrolizumab per kilogram of body weight, once every 3 weeks.
The recommended dose of pembrolizumab as monotherapy in patients aged 12 years and older with melanoma 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 pembrolizumab until disease progression or unacceptable toxicity (and up to maximum duration of therapy if specified for an indication). 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 trea tment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.
No dose reductions of pembrolizumab are recommended. Pembrolizumab should be withheld or discontinued to manage adverse reactions as described in Table 1.
Table 1. Recommended treatment modifications for pembrolizumab:
| Immune-mediated 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. | 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-mediated 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 Grades 3 or 4 encephalitis 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 pembrolizumab, or if corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks, pembrolizumab should be permanently discontinued.
The safety of re-initiating pembrolizumab therapy in patients previously experiencing immune-mediated myocarditis is not known.
Pembrolizumab, as monotherapy or as combination therapy, should be permanently discontinued for Grade 4 or recurrent Grade 3 immune-mediated adverse reactions, unless otherwise specified in Table 1.
For Grade 4 haematological toxicity, only in patients with cHL, pembrolizumab should be withheld until adverse reactions recover to Grades 0-1.
Intravenous infusion over 30 minutes.
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