What is pembrolizumab?
Pembrolizumab (trade name Keytruda®, formerly known as lambrolizumab) is a drug marketed by Merck and Co (New Jersey, USA) that targets the programmed death 1 (PD-1) receptor. The drug is intended for use in treating metastatic melanoma.
On September 4, 2014 the US Food and Drug Administration (FDA) approved pembrolizumab as a breakthrough therapy for the treatment of metastatic melanoma. It was approved for use in New Zealand in September 2015, and funded by PHARMAC for some patients with unresectable or metastatic melanoma from September 2016.
Which patients benefit from pembrolizumab treatment?
Pembrolizumab is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following treatment with ipilimumab. For melanoma patients whose tumours express a gene mutation called BRAFV600, pembrolizumab is intended for use after treatment with ipilimumab and a BRAF inhibitor (eg vemurafenib or dabrafenib), a therapy that blocks activity of BRAF gene mutations.
Combination therapy is under investigation and may improve response rates. Pembrolizumab is under investigation in other malignancies. It has been reported to have some effect in metastatic merkel cell carcinoma.
How does pembrolizumab work?
The programmed death receptor 1 (PD-1) is a surface molecule expressed on antigen-stimulated T-cells as well as monocytes, B-cells, and dendritic cells. In normal cells the PD-1 receptor acts as an immune checkpoint receptor enabling self-tolerance by T-cells, thus preventing autoimmune reactions.
When unbound, PD-1 allows the normal response by T-cells to proceed.
However, binding of PD-1 to its ligands, PD-L1 (programmed death receptor ligand 1) and PD-L2, suppresses the immune response by inducing downstream signalling that inhibits the proliferation of T-cells, cytokine release and cytotoxicity.
- Abnormal PD-L1 expression on the surface of melanoma cells activates PD-1 and suppresses cytotoxic T-cell activity.
- This T-cell tolerance enables the tumour cells to avoid recognition and attack by the immune system.
- Pembrolizumab is a highly selective humanized monoclonal IgG4 antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing the PD-1 pathway-mediated inhibition of immune response against tumour cells.
How is pembrolizumab administered?
- The recommended dose of pembrolizumab is 2 mg/kg administered as an intravenous infusion over 30 minutes, every 3 weeks until disease progression or unacceptable toxicity.
- Pembrolizumab should be withheld in patients with Grade 2 pneumonitis, Grade 2 or 3 colitis, Grade 2 nephritis, Grade 3 hyperthyroidism, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 and up to 5 times upper limit of normal (ULN) or total bilirubin > 1.5 and up to 3 times UNL. In addition to withholding this medication, a tapering course of corticosteroids can be initiated.
- Pembrolizumab could be resumed in patients whose adverse reactions recover to Grade 0-1.
- The drug should be discontinued permanently in Grade 3 or 4 adverse reactions.
Potential drug interactions with pembrolizumab
No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab.
What adverse events can pembrolizumab cause?
In clinical trials, the most common side effects (greater than or equal to 20%) in patients receiving pembrolizumab 2 mg/kg every 3 weeks were:
- pruritus (itch)
- rash (unspecified)
- decreased appetite
The most frequent (greater than or equal to 2%) serious adverse drug reactions observed with pembrolizumab were renal failure, dyspnoea, pneumonia, and cellulitis.
Pembrolizumab also has the potential for severe immune-mediated adverse effects. In the 411 clinical trial participants with advanced melanoma, severe immune-mediated adverse effects included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis.
Cutaneous adverse effects
One report has described skin problems arising in 42% of 83 patients on pembrolizumab. Development of skin problems was associated with longer progression-free intervals.
- Morbilliform eruption
- Lichenoid eruption
- Vitiligo and poliosis (whitening of hair)
- Bullous pemphigoid
- Sarcoid-like granuloma
Darkening of hair has been reported in a few patients taking PD-1 inhibitors for non-small cell lung cancer .
Use in pregnancy
- Pembrolizumab may cause fetal harm when administered to a pregnant woman.
- In animal studies potential risks of administering pembrolizumab during pregnancy included increased rates of abortion or stillbirth.
- Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus.
- Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response.
Use in nursing mothers
- It is not known whether pembrolizumab or its metabolites are excreted in human milk.
- Because many drugs are excreted in human milk, mothers should discontinue nursing prior to using pembrolizumab .
- The safety and effectiveness of pembrolizumab have not been established in children.
- Of the 411 clinical trial patients treated with pembrolizumab, 39% were 65 years and over. No overall differences in safety or efficacy were reported between elderly patients and younger patients.
- Based on population pharmacokinetic analysis, no dose adjustment is needed for patients with renal impairment.
- Based on population pharmacokinetic analysis, no dose adjustment is needed for patients with mild hepatic impairment.
- Pembrolizumab has not been studied in patients with moderate or severe hepatic impairment.