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Like the recently launched nivolumab (Opdivo), pembrolizumab binds to the programmed death-1 (PD-1) receptor.
Activation of PD-1 by tumour cells triggers an immune checkpoint resulting in inhibition of T cells directed against the cancer antigens, preventing the immune system from attacking the tumour. Pembrolizumab blocks the PD-1 receptor, overriding the checkpoint and allowing T cells to kill the tumour cells.
Further information
View Keytruda drug record
Summary of Product Characteristics
Manufacturer: MSD
As a new class of cancer treatments, checkpoint inhibitors have drawn attention from oncologists for the high response rates and significant survival benefits they have shown in clinical trials.
Pembrolizumab is a humanised monoclonal antibody. It is administered by intravenous infusion every 3 weeks.
Survival benefit vs standard of care
Three trials provided evidence to support the approval of pembrolizumab for the treatment of advanced melanoma.
The randomised, controlled, phase III KEYNOTE-006 study compared pembrolizumab with the CTLA-4 checkpoint inhibitor ipilimumab, the standard-of-care treatment for advanced melanoma.
Investigators assigned 834 patients with advanced melanoma to receive pembrolizumab 10mg/kg every 2 weeks or every 3 weeks, or four doses of ipilimumab 3mg/kg every 3 weeks.
Progression-free and overall survival (primary endpoints) were both significantly greater in patients treated with either pembrolizumab regimen than in those who were given ipilimumab. Dosed every 3 weeks, pembrolizumab reduced the risk of disease progression by 42% at 6 months and the risk of death by 31% at 12 months compared with ipilimumab.
In patients given pembrolizumab 2-weekly and 3-weekly, progression-free survival was 47.3% and 46.4%, respectively, vs 26.5% for those who received ipilimumab (hazard ratio for disease progression 0.58; p<0.001 for both comparisons; 95% CI 0.46–0.72 and 0.47–0.72, respectively).
Estimated 12-month survival rates with pembrolizumab 2-weekly or 3-weekly were 74.1% and 68.4%, respectively, compared with 58.2% with ipilimumab (hazard ratio for death 0.63 for pembrolizumab 2-weekly [95% CI 0.47–0.83; p=0.0005] and 0.69 for pembrolizumab 3-weekly [95% CI 0.52–0.90; p=0.0036]).
Treatment-related adverse events of grade 3 to 5 severity were less frequent in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).
Effective in ipilimumab-refractory melanoma
The phase II KEYNOTE-002 trial showed that pembrolizumab was more effective than the investigator's choice of chemotherapy in patients refractory to ipilimumab (n=540).
At 6 months, progression-free survival was significantly greater in patients randomised to pembrolizumab 2mg/kg or 10mg/kg every 3 weeks than those assigned to chemotherapy (34% and 38%, respectively, vs 16%; hazard ratios 0.57 [95% CI 0.45–0.73] and 0.50 [95% CI 0.39–0.64], respectively; p<0.0001 for both). Treatment-related grade 3 or 4 adverse events were less common with pembrolizumab than with chemotherapy (11% for the 2mg/kg dose and 14% for the 10mg/kg dose, vs 26% with chemotherapy).
The open-label single-arm phase Ib KEYNOTE-001 trial enrolled ipilimumab-naïve (n=103) and ipilimumab-refractory patients (n=173); the investigators reported overall response rates with pembrolizumab 2mg/kg 3-weekly of 33% and 25% in the two groups respectively, and similar results with the 10mg/kg dose.
Immune-related reactions
The most common adverse reactions associated with pembrolizumab were diarrhoea (15%), nausea (12%), pruritus (25%), rash (25%), arthralgia (13%) and fatigue (33%), all of which were generally mild. The most serious reactions were immune-related events (including pneumonitis, colitis, hepatitis, nephritis and endocrinopathies) and severe infusion-related reactions.
