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.
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.
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.
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.