Key clinical-trial evidence for pembrolizumab
Pembrolizumab is a highly selective humanized monoclonal antibody directed against the PD-1 receptor on T-cells. The drug blocks the PD-1 receptor, thereby preventing the formation of PD-1/PD-L1 (programme death ligand one) complexes. This mechanism causes the activation of T-cell mediated immune responses against tumour cells.
On September 4, 2014 the US Food and Drug Administration (FDA) approved pembrolizumab as a breakthrough therapy for the treatment of metastatic melanoma, based on response rates demonstrated in clinical trial data from 173 patients with melanoma in a cohort of the KEYNOTE-001 study.
- The efficacy of pembrolizumab (KEYTRUDA®) was investigated in a multicenter, open-label, randomized (1:1), dose comparative phase 1b study.
- Key eligibility criteria were unresectable or metastatic melanoma with progression of disease and refractory to treatment with two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab.
- The trial excluded patients with autoimmune disease; a medical condition that required immunosuppression, and a history of severe immune-mediated adverse reactions with ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks.
- Patients were randomized to receive 2 mg/kg (n=89) or 10 mg/kg (n=84) of pembrolizumab every 3 weeks until unacceptable toxicity or disease progression that was symptomatic.
- Assessment of tumour status was performed 12 weeks after the first dose of pembrolizumab and every 12 weeks thereafter.
- The major efficacy outcome measures were duration of response and confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1) as assessed by blinded independent central review.
- Among the 173 patients enrolled, the median age was 61 years (36% age 65 or older); 60% male; 97% White; and 66% and 34% with an ECOG (Eastern Cooperative Oncology Group) performance status 0 and 1, respectively.
- The ORR was 24% (95% CI: 15, 34) in the 2 mg/kg arm, consisting of one complete response and 20 partial responses.
- Among the 21 patients with an objective response, 3 (14%) had disease progression at 2.8, 2.9, and 8.2 months, respectively, after initial response.
- The duration of response in the remaining 18 patients (86%) varied from 1.4 to 8.5 months and included 8 patients with ongoing responses of 6 months or longer.
- Similar ORR results were observed in the 10 mg/kg arm.
- The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not.
- Table 1 presents adverse reactions identified from analyses of the 89 patients with unresectable or metastatic melanoma who received pembrolizumab 2 mg/kg every three weeks.
- The median duration of exposure to pembrolizumab was 6.2 months (range 1 day to 15.3 months) with a median of nine doses (range 1 to 23).
- Pembrolizumab was discontinued in 6% of the 89 patients because of adverse events.
|Pembrolizumab 2 mg/kg every 3 weeks (n = 89)|
|Adverse reaction||All grades (%)||Grade 3 (%)|
|General disorders and administration site conditions|
|Nervous system disorders|
- Pembrolizumab is now registered for the treatment of advanced (metastatic or unresectable) melanoma in many countries worldwide, including Europe, UK and New Zealand.
- The originator of pembrolizumab, Merck and Co. has entered into collaboration agreements with a number of other pharmaceutical companies to conduct trials of pembrolizumab in combination with other antimelanoma agents.
- Merck is collaborating with Glaxo Smith Kline on a phase I/II trial of pembrolizumab plus trametinib and dabrafenib in patients with advanced melanoma (KEY NOTE 022).
- The Keynote-006 study has since shown one-year survival for pembrolizumab was 74% verses 58% for ipilimumab in patients with advanced melanoma.