FDA Approval for Pembrolizumab
Brand name(s): Keytruda®
- Approved for unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor
Full prescribing information is available, including clinical trial information, safety, dosing, drug–drug interactions, and contraindications.
On September 4, 2014, the Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (Keytruda, made by Merck Sharp & Dohme Corp.) for the treatment of patients with unresectable or metastatic melanoma whose disease progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including anti-tumor immune response.
Approval was based on the results from a dose-comparing, activity-estimating cohort within a multicenter open-label randomized phase 1b clinical trial, KEYNOTE-001. In this cohort, 173 patients with unresectable or metastatic melanoma who experienced disease progression within 24 weeks of the last dose of ipilimumab and, if BRAF V600 mutation-positive, prior treatment with a BRAF inhibitor, were randomly assigned to receive 2 mg/kg (n=89) or 10 mg/kg (n=84) of pembrolizumab intravenously once every 3 weeks until further disease progression or unacceptable toxicity.
Key exclusion criteria were an autoimmune disease, a medical condition that required immunosuppression, and/or a history of severe immune-mediated adverse reactions from treatment with ipilimumab. Severe immune-mediated adverse reactions were defined as any life-threatening (CTCAE grade 4) toxic effect that required treatment with corticosteroids or a severe (grade 3) toxic effect that required corticosteroid treatment (more than 10 mg/day prednisone or equivalent dose) for longer than 12 weeks.
Among the 173 patients, the median age was 61 years (64 percent were under age 65). Forty percent were female; 97 percent were white; and 66 percent and 34 percent had ECOG performance status 0 and 1, respectively. Seventeen percent were BRAF V600 mutation positive, 39 percent had elevated lactate dehydrogenase, and 82 percent had advanced metastases (M1c). Furthermore, 9 percent had brain metastases, and 73 percent had had two or more prior therapies for advanced or metastatic disease.
The major efficacy endpoints were confirmed overall response rate (according to Response Evaluation Criteria in Solid Tumors, or RECIST, v1.1 as assessed by a blinded independent review committee) and duration of response. The overall response rate was 24 percent (95 percent 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 percent) experienced disease progression at 2.8, 2.9, and 8.2 months after initial response. The remaining 18 patients (86 percent) have ongoing responses, ranging from more than 1.4 months to more than 8.5 months. Eight of these patients have ongoing responses of 6 months or longer. Similar overall response rates were observed in the 10 mg/kg arm.
The most common adverse reactions (occurring in 20 percent or more of patients) among those receiving the lower dose of pembrolizumab were fatigue, cough, nausea, itchy skin, rash, decreased appetite, constipation, muscle pain, and diarrhea.
The most frequent serious adverse drug reactions (occurring in 2 percent or more of patients) observed with pembrolizumab were kidney failure, difficult or painful breathing (dyspnea), pneumonia, and cellulitis. Additional clinically significant immune-mediated adverse reactions included changes in thyroid activity (hyperthyroidism or hypothyroidism) and inflammation of the lungs (pneumonitis), colon (colitis), pituitary gland (hypophysitis), kidneys (nephritis), and liver (hepatitis).
As a condition of this accelerated approval, Merck is required to conduct a multicenter randomized trial establishing the superiority of pembrolizumab over standard therapy to verify and describe its clinical benefit. Merck has two ongoing multicenter randomized controlled therapeutic confirmatory trials in patients with unresectable or metastatic melanoma, either refractory to ipilimumab (KEYNOTE-002) or ipilimumab naïve (KEYNOTE-006), each with co-primary endpoints of progression-free survival and overall survival.
FDA granted breakthrough therapy designation for pembrolizumab for this indication in early 2013 based on preliminary evidence of clinical activity in patients with unresectable or metastatic melanoma, previously untreated with or refractory to ipilimumab.
The recommended dose of pembrolizumab is 2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Office of Hematology and Oncology Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.