Keytruda by Merck

BACKGROUND^1,2

Keytruda (pembrolizumab), manufactured by Merck, is indicated for treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and a BRAF inhibitor (if the patient is BRAF V600 mutationpositive). Newly approved on an accelerated basis in September 2014, Keytruda is the first in its therapeutic class as a programmed death (PD)-1 inhibitor, blocking a cellular pathway that restricts the immune system from attacking melanoma cells. The FDA designated Keytruda as an orphan product, and it is the sixth new melanoma treatment that has emerged since 2011.

PHARMACOLOGY/ PHARMACOKINETICS^1,3

When the PD-1 ligands, PD-L1 and PD-L2 bind to the PD-1 receptor found on T-cells, T-cell proliferation and cytokine production are inhibited. Upregulation of these ligands occurs on the cell surface of some tumors, including melanoma, effectively decreasing active T-cell surveillance of these tumors. Keytruda, a humanized monoclonal antibody, binds to the PD-1 receptor with high selectivity, blocking its interaction with these ligands. The pharmacokinetics of Keytruda were studied in 479 patients who received doses of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. The peak concentration, trough concentration, and area under the plasma concentration versus time curve at a steady state increased dose-proportionally in the range of 2 to 10 mg/kg every 3 weeks. Keytruda has a mean clearance of 0.22 L/day and elimination half-life of 26 days.

DOSING^1,3

Recommended dosing of Keytruda is 2 mg/kg administered as an intravenous (IV) infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity occurs. With its novel mechanism of action, Keytruda has the potential for severe immune-mediated adverse effects (AEs). Doses should be withheld if grade 2 pneumonitis or nephritis, grade 2 or 3 colitis, grade 3 hyperthyroidism, liver function test (LFT) elevations 3 to 5 times the upper limit of normal (ULN), or any other severe or grade 3 treatment-related adverse reactions occur. Keytruda should be permanently discontinued if LFTs increase greater than 5 times ULN, if persistent grade 2 or 3 adverse reactions do not recover to grade 0 to 1 within 12 weeks after last dose, or if grade 3 or 4 pneumonitis, nephritis, or infusion-related reactions occur.

CLINICAL EFFICACY⁴

Keytruda was approved based on a randomized, open-label, international expansion cohort of a phase 1 clinical trial in which 173 adult patients with advanced melanoma, whose disease had progressed after being given at least 2 doses of ipilimumab, were randomly assigned to IV pembrolizumab at a 1:1 ratio of either 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. Patients were treated until disease progression, intolerable toxicity, or consent withdrawal occurred. The primary end point was the overall response rate, assessed with Response Evaluation Criteria in Solid Tumors, and was found to be 26% at both doses (P = 0.96). Treatment was generally well tolerated with similar safety profiles in both dosing regimens: there were no drug-related deaths, and only 12% of patients overall experienced drug-related grade 3 or 4 AEs, few of which were potentially immune-mediated. Investigators concluded that Keytruda at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in ipilimumab-refractory advanced melanoma patients for whom there are few effective treatment options.

MEDICATION SAFETY^1,3

The most common AEs seen in clinical studies were fatigue, cough, nausea, diarrhea, constipation, anorexia, arthralgia, pruritus, and rash. Keytruda is a Pregnancy Category D medication solely based on its mechanism of action; no formal animal reproduction studies have yet been conducted. Previous animal models have demonstrated the role of the PD-1/ PDL-1 signaling pathway with pregnancy maintenance through induction of maternal immune tolerance to fetal tissue. Thus, potential risks of administering Keytruda during pregnancy may include increased rates of abortion or stillbirth. It is unknown whether Keytruda is excreted in breast milk.

AVAILABILITY AND COST^1,5

Keytruda is supplied as 50-mg single-use vials that should be stored under refrigeration at 2°C to 8°C (36°F-46°F). Each vial should be reconstituted with 2.3 mL of sterile water for injection and then gently swirled and inspected for particulate matter. The required drug volume should then be withdrawn from the vial and transferred to an IV bag containing normal saline. After gently inverting for adequate mixing, this diluted solution should have a final concentration between 1 and 10 mg/mL. The acquisition cost of Keytruda is $5179 per vial. More information is available at www.keytruda.com.

Ashley L. Pappas, PharmD, BCPS, is a drug information specialist at University of North Carolina (UNC) Hospitals and an adjunct assistant professor at the UNC Eshelman School of Pharmacy.Sandra Hanna, PharmD candidate, is a third-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.

References

• Keytruda [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; September 2014.
• FDA approves Keytruda for advanced melanoma [press release]. Silver Spring, MD: FDA; September 10, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412802.htm.
• Keytruda. Facts & Comparisons [online database]. St. Louis, MO: Wolters Kluwer Health, Inc; September 2014. Accessed January 28, 2015.
• Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109-1117.
• Pricing obtained from AmerisourceBergen wholesaler.