On May 18, 2017, the U.S. Food and Drug Administration granted regular approval to pembrolizumab (KEYTRUDA, Merck and Co., Inc.) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
FDA also granted accelerated approval to pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
The regular approval for the second-line indication was based on data from Trial KEYNOTE-045, a multicenter, randomized, active-controlled trial in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. Patients were randomly assigned (1:1) to receive either pembrolizumab 200 mg every 3 weeks (n=270) or investigator’s choice of a chemotherapy regimen (paclitaxel [n=84], docetaxel [n=84], or vinflunine [n=87]) every 3 weeks (n=272). The trial demonstrated statistically significant improvements in overall survival (OS) and objective response rate (ORR) for patients assigned to pembrolizumab as compared to chemotherapy. Median OS was 10.3 and 7.4 months in the pembrolizumab and chemotherapy arms, respectively (HR 0.73; 95% CI: 0.59, 0.91, p=0.004). ORR was 21% for pembrolizumab and 11% for chemotherapy (p=0.002). No statistically significant difference in progression-free survival between the two arms was observed.
The accelerated approval for the first-line indication was based on data from KEYNOTE-052, a single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. Patients received pembrolizumab 200 mg every 3 weeks. With a median follow-up time of 7.8 months, the ORR was 28.6% (95% CI 24, 34) and the median response duration was not reached (range 1.4+, 17.8+ months).
The most common adverse reactions reported for at least 20% of pembrolizumab-treated patients in either of the two trials included fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of pembrolizumab secondary to adverse reactions occurred in 8% of patients in KEYNOTE-045 and in 11% in KEYNOTE-052. Dose interruption of pembrolizumab occurred in approximately 20% of patients in either trial. Serious adverse reactions occurred in approximately 40% of pembrolizumab-treated patients. Immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, and endocrinopathies, were reported in the trials and were managed according to guidelines in Warnings and Precautions of the label.
The recommended pembrolizumab dose and schedule for the treatment of urothelial carcinoma is 200 mg as an intravenous infusion over 30 minutes every 3 weeks.
Full prescribing information for pembrolizumab is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s017s018lbl.pdf
FDA granted pembrolizumab priority review status for these indications. Prior to the submission, pembrolizumab received Breakthrough Therapy Designation for the second-line indication. An additional trial is required to confirm clinical benefit of pembrolizumab for the first-line indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
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