FDA Accepts Two sBLAs for Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer in Cisplatin-Ineligible First-Line and Second-Line Post-Platinum Failure Treatment Settings

Pembrolizumab also receives Breakthrough Therapy Designation for second-line treatment based on KEYNOTE-045

On 3 February, 2017 Merck, known as MSD outside the United States and Canada, announced that the US Food and Drug Administration (FDA) has accepted for review two supplemental Biologics License Applications (sBLAs) for pembrolizumab (KEYTRUDA®), anti-PD-1 therapy, in patients with locally advanced or metastatic urothelial cancer. Specifically, the application for first-line use was accepted and granted Priority Review for the treatment of the patients who are ineligible for cisplatin-containing therapy. The application for second-line use was also accepted and granted Priority Review for the patients with disease progression on or after platinum-containing chemotherapy. The PDUFA, or target action, date for both applications is 14 June, 2017.

The FDA previously granted Breakthrough Therapy Designation to pembrolizumab for the second-line treatment of patients with locally advanced or metastatic urothelial cancer with disease progression on or after platinum-containing chemotherapy.

The applications, which are seeking approval for pembrolizumab monotherapy at a dose of 200 mg administered intravenously every three weeks, are based on data from the phase II KEYNOTE-052 trial and the phase III KEYNOTE-045 trial, respectively.

KEYNOTE-052 is an open-label study investigating pembrolizumab as a first-line treatment in patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing therapy.

KEYNOTE-045 is a randomised study investigating pembrolizumab as a second-line therapy compared to investigator-choice chemotherapy ( paclitaxel, docetaxel, vinflunine) in patients with locally advanced or metastatic urothelial cancer that has recurred or progressed on or after platinum-containing chemotherapy. In October 2016, the company announced that, although it did not show significant improvement in progression-free survival (PFS), the trial met its co-primary endpoint of overall survival (OS) and was stopped early at the recommendation of an independent Data Monitoring Committee.

The results of the KEYNOTE-045 study are published in The New England Journal of Medicine. The median OS in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the investigator-choice chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; p = 0.002). The median OS among patients who had a tumour PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the investigator-choice chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; p = 0.005).

Pembrolizumab was also associated with significantly lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma.

At 2017 Genitourinary Cancers Symposium (16-18 February, Orlando, US), the KEYNOTE-045 investigators presented health-related quality of life data (HRQoL). Pembrolizumab was associated with substantially better HRQoL for a longer duration than investigator-choice chemotherapy in patients with previously treated advanced urothelial cancer.

References

Bellmunt J, De Wit R, VaughnDJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. NEJM; Published online 17 February. DOI: 10.1056/NEJMoa1613683 

Vaughn DJ, Bellmunt J, De Wit R, et al. Health-related quality of life (HRQoL) in the KEYNOTE-045 study of pembrolizumab versus investigator-choice chemotherapy for previously treated advanced urothelial cancer. J Clin Oncol 35, 2017 (suppl 6S; abstract 282).