The European Commission (EC) has approved pembrolizumab (Keytruda) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have received prior platinum-containing chemotherapy, or who are not eligible for cisplatin-containing chemotherapy.
The frontline approval for cisplatin-ineligible patients was based on the phase II KEYNOTE-052 trial, in which the overall response rate (ORR) was 29% (95% CI, 25-34), with a clinical benefit rate of 47%.1
The second-line approval was based on the phase III KEYNOTE-045 study, in which pembrolizumab reduced the risk of death by 27% compared with chemotherapy in patients with advanced urothelial carcinoma whose disease progressed after prior treatment.2
The EC’s decision follows a positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use. Pembrolizumab can now be marketed for these 2 new indications in all 28 EU member states plus Iceland, Lichtenstein, and Norway.
“Despite advances, there remain limited treatment options available to patients with locally advanced or metastatic urothelial carcinoma who are either not eligible to receive cisplatin-containing chemotherapy—which is platinum-based and currently the standard of care—or for those patients whose cancer returns after receiving prior platinum-containing chemotherapy,” Ronald de Wit, MD, PhD, group leader experimental systemic therapy of urogenital cancers, Erasmus MC Cancer Institute, said in a statement. “It is exciting that with this approval of Keytruda, we now also have a new treatment option for patients previously treated with platinum-containing chemotherapy that has shown a clinically meaningful and improved overall survival (OS) benefit versus chemotherapy in this difficult-to-treat population.”
KEYNOTE-045 was designed for patients with locally advanced or metastatic, unresectable urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra who had progressed after 1 to 2 lines of platinum-based chemotherapy or who had experienced recurrence after 12 months of chemotherapy.
Overall, 542 patients were randomized to pembrolizumab (200 mg IV) every 3 weeks for 2 years versus chemotherapy consisting of either paclitaxel (175 mg/m2
), docetaxel (75 mg/m2
), or vinflunine (320 mg/m2
) every 3 weeks for 2 years. The median age was 67 years in the pembrolizumab arm and 65 years in the chemotherapy cohort.
The treatment groups were well balanced for 4 key prognostic factors: hemoglobin level (>10 g/dL vs ≥10 g/dL); ECOG performance status (0/1 vs 2); liver metastases (yes vs no); and time from last chemotherapy dose (<3 vs ≥3 months).
The primary endpoints were OS and progression-free survival (PFS) in the total population and among participants with a combined positive score (CPS) ≥10% for PD-L1 expression. The CPS consisted of the percentage of PD-L1–positive tumor cells (TCs) and infiltrating immune cells relative to the total number of TCs as measured using the PD-L1 IHC 22C3 pharmDx assay on samples collected by core needle or excisional biopsies or in resected tissue.
The median OS for patients receiving pembrolizumab was 10.3 months (95% CI, 8.0-11.8 months) compared with 7.4 months (95% CI, 6.1-8.3 months) for those who received a chemotherapy regimen. The difference resulted in a hazard ratio of 0.73 (95% CI, 0.59-0.91; P
= .002). The survival benefit was observed regardless of PD-L1 expression status.
PFS, however, was not superior with pembrolizumab by the time of data cutoff on September 7. The median PFS was 2.1 months (95% CI, 2.0-2.2 months) with the immunotherapy versus 3.3 months (95% CI, 2.3-3.5 months) with chemotherapy (P
The OS analysis of patients with CPS ≥10% showed that there was a 43% reduction in the risk of death with pembrolizumab compared with chemotherapy (HR, 0.57; 95% CI, 0.37 -0.88; P
= .0048). The median OS was 8.0 months (95% CI, 5.0-12.3 months) with pembrolizumab versus 5.2 months (95% CI, 4.0-7.4 months) with chemotherapy.
The ORR was 21% with pembrolizumab compared with 11% with chemotherapy (P
= .002). The complete response (CR) rate was also much higher with pembrolizumab at 7.0% compared with a 3.3% CR with chemotherapy.
The median duration of response in the pembrolizumab arm was not reached (range, 1.6+ to 15+ months) with an estimated 68% of responders considered likely to maintain a response for ≥12 months. By comparison, the median duration of response in the chemotherapy arm was 4.3 months (range, 1.4+ to 15.4+ months) with an estimated 35% likely to maintain a response for ≥12 months.
Patients who received pembrolizumab had fewer toxicities than those treated with chemotherapy. The incidence of treatment-related adverse events (AEs) was lower with pembrolizumab compared with chemotherapy, respectively, for any grade (60.9% vs 90.2%) and for AEs of grade 3 to 5 severity (15.0% vs 49.4%).