Pembrolizumab Receives European Approval for Treatment of Urothelial Carcinoma

Pembrolizumab has been approved by the European Commission 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.

Pembrolizumab (Ketruda) has been approved by the European Commission (EC) 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 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.

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%.1The 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

“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= .42).

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%).

Treatment-related AEs occurring in ≥10% of participants were generally lower with pembrolizumab as opposed to chemotherapy, respectively, including for fatigue (13.9% vs 27.8%), nausea (10.9% vs 24.3%), diarrhea (9.0% vs 12.9%), asthenia (5.6% vs 14.1%), and anemia (3.4% vs 24.7% with chemotherapy).

The incidence of pruritus was higher in the pembrolizumab arm at 19.5% versus the chemotherapy group at 2.7%. Immune-related AEs that were higher with pembrolizumab compared with chemotherapy, respectively, included thyroid abnormalities (9.4% vs 1.6%), pneumonitis (4.1% vs 0.4%), and colitis (2.3% vs 0.4%).

Fifteen patients in the pembrolizumab arm and 28 patients in the chemotherapy group discontinued treatment due to a treatment-related AE. Each arm had 4 treatment-related deaths.

The phase II KEYNOTE-052 trial enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. In the single-arm trial, pembrolizumab was administered at a flat 200 mg dose intravenously on day 1 of each 3-week cycle for up to 24 months.

The median age was 74 and 29% of the cohort was 80 or older. The primary tumor location was the lower tract for 81% of patients and 21% had liver metastases.

At median follow-up of 9.5 months, 7% of patients had a complete response, 22% had a partial response, and 18% had stable disease. More than 40% of patients in the study had progressive disease.

The response was consistent across demographic groups, including patients younger than 85 (29%; 95% CI, 20-35), patients ≥85 (28%; 95% CI, 15-44), and those with an ECOG performance status of 2 (27%, 95% CI, 20-35).

Among patients who had at least 1 post-baseline scan, 58% experienced a decrease in tumor lesions.

Median time-to-response was 2 months, and 82% of responses lasted at least 6 months. Median duration of response has not been reached.

Investigators created a training set of the first 100 patients enrolled to identify the CPS cut point for PD-L1 expression and a validation set that included all patients except for that first 100 to confirm results. Investigators found that a CPS ≥10% was the optimal enrichment cutoff for predicting response.

In the training set, patients with a CPS <10% had an ORR of 17% with 3 complete responses and 8 partial responses. ORR was 37% for CPS-high patients with 4 complete responses and 7 partial responses.

Response was even stronger in the validation set. ORR was 51% for CPS-high patients, with 14 complete responses and 27 partial responses. ORR was 23% for CPS-low patients, with 5 complete responses and 37 partial responses.

Two-thirds of patients reported treatment-related AEs of any grade, with fatigue (18%), pruritus (17%), and rash (12%) being the most common. Seventy patients (19%) reported grade ≥3 AEs, including fatigue (2%) and colitis (2%). Other grade ≥3 AEs appeared in just 1% of patients. Investigators recorded a single treatment-related AE that resulted in death—myositis in an 83-year-old patient.


  1. O&rsquo;Donnell PH, Grivas P, Balar AV, et al. Biomarker findings and mature clinical results from KEYNOTE-052: First-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC).J Clin Oncol.35, 2017 (suppl; abstr 4502).
  2. Bellmunt J, de Wit R, Vaughn DJ, et al. Keynote-045: open-label, phase III study of pembrolizumab versus investigator&rsquo;s choice of paclitaxel, docetaxel, or vinflunine for previously treated advanced urothelial cancer. Presented at: 2016 SITC Annual Meeting; November 9-13, 2016; National Harbor, MD. Abstract 470.