Pembrolizumab Receives European Approval for Treatment of Urothelial Carcinoma

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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 &ge;10 g/dL); ECOG performance status (0/1 vs 2); liver metastases (yes vs no); and time from last chemotherapy dose (<3 vs &ge;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) &ge;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 &ge;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 &ge;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 &ge;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 &ge;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 &ge;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 &ge;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 &ge;3 AEs, including fatigue (2%) and colitis (2%). Other grade &ge;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.

References:

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.