FDA Grants Pembrolizumab Priority Review in Second-Line Bladder Cancer

Roger Dansey, MD

The FDA has granted a priority review to a supplemental Biologics License Application (sBLA) for pembrolizumab (Keytruda) for the treatment of patients with locally advanced or metastatic urothelial cancer who progress following platinum-containing chemotherapy, according to Merck, the manufacturer of the PD-1 inhibitor.

The sBLA is based on data from the phase III KEYNOTE-045 study, in which single-agent pembrolizumab reduced the risk of death by 27% compared with chemotherapy in patients with advanced urothelial carcinoma whose disease progressed after prior treatment.

The agency is scheduled to make a decision on the sBLA by June 14, 2017, as part of the “Over the past 30 years, there have been very few clinical advances in the treatment of bladder cancer,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said in a statement.

“The data with Keytruda administered to patients with advanced urothelial cancer are promising, and we look forward to working with the FDA throughout the review process with the goal of bringing Keytruda to patients who may benefit as quickly as possible,” added Dansey.

KEYNOTE-045 study 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 overall survival (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 months). 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 objective response rate was 21.1% with pembrolizumab compared with 11.4% with chemotherapy (P = .0011). 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 3-5 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, according to Merck.

Pembrolizumab currently has approved indications in melanoma, lung cancer, and head and neck cancer.

Bellmunt J, de Wit R, Vaughn DJ, et al. Keynote-045: open-label, phase III study of pembrolizumab versus investigator’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.