FDA Approves Keytruda Approved for Urothelial Carcinoma

Keytruda (pembrolizumab) was granted an approval by the Food and Drug Administration (FDA) to treat patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Additionally, the FDA granted an accelerated approval to frontline Keytruda for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

The approval in the second-line setting is based on the phase 3 KEYNOTE-045 study, in which single-agent Keytruda reduced the risk of death by 27 percent compared with chemotherapy in patients with advanced urothelial carcinoma whose disease progressed after prior treatment.

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 one to two lines of platinum-based chemotherapy or who had experienced recurrence after 12 months of chemotherapy.

Overall, 542 patients were randomized to Keytruda (200 mg IV) every three weeks for two years versus chemotherapy consisting of either paclitaxel (175 mg/m²), docetaxel (75 mg/m²) or vinflunine (320 mg/m²) every three weeks for two years. The median age was 67 years in the Keytruda 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 (less than three vs 3 months or longer).

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) at least 10 percent 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 Keytruda was 10.3 months compared with 7.4 months for those who received a chemotherapy regimen. The difference resulted in a hazard ratio of 0.73. The survival benefit was observed regardless of PD-L1 expression status.

PFS, however, was not superior with Keytruda by the time of data cutoff on Sept. 7. The median PFS was 2.1 months with the immunotherapy versus 3.3 months with chemotherapy.

The OS analysis of patients with CPS 10 percent or more showed that there was a 43 percent reduction in the risk of death with Keytruda compared with chemotherapy. The median OS was eight months with Keytruda versus 5.2 months with chemotherapy.

The objective response rate was 21 percent with Keytruda compared with 11 percent with chemotherapy. The complete response (CR) rate was also much higher with Keytruda at 7 percent compared with a 3.3 percent CR with chemotherapy.

The median duration of response in the Keytruda arm was not reached with an estimated 68 percent of responders considered likely to maintain a response for at least 12 months. By comparison, the median duration of response in the chemotherapy arm was 4.3 months with an estimated 35 percent likely to maintain a response for at least 12 months.

Patients who received Keytruda had fewer toxicities than those treated with chemotherapy. The incidence of treatment-related adverse events (AEs) was lower with Keytruda compared with chemotherapy, respectively, for any grade (60.9 percent vs 90.2 percent) and for AEs of grade 3-5 severity (15.0 percent vs 49.4 percent).

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

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

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

The accelerated approval of Keytruda in the first-line setting was based on the phase 2 KEYNOTE-052 trial, which enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. In the single-arm trial, Keytruda was administered at a flat 200 mg dose intravenously on day one of each three-week cycle for up to 24 months.

The median age for the first 100 patients was 75 years (range, 44-94), and 87 percent had visceral metastases at baseline. Patients had an ECOG performance status of 3 (1 percent) 2, (45 percent), 1 (30 percent) and 0 (24 percent).

At a median follow-up of 7.8 months, the ORR was 28.6 percent and the median response duration was not reached (range 1.4+ to 17.8+ months).

The accelerated approval for frontline Keytruda in urothelial carcinoma is contingent on the results of a confirmatory trial.

Keytruda has additional approved indications in melanoma, lung cancer, and head and neck cancer.