FDA Approves Pembrolizumab for Urothelial Carcinoma

The FDA approved pembrolizumab (Keytruda) for the treatment of 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 pembrolizumab 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 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.¹

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 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; P = .004). 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% 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 3-5 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 accelerated approval of pembrolizumab in the first-line setting was based on the phase II 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, 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 for the first 100 patients was 75 years (range, 44-94), and 87% had visceral metastases at baseline. Patients had an ECOG performance status of 3 (1%), 2 (45%), 1 (30%), and 0 (24%).

At a median follow-up of 7.8 months, the ORR was 28.6% (95% CI, 24-34) and the median response duration was not reached (range 1.4+ to 17.8+ months). The CR rate was 7% and the partial response rate was 22%.

Results from the study presented at the 2016 ESMO Congress reported that AEs were consistent with prior trials exploring the PD-1 inhibitor.² Overall, 5 patients discontinued treatment due to a treatment-related AE. There were no deaths attributed to treatment-related AEs.

All-grade treatment-related AEs were experienced by 67% of patients and included fatigue (14%), pruritus (12%), pyrexia (8%), decreased appetite (7%), diarrhea (7%), rash (7%), chills (6%), hypothyroidism (6%), and nausea (6%). Grade 3/4 treatment-related AEs were experienced by 16% of patients, and included fatigue (4%), muscle spasms (2%), decreased appetite (1%), and diarrhea (1%).

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

Pembrolizumab has additional approved indications in melanoma, lung cancer, head and neck cancer, and Hodgkin lymphoma.

References

1. 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.
2. Balar A, Bellmunt J, O’Donnell PH, et al. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase II KEYNOTE-052 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA32.

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).