Pembrolizumab Improves OS Versus Chemo in Phase III Bladder Cancer Study

Treatment with pembrolizumab improved overall survival by 2.9 months compared with chemotherapy for patients with advanced urothelial carcinoma whose disease progressed after prior treatment.


In the KEYNOTE-045 trial, patients treated with pembrolizumab achieved a median OS of 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 and there were fewer adverse events (AEs) with the immunotherapy, Bellmunt said.

“Bladder cancer is a disease where nothing has changed in the last 20 years,” said Bellmunt, an associate professor of Medicine at Harvard Medical School and director of the Bladder Cancer Center at Dana-Farber Cancer Institute. “Now, for the first time, we have an agent that in fact improves survival in the second-line setting.”

The 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 primary endpoints were OS and 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 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). Bellmunt said these factors had proved significant differentiators of response in prior bladder cancer trials.

Pembrolizumab therapy also resulted in a significantly higher objective response rate (ORR) of 21.1% compared with 11.4% with chemotherapy (P= .0011). Similarly, the complete response (CR) rate was 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.

By contrast, progression-free survival (PFS) 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). Bellmunt noted that the PFS curves started to separate in favor of pembrolizumab at about 12 months, indicating that the immunotherapy benefit may be greater as time goes on. The results he presented at SITC 2016 were based on a median follow-up of 14.1 months (range, 9.9-22.1 months).

In the OS analysis of patients with CPS &ge;10%, 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.

Although the advantage was maintained in the PD-L1—high population, Bellmunt said it was surprising that the benefit was not more pronounced for these patients. This development might have occurred because primary resected tumors were used and patients subsequently underwent first-line therapy, which may have altered the PD-L1 expression, he said. Clinical trials are now using samples collected more recently to evaluate PD-L1 levels.

In terms of AEs, patients who received pembrolizumab had fewer toxicities than those treated with chemotherapy. The incidence of treatment-related 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 &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, according to Merck, which is developing the drug.


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.

FDA approves new, targeted treatment for bladder cancer [news release]. US Food and Drug Administration. Published May 18, 2016. Accessed November 12, 2016.

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