Joaquim Bellmunt, MD, PhD
Pembrolizumab (Keytruda) monotherapy reduced the risk of death by 27% compared with chemotherapy for patients with advanced urothelial carcinoma whose disease progressed after prior treatment. The results are being hailed as setting a new second-line standard for the most common form of bladder cancer.
Findings from the phase III KEYNOTE-045 trial represent the first therapy to demonstrate an overall survival (OS) benefit over an active comparator for this population, said principal investigator Joaquim Bellmunt, MD, PhD, in presenting the results at the 2016 SITC Annual Meeting.1
He said the OS benefit combined with a low rate of treatment-related adverse events (AEs) make the PD-1 inhibitor the preferred therapy for patients with previously treated recurrent or progressive disease.
“Bladder cancer is a disease where nothing has changed in the last 20 years,” Bellmunt, an associate professor of Medicine at Harvard Medical School and director of the Bladder Cancer Center at Dana-Farber Cancer Institute, said in an interview with OncLive
. “Now, for the first time, we have an agent that in fact improves survival in the second-line setting.”
Bellmunt noted that there is no standard therapy in the United States for patients with advanced urothelial carcinoma who progress after first-line platinum-based chemotherapy. He said chemotherapy regimens typically used in second-line settings yield a median OS rate of 7 to 9 months at the cost of significant toxicities.
In May 2016, the FDA approved the PD-L1 inhibitor atezolizumab (Tecentriq) for the second-line treatment of patients with advanced or metastatic recurrent urothelial cancer based on a single-arm, phase II study that demonstrated a 14.8% response rate with durations of more than 2.1 months to more than 13.8 monts.2
The approval was granted on an accelerated basis pending confirmatory trial data.
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, Bellmunt said.
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.
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
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).
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.
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.
In the OS analysis of patients with CPS ≥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.
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.