Mature results from the KEYNOTE-045 trial confirmed the significantly longer overall survival (OS) in patients with advanced urothelial cancer who received the checkpoint inhibitor pembrolizumab after initial chemotherapy, compared to an alternative chemotherapy regimen. These new data back-up the interim findings of this trial that were reported in the New England Journal of Medicine earlier this year
The phase III KEYNOTE-045 study randomly assigned patients whose urothelial cancer had recurred or progressed after platinum-based chemotherapy, to either pembrolizumab (N = 272) (200mg Q3W) or the investigator’s choice of paclitaxel (175mg/m2 Q3W), docetaxel (75mg/m2 Q3W), or vinflunine (320mg/m2 Q3W) chemotherapy (N = 270). The co-primary endpoints of the study were OS and progression-free survival (PFS), with secondary objectives including objective response rate (ORR) and safety.
Results after 22.5 months of follow-up showed an approximately 3 month advantage in OS in the pembrolizumab-treated patients compared to those receiving a second line of chemotherapy (median 10.3 months versus 7.4 months), with a further improvement in the hazard ratio [HR] from 0.73 to 0.70 (p= 0.0003) since the interim analysis. In patients expressing PD-L1 in 10% of tumor and inflammatory cells or more, the median OS was 8.0 months with pembrolizumab versus 5.2 months with chemotherapy (HR: 0.58; p = 0.003). A subgroup analysis demonstrated that the OS benefit of pembrolizumab over chemotherapy was seen regardless of age, liver metastases, hemoglobin, visceral disease, and choice of chemotherapy. After 18 months, 33.2% of the pembrolizumab treated patients was still alive as compared to 19.7% with chemotherapy. The median PFS was not significantly different (2.1 months for pembrolizumab versus 3.3 months for chemotherapy; HR: 0.96; p= 0.32). The ORR reached 21.1% with pembrolizumab as compared to 11.0% with chemotherapy. Responses were not only more frequent with pembrolizumab than with chemotherapy, they were also more durable with a median duration of response (DoR) that was not reached with pembrolizumab and 4.4 months with chemotherapy. In addition, quality of life (QoL), measured at week 15 and reported earlier this year, showed better results in the pembrolizumab arm. Treatment-related adverse events of any grade occurred in 62.0% of the pembrolizumab treated patients and in 90.6% of patients in the chemotherapy arm (grade ≥3 treatment-related adverse events: 16.5% versus 50.2%).
These updated KEYNOTE-045 results confirm the OS benefit of pembrolizumab compared to chemotherapy (investigator's choice) in platinum-pretreated patients. This superior OS, combined with the better adverse event profile, the better QoL and the higher rate of (more durable) responses render pembrolizumab a new standard of care in the second line treatment for patients with advanced urothelial cell cancer.
de Wit R, Vaughn D, Fradet Y, et al. Pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer (UC): mature results from the phase 3 KEYNOTE-045 trial. Presented at ESMO 2017; abstract LBA37_PR.