Extended Follow-Up Confirms Survival Benefit with Pembrolizumab in Urothelial Cancer

Charles Bankhead


Chicago, IL—Treatment with the PD-1 inhibitor pembrolizumab (Keytruda) significantly prolonged overall survival (OS) compared with chemotherapy in patients with advanced urothelial carcinoma that progressed during or after first-line chemotherapy, said Dean F. Bajorin, MD, FACP, FASCO, Medical Oncologist and Frederick R. Adler Senior Faculty Chair, Memorial Sloan Kettering Cancer Center, New York City, at the 2017 ASCO annual meeting.

Dr Bajorin reported on survival data and other outcomes after extended follow-­up of the KEYNOTE-045 clinical trial.

With a median follow-up of 18.5 months, patients had a median OS of 10.3 months with pembrolizumab versus 7.4 months with standard chemotherapy. Landmark analyses at 12 and 18 months also demonstrated substantially better OS with pembrolizumab.

These results justified the recent FDA approval of pembrolizumab for use in urothelial carcinoma after failure of platinum-based chemotherapy, said Dr Bajorin.

“Pembrolizumab is the first immunotherapy to demonstrate superior survival over chemotherapy in patients with advanced urothelial carcinoma after failure of platinum-based therapy,” said Dr Bajorin. “Pembrolizumab should be considered a standard of care for these patients, supported by level one evidence,” he added.

No consensus exists regarding therapy for recurrent urothelial carcinoma after initial platinum-based chemotherapy. Vinflunine (Javlor) is approved in Europe for recurrent urothelial carcinoma after platinum-based chemotherapy and is frequently used for this indication. In the United States, guideline-recommended taxanes are often used in patients with recurrent urothelial carcinoma after failure with platinum-based chemotherapy.

Pembrolizumab demonstrated activity and safety in recurrent urothelial cancer in phase 2 and phase 3 clinical trials. The phase 3 KEYNOTE-045 clinical trial demonstrated a survival advantage with pembrolizumab over chemotherapy in patients with recurrent urothelial cancer after a median follow-up of 14 months. In May 2017, the FDA granted full approval to pembrolizumab for the treatment of patients with recurrent urothelial cancer after failure of platinum-containing chemotherapy, based on results from the KEYNOTE-045 clinical trial.

Extended Follow-Up of KEYNOTE-045

Investigators in the multicenter, KEYNOTE-045 clinical trial enrolled patients who had recurrent urothelial carcinoma that progressed after 1 or 2 previous lines of platinum-based chemotherapy or recurred less than 12 months after perioperative platinum-based chemotherapy. Patients were randomized to receive pembrolizumab or investigator’s choice of chemotherapy, including docetaxel, paclitaxel, or vinflunine.

The 2 primary end points included OS and progression-free survival (PFS). PD-L1 expression was evaluated by central assessment, using a standardized immunohistochemical assay, and included staining of tumor cells, lymphocytes, and macrophages.

Data analysis comprised 542 patients. The patients’ median age was approximately 66 years. Men accounted for 75% of the study patient population, and 86% of patients had lower-tract disease. Overall, 85% to 90% of patients had visceral metastases, and 33% had liver metastases, reported Dr Bajorin. The majority of the patients received their most recent previous therapy in the first-line setting. Overall, 75% of patients had received cisplatin as their previous platinum-based chemotherapy.

The 2.9-month difference in the median OS translated into a 30% reduction in the hazard, in favor of the pembrolizumab arm (95% confidence interval, 0.57-0.86; P = .0004). The 12-month OS was 44.4% with pembrolizumab versus 30.2% with chemotherapy, and the 18-month OS was 36.1% with pembrolizumab versus 20.5% with chemotherapy. Subgroup analysis showed a consistent advantage of pembrolizumab over standard chemotherapy across all of the assessed clinical and demographic variables.

PFS did not differ between groups at 6 months (approximately 29%) but favored the pembrolizumab arm over the chemotherapy arm at 12 months (17.% vs 7.9%, respectively) and at 18 months (16.8% vs 3.5%, respectively). The median PFS did not differ significantly between the groups: 2.1 months with pembrolizumab versus 3.3 months with chemotherapy.

The objective response rate was nearly twice as high in the pembrolizumab arm (21.1%) versus the chemotherapy arm (11.0%). Responses to chemotherapy had a median duration of 4.4 months, whereas the median duration of response had yet to be reached with pembrolizumab.

Increased PD-L1 expression correlated with improved survival; patients who had combined PD-L1 staining ≥10% had a 43% reduction in the survival hazard with pembrolizumab (P = .0034). The objective response rate among patients with ≥10% combined PD-L1 staining was 20.3% with pembrolizumab compared with 6.7% with chemotherapy.

Pembrolizumab was associated with a more favorable safety profile compared with standard chemotherapy, because pruritus was the only adverse event that occurred more often with the PD-L1 inhibitor than with standard chemotherapy.

“The pembrolizumab survival benefit was maintained with longer follow-up,” said Dr Bajorin. “We observed a continued higher objective response rate with pembrolizumab, and responses were more durable with pembrolizumab versus chemotherapy. Pembrolizumab also had a better safety profile versus chemotherapy,” concluded Dr Bajorin.