Results of an international randomized phase III study show that pembrolizumab (Keytruda) as second-line therapy for advanced urothelial carcinoma provided superior overall survival and a better safety profile compared with commonly used chemotherapy options.
Results of KEYNOTE-045, an international randomized phase III study, show that pembrolizumab (Keytruda) as second-line therapy for advanced urothelial carcinoma (UC) provided superior overall survival and a better safety profile compared with commonly used chemotherapy options.
The findings were published online in the New England Journal of Medicine (Feb. 17, 2017). As reported at the Genitourinary Cancers Symposium in Orlando, FL, pembrolizumab was also associated with substantially better health-related quality of life relative to chemotherapy, said Joaquim Bellmunt, MD, PhD.
Dr. Bellmunt, of Harvard Medical School and Dana-Farber Cancer Institute, Boston, is lead author of the New England Journal of Medicine study. He told Urology Times, “Pembrolizumab is the first and, at this point, the only checkpoint inhibitor to demonstrate an overall survival advantage over chemotherapy for advanced UC in a randomized phase III study. Pembrolizumab is also the only checkpoint inhibitor to demonstrate a substantial improvement in health-related quality of life in patients with advanced UC.”
“Nivolumab (Opdivo), atezolizumab (Tecentriq), and durvalumab have demonstrated promising outcomes as second-line therapy for advanced UC in phase II studies, and data from phase III trials for some of these checkpoint inhibitors are eagerly awaited.”
Patients enrolled in KEYNOTE-045 had advanced UC that recurred or progressed after platinum-based chemotherapy. A total of 542 patients were randomized to receive pembrolizumab, 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel (Taxol), docetaxel (Taxotere), or vinflunine.
After a median follow-up duration of 14.1 months, there were a total of 334 deaths. Median overall survival was approximately 3 months longer in patients treated with pembrolizumab compared with the control group (10.3 months vs. 7.4 months; hazard ratio for death 0.73, p=.002). Estimated survival rate at 12 months was 43.9% for pembrolizumab and 30.7% for chemotherapy.
Subgroup analyses showed that the benefit of pembrolizumab for improving overall survival was consistent regardless of ECOG performance status, tumor programmed death-ligand 1 (PD-L1) expression level, primary tumor location (upper or lower tract), or receipt of one versus two prior therapies for advanced disease.
Progression-free survival (PFS), which was analyzed as a coprimary endpoint, did not differ significantly between the pembrolizumab and chemotherapy groups (hazard ratio 0.98, p=.42). Pembrolizumab was associated with a significantly higher objective response rate compared with chemotherapy (21.1% vs 11.4%; p=.001).
Dr. Bellmunt noted that results from several other phase III studies investigating checkpoint inhibitors as second-line therapy in patients with other types of cancer similarly showed no PFS advantage for the immunotherapy compared with chemotherapy or targeted therapy.
“Improved overall survival benefit remains the gold standard for assessing the benefit of anticancer immunotherapies. The general lack of a PFS benefit for immunotherapy compared with chemotherapy and targeted therapy may reflect underlying differences in mechanism of action, but it is interesting to note that PFS curves do start to separate in favor of immunotherapy at 12 months,” Dr. Bellmunt said.
The KEYNOTE-045 safety analysis showed pembrolizumab was associated with lower rates of both treatment-related adverse events compared with chemotherapy (60.9% vs 90.2%) and grade 3-5 treatment-related adverse events (15.0% vs 49.4%, respectively). The most common treatment-related adverse events in the pembrolizumab group were pruritus (19.5%), fatigue (13.9%), and nausea (10.9%). No grade 3-5 treatment-related adverse events associated with pembrolizumab occurred at a rate ≥5%.
A role for pembrolizumab as earlier intervention for bladder cancer (eg, bacillus Calmette–Guérin-refractory non-muscle invasive bladder cancer) is also under investigation. Positive results were also reported at the Genitourinary Cancers Symposium from the single-arm, first-line phase II KEYNOTE-052 study investigating pembrolizumab as first-line treatment for metastatic or locally advanced bladder cancer in “unfit patients,” Dr. Bellmunt said.
“In KEYNOTE-052, pembrolizumab showed encouraging antitumor activity and a manageable safety profile in patients with advanced bladder cancer not eligible for first-line cisplatin-based therapy, particularly in the subgroup with strong tumor PD-L1 expression (combined positive score >10%). Now, the phase III KEYNOTE-361 study is underway investigating pembrolizumab as first-line therapy for advanced UC compared with pembrolizumab plus standard-of-care chemotherapy or standard-of-care chemotherapy alone,” Dr. Bellmunt added.
The study was supported by Merck. Dr. Bellmunt is a consultant to and on the advisory boards for Genentech, Merck, Astra-Zeneca and Pfizer. For a full list of disclosures, click here.
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