The PD-L1 inhibitor pembrolizumab continued to demonstrate an overall survival (OS) benefit compared with chemotherapy among patients with advanced urothelial cancer with no new safety signals, according to the third planned survival analysis of KEYNOTE-045 presented on June 5 (Abstract 4501).
KEYNOTE-045 was an open-label phase III trial in which 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy were randomly assigned 1:1 to receive pembrolizumab (200 mg every 3 weeks) or the investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine). It is now a mature trial, with 33 patients continuing to receive the study drug compared with no patients in the chemotherapy arm, Dean F. Bajorin, MD, FACP, FASCO, of Memorial Sloan Kettering Cancer Center, said.
Earlier data from the trial presented after a median follow-up of 14.1 months and published in The New England Journal of Medicine in March 2017 showed significantly longer median OS with pembrolizumab (10.3 months) compared with chemotherapy (7.4 months; hazard ratio [HR] for death 0.73, 95% CI [0.59, 0.91]; p = 0.002).1
That survival benefit was maintained at 18.5 months, Dr. Bajorin said, with an HR for death of 0.70 (95% CI [0.57, 0.86]; p = 0.0004). The benefit was maintained across all subgroups, regardless of age, ECOG performance status, prior therapy, liver metastases, histology, or investigator choice of chemotherapy.
The median survival in the pembrolizumab arm was the same as previously reported: 10.3 months (95% CI [8.0, 12.3]) compared with 7.4 months in the chemotherapy arm (95% CI [6.1, 8.1]), with significance remaining regardless of PD-L1 expression. At 18 months, 36.1% of patients receiving pembrolizumab were alive compared with 20.5% of patients receiving chemotherapy.
Progression-free survival (PFS) was not statistically significant. However, Dr. Bajorin said, the PFS at 18 months was 16.8% in the pembrolizumab arm compared with 3.5% for the chemotherapy arm, “inferring that the survival distribution and benefit will not change over further observation times.”
Patients receiving pembrolizumab demonstrated an objective response rate of 21.1% and a complete response rate of 7.8%, compared with 11.0% and 2.9%, respectively, in the chemotherapy arm.
The duration of response remains ongoing with pembrolizumab, Dr. Bajorin said, but was 4.4 months among patients receiving chemotherapy.
Fewer patients experienced treatment-related adverse events (AEs) with pembrolizumab compared with chemotherapy (any grade, 61.3% vs. 90.2%, respectively; grade > 3, 16.5% vs. 49.8%, respectively). The majority of AEs in the pembrolizumab cohort were pruritus, fatigue, and nausea, most of which were grades 1 and 2. Decreased neutrophil levels and neutropenia were rare among the patients who received pembrolizumab, but developed in approximately 15% of patients receiving chemotherapy, with a 7.5% febrile neutropenia rate.
Immune-related AEs were primarily grade 1 and 2, with hypothyroidism, pneumonitis, and hyperthyroidism as the most common. All immune-related AEs occurred in fewer than 10 patients.
“Data from this study support the use of pembrolizumab in patients following platinum chemotherapy as a new standard of care with level 1 evidence,” discussant Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center, said. However, he added, “it is worth noting that there are late adverse events related to immune events that are seen even beyond 1 year of therapy, and, therefore, continued monitoring and vigilance with these patients is necessary.”
Dr. Rosenberg called immunotherapy a “groundbreaking, dramatic breakthrough” in the treatment of urothelial cancer. “It has transformed the treatment of previously treated patients and patients with cisplatin-ineligible metastatic bladder cancer.”
However, he said, “despite these advances, a minority of patients benefit, with an objective response rate in the second-line setting ranging from 14.8% to 21.1%, and the median survival less than a year. More work is yet to be done.”