Updated findings from the phase III KEYNOTE-045 trial confirmed the benefit of pembrolizumab (Keytruda) compared with chemotherapy in pretreated patients with locally advanced or recurrent urothelial cancer. Two-year follow-up of the trial presented at the 2018 Genitourinary Cancers Symposium demonstrated that overall survival was improved with pembrolizumab.
Joaquim Bellmunt MD, PhD
Updated findings from the phase III KEYNOTE-045 trial confirmed the benefit of pembrolizumab (Keytruda) compared with chemotherapy in pretreated patients with locally advanced or recurrent urothelial cancer. Two-year follow-up of the trial presented at the 2018 Genitourinary Cancers Symposium demonstrated that overall survival (OS) was improved with pembrolizumab.1
After median follow-up of 27.7 months, median OS was 10.3 months for patients treated with pembrolizumab versus 7.3 months for those randomized to chemotherapy. The risk of death was reduced by 30% with pembrolizumab compared with chemotherapy as a second-line treatment following disease progression on platinum-based chemotherapy (HR, 0.70;P= .00017).
“Level 1 evidence supports the use of pembrolizumab as a standard of care for this patient population,” said lead investigator Joaquim Bellmunt, MD, PhD, director of the Bladder Cancer Center, Dana-Farber Cancer Institute, Boston. “Pembrolizumab is the first immunotherapy to demonstrate superior survival over chemotherapy in patients with advanced urothelial carcinoma after failing platinum-based therapy.”
The KEYNOTE-045 was stopped prematurely after a planned interim analysis, with initial findings published in New England Journal of Medicine.2In these first results, median OS was 10.3 months with pembrolizumab versus 7.4 months for chemotherapy (HR, 0.73, P= .0022). The median progression-free survival (PFS) was 2.1 months in the pembrolizumab arm versus 3.3 months for chemotherapy arm (HR, 0.98; 95% CI, 0.81-1.19; P= .42). The objective response rate (ORR) was 21.1% versus 11.4% with chemotherapy, which consisted of complete response rates of 7% and 3.3%, respectively.
In the phase III study, patients with histologically or cytologically confirmed urothelial carcinoma who progressed and received ≤2 lines of systemic therapy were randomized to pembrolizumab (n = 270) at 200 mg every 3 weeks or investigator’s choice of chemotherapy (n = 272), which consisted of paclitaxel at 175 mg/m2, docetaxel at 75 mg/m2, or vinflunine at 320 mg/m2, each administered every 3 weeks.
The data cut-off for the updated analysis was October 26, 2017. At 24 months, 27% of patients in the pembrolizumab arm were still alive compared with 14.3% in the chemotherapy arm. The 27% “is similar to what we are seeing with other immune-sensitive diseases like melanoma,” Bellmunt said.
In the chemotherapy arm, 60.6% of patients received subsequent therapies, and some crossed over to immunotherapy. The extent to which this affected OS requires further exploration, said Bellmunt. As in the interim analysis, PFS did not differ significantly by treatment group, with a median of 2.1 months in the pembrolizumab arm versus 3.3 months in the chemotherapy arm (HR, 0.96,P= .31714).
The OS benefit with pembrolizumab was apparent regardless of the primary tumor site, expression of PD-L1, investigator’s choice of chemotherapy, presence of liver metastases, hemoglobin levels, and presence of visceral disease.
In PD-L1­positive patients, defined as ≥10% combined positive score (CPS), median OS was 8.9 months and 4.9 months in the pembrolizumab and chemotherapy arms, respectively, representing a 44% reduction in the risk of death (HR, 0.56;P= .00153). In those with low (<10 CPS) PD-L1 expression, median OS was again significantly superior in the pembrolizumab arm, at 10.8 months compared with 7.7 months in the chemotherapy arm (HR, 0.75;P= .00859).
ORR per RECIST v1.1, as assessed by blinded central review, was 21.1% versus 11.0% in the pembrolizumab and chemotherapy arms, respectively. In the pembrolizumab arm, the rate of CR improved to 9.3%, with no major change in the chemotherapy arm. The median time to response was 2.1 months in each group. The median duration of response was not reached in the pembrolizumab arm compared with 4.4 months in the chemotherapy arm.
In addition to OS, response rates were superior with pembrolizumab regardless of PD-L1 expression. In the PD-L1positive group, the median duration of response was not reached in the pembrolizumab arm and was 4.4 months in the chemotherapy arm. In those with PD-L1 CPS <10%, median duration of response was 24.6 months in the pembrolizumab arm and 6.9 months in the chemotherapy arm.
The toxicity profile was the same as that observed at the earlier analysis. The incidence of treatment-related adverse events (AEs) was lower with pembrolizumab compared with chemotherapy, respectively, for any grade (60.9% vs 90.2%) and for AEs of grade 3-5 severity (15.0% vs 49.4%). “We haven’t seen any signals of cumulative toxicity with subsequent follow-up,” said Bellmunt.
The discontinuation rates resulting from treatment-related AEs was 7.1% in the pembrolizumab arm and 12.9% in the chemotherapy arm.
“I think it is now clear that PD-1/PD-L1 targeted immunotherapy now has a role for most patients with advanced urothelial cancer,” said invited discussant Robert J. Jones, MD, PhD, director, CRUK Clinical Trials Unit, University of Glasgow, Beatson West of Scotland Cancer Center. In describing the magnitude of benefit with pembrolizumab in KEYNOTE-045, he pointed to the significant separation of the survival curves at 2 years, and the consistency of OS data with chemotherapy in this setting. “The chemotherapy arm is certainly not underperforming in this study,” he said. “If you look at the HR, it now appears to be quite stable.”
The FDA approved pembrolizumab as a second-line treatment for patients with urothelial carcinoma in May 2017, based on the initial analysis of the KEYNOTE-045 trial. The PD-1 inhibitor is also approved as a frontline therapy for patients with urothelial carcinoma, based on findings from the phase II KEYNOTE-052 trial. To support this approval, the phase III KEYNOTE-361 trial is currently exploring pembrolizumab with or without chemotherapy compared with chemotherapy alone (NCT02853305).