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Pembrolizumab Continues to Demonstrate Durable Efficacy with No New Safety Signals After Up To 5 Years of Follow-Up in Patients with Metastatic Urothelium Cancer

Findings from the KEYNOTE-045 study in patients with platinum-resistant metastatic urothelial cancer and from the KEYNOTE-052 as first-line treatment for cisplatin-ineligible patients
17 Jan 2023
Urothelial Cancer

After up to 5 years of follow-up, use of pembrolizumab in the KEYNOTE-045 and KEYNOTE-052 studies continued to demonstrate durable responses and tolerability with no new safety signals. Consistent with prior results, pembrolizumab continued to demonstrate overall survival (OS) benefit versus chemotherapy in the second-line setting for patients with metastatic urothelial cancer whose disease progressed on platinum-containing chemotherapy. OS rates at 48 months were higher and the median duration of response (DoR) was more than sixfold longer for pembrolizumab than for chemotherapy in KEYNOTE-045. Fewer patients experienced treatment-related adverse events with pembrolizumab than with chemotherapy, which is similar to the prior analysis. KEYNOTE-052 represents the largest dataset of treatment-naive, cisplatin-ineligible patients with metastatic urothelial cancer treated with single-agent immune checkpoint inhibitor (ICI). Front-line pembrolizumab continued to demonstrate durable clinical benefit, with an objective response rate (ORR), median DoR and 36-month DoR results consistent with prior studies of other ICIs in a similar patient population. Findings from updated safety and efficacy results after up to 5 years of follow-up of the KEYNOTE-045 and KEYNOTE-052 studies are published by Dr. Ronald de Wit of the Department of Medical Oncology, Erasmus MC Cancer Institute in Rotterdam, The Netherlands, Dr. Peter H. O’Donnell of the Department of Medicine, Section of Hematology/Oncology, The University of Chicago in Chicago, IL, USA and colleagues on 6 December 2022 in the Annals of Oncology.  

The treatment landscape in advanced urothelial carcinoma changed as ICIs became an established option for patients both in the first-line cisplatin-ineligible setting and in patients who experienced failure of platinum-containing chemotherapy.

In the phase III KEYNOTE-045 study in the platinum-refractory metastatic urothelial cancer setting, OS was significantly longer for patients treated with the PD1 inhibitor pembrolizumab versus docetaxel, paclitaxel, or vinflunine chemotherapy. In addition, the rate of treatment-related adverse events was lower for pembrolizumab versus chemotherapy, suggesting a favourable safety profile. These data formed the foundation for use of pembrolizumab as a standard treatment option in patients with platinum-refractory metastatic urothelial cancer.

To address the need for alternative front-line treatments for cisplatin-ineligible patients, the phase II KEYNOTE-052 study of first-line pembrolizumab in patients with cisplatin-ineligible metastatic urothelial cancer demonstrated a confirmed ORR of 28.6% with a median DoR of 30.1 months (95% confidence interval [CI] 18.1 months to not reached). These data currently support the US Food and Drug Administration (FDA) indication for pembrolizumab in platinum-ineligible patients with metastatic UC, as well as the European Medicines Agency indication in cisplatin-ineligible patients with metastatic urothelial cancer and a PD-L1 combined positive score of ≥10.

Given the potential for long-term durable disease control with immunotherapies in other cancers, longer-term follow-up data are of interest to confirm the durability of these practice-changing results for pembrolizumab in advanced urothelial cancer. In the latest article published in the Annals of Oncology, the authors presented updated safety and efficacy results after up to 5 years of follow-up in KEYNOTE-045 and KEYNOTE-052 studies.

In KEYNOTE-045, patients with metastatic urothelial cancer that progressed on platinum-containing chemotherapy were randomly assigned 1:1 to receive pembrolizumab or investigator’s choice of paclitaxel, docetaxel, or vinflunine. Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and OS. In KEYNOTE-052, cisplatin-ineligible patients with metastatic urothelial cancer received first-line pembrolizumab. The primary endpoint was ORR per RECIST v1.1 assessed by BICR.

A total of 542 patients were randomly assigned in KEYNOTE-045 study, 270 patients to pembrolizumab and 272 to chemotherapy. At data cut-off on 1 October 2020, the median follow-up was 62.9 months (range, 58.6-70.9 months). At 48 months, OS rates were 16.7% for pembrolizumab and 10.1% for chemotherapy; PFS rates were 9.5% and 2.7%, respectively. The median DoR was 29.7 months (range, 1.6+ to 60.5+ months) for pembrolizumab and 4.4 months (range, 1.4+ to 63.1+ months) for chemotherapy; 36-month DoR rates were 44.4% and 28.3%, respectively.

A total of 370 patients were enrolled in KEYNOTE-052 study. At data cut-off on 26 September 2020, the median follow-up was 56.3 months (range, 51.2-65.3 months). The confirmed ORR rate was 28.9% (95% CI 24.3-33.8), and the median DoR was 33.4 months (range, 1.4+ to 60.7+ months); the 36-month DoR rate was 44.8%.

Most treatment-related adverse events for pembrolizumab in either study were grade 1 or 2 and manageable, which is consistent with prior reports.

The authors commented thar a number of biomarkers that characterise the tumour microenvironment, such as the 18-gene T-cell–inflamed gene expression profile (TcellinfGEP) and tumour mutational burden (TMB), are hypothesized to be associated with response or resistance to PD1/PD-L1 inhibitors. An exploratory analysis of KEYNOTE-045 and KEYNOTE-052 examined whether TcellinfGEP, TMB, and epithelial-mesenchymal transitional/stroma-related gene expression (stromal signature) were associated with outcomes of pembrolizumab monotherapy in advanced urothelial cancer. The association between PD-L1 expression and clinical outcomes was evaluated in a parallel analysis.

PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes in KEYNOTE-052, whereas in KEYNOTE-045 only TMB and TcellinfGEP were associated with improved outcomes. In addition, no biomarkers were consistently associated with any outcomes for patients who received chemotherapy in KEYNOTE-045. Further investigation into biomarkers as predictors of response is warranted.

The authors concluded that pembrolizumab continued to show durable antitumour activity with manageable safety both in the first-line setting for cisplatin-ineligible patients and in the second-line platinum-refractory setting up to 5 years after the last patient enrolled. Pembrolizumab continued to show an OS benefit over chemotherapy in patients with advanced platinum-resistant or platinum-refractory urothelial cancer enrolled in KEYNOTE-045, providing level I evidence in this setting. The role of and FDA approval of pembrolizumab in the first-line setting are limited to platinum-ineligible patients.

The data were previously presented in part at the ASCO 2021 Annual Meeting.

This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.


Balar AV, Castellano DE, Grivas P, et al. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Annals of Oncology; Published online 6 December 2022. DOI: https://doi.org/10.1016/j.annonc.2022.11.012

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