Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up.

Background: Immune checkpoint inhibitors are a standard therapy in metastatic urothelial carcinoma (UC). Long-term follow-up is necessary to confirm durability of response and identify further safety concerns.
Patients and Methods: In KEYNOTE-045, patients with metastatic UC that progressed on platinum-containing chemotherapy were randomly assigned 1:1 to receive pembrolizumab or investigator's choice of paclitaxel, docetaxel, or vinflunine. Primary end points were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). In KEYNOTE-052, cisplatin-ineligible patients with metastatic UC received first-line pembrolizumab. The primary end point was objective response rate (ORR) per RECIST v1.1 by BICR.
Results: A total of 542 patients (pembrolizumab, n = 270; chemotherapy, n = 272) were randomly assigned in KEYNOTE-045. Median follow-up was 62.9 months (range, 58.6-70.9; data cutoff October 1, 2020). At 48 months, OS rates were 16.7% for pembrolizumab and 10.1% for chemotherapy; PFS rates were 9.5% and 2.7%, respectively. Median duration of response (DOR) was 29.7 months (range, 1.6+ to 60.5+) for pembrolizumab and 4.4 months (range, 1.4+ to 63.1+) for chemotherapy; 36-month DOR rates were 44.4% and 28.3%, respectively. A total of 370 patients were enrolled in KEYNOTE-052. Median follow-up was 56.3 months (range, 51.2-65.3; data cutoff September 26, 2020). Confirmed ORR was 28.9% (95% CI, 24.3-33.8), and median DOR was 33.4 months (range, 1.4+ to 60.7+); 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.
Conclusion: With approximately 5 years of follow-up, pembrolizumab monotherapy continued to demonstrate durable efficacy with no new safety signals in patients with platinum-resistant metastatic UC and as first-line therapy in cisplatin-ineligible patients. Clinical trial registry and ID: ClinicalTrials.gov, NCT02256436 (KEYNOTE-045) and NCT02335424 (KEYNOTE-052).
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