EAU 2017: Pembrolizumab produces clinically meaningful responses as first-line therapy in cisplatin-ineligible advanced urothelial cancer: Results from subgroup analyses of KEYNOTE-052

London, England (UroToday.com) Immunotherapy, as is well known, can have a potentially huge impact in the management of urothelial carcinoma. Bladder cancer, with its large mutational load, appears to be acutely susceptible to immunotherapy. Pembrolizumab (Pembro) is a PD-1 receptor inhibitor, previously established in the Keynote-045 study, to be effective in patients with metastatic urothelial carcinoma as a second-line agent after failing cisplatin based chemotherapy. However, in this study, Keynote-052 (NCT02335424), the focus is moving Pembro into the pre-chemotherapy space as a first line agent. Specifically, they utilize it in patients who are cisplatin ineligible.

This large, randomized controlled trial was completed at 12 international institutions.

Key eligibility criteria:
Age ≥18 y
Advanced UC of the renal pelvis, ureter, bladder, or urethra
Cisplatin ineligibility (ECOG PS 2, creatinine clearance ≥30 to <60 mL/min, grade ≥2 neuropathy or hearing loss, NYHA Class 3 heart failure)
No prior systemic chemotherapy for advanced UC
Measurable disease (RECIST v1.1)
Provision of a tumor sample for biomarker analyses.

* Of note, 42% of patients were ECOG 2. 85% had visceral metastases. This is a very high-risk group.

Methods: Pembro 200 mg was administered every 3 weeks.
Imaging was performed at week 9, then every 6 weeks for the first year, and every 12 wk thereafter.

Outcomes: The primary end point was confirmed overall response rate (ORR; RECIST v1.1). This was completed as an independent review. Efficacy data are presented for patients with ≥4 mo follow-up. Safety data was a secondary endpoint.

Key Findings: (images not available)
370 patients enrolled.

  • ORR was 24% for all patients
  • In patients who were enrolled at least 4 months – 27%
  • 58% had tumor size reduction
  • Median time to response: 2 months
  • 83% of patients had ongoing response
  • Median response has not been reached
  • 6% of patients achieved a complete response (CR)
  • Essentially all subsets demonstrated benefit
  • Biomarker specific for pembrolizumab = “combined positive score” (CPS)
  • CPS ≥10% PD-L1 (tumor and immune cell PD-L1 expression) with ≥4 mo: ORR 44% (34%-55%)
  • Noted that this group also had a higher CR rate ~10%
  • Only 19 patients discontinued medication due to drug-related toxicity

These results are very exciting and are part of the new era of bladder cancer therapy.
This abstract won best poster in session.

Limitations / Discussion Points:
As Dr. Powles mentioned, the future discussion may not revolve around cisplatin eligibility, but rather biomarker positivity.

Presented by: Thomas Powles

Co-Authors: Bellmunt J., Castellano D., O’Donnell P., Grivas P., Vuky J., Plimack E., Hahn N., Balar A., Pang L., Savage M., Perini R., Keefe S., Bajorin D., De Wit R.

Institution(s): 12 International (European, UK, US) institutions

Written by: Thenappan Chandrasekar, Clinical Fellow, University of Toronto

Twitter: @tchandra_uromd

at the #EAU17 -March 24-28, 2017- London, England