The following checkpoint inhibitors are approved by the FDA for use in the US for urothelial carcinoma, all at q2-3 week scheduling: Atezolizumab, Nivolumab, Durvalumab, Avelumab, and Pembrolizumab. However, only Pembrolizumab has level 1 evidence that supports its use.
The KEYNOTE 45 study (NCT02256436) evaluated patients with predominately transitional cell carcinoma of the renal pelvis, ureter, bladder or urethra treated with pembrolizumab in the post-cisplatin space. 542 patients were randomized to: 1) pembrolizumab or 2) paclitaxel or docetaxel or vinflunine, with primary end points of overall and progression free survival. Of all patients in the pembrolizumab cohort, 21.1% of patients had an objective response (7.8% complete, 13.3% partial), compared to 11.0% in the chemotherapy cohort (2.9% complete, 8.1% partial). However, in PD-L1 positive patients, pembrolizumab had a complete response of 20.3% compared to 6.7% in the chemotherapy cohort. There were no differences in progression free survival (p=0.32), but there were statistical improvements in overall survival (HR 0.70 95%CI 0.57-0.86). When analyzed by subgroup, current smokers tended to have better responses with pembrolizumab compared to chemotherapy, but no differences were demonstrated on PD-L1 status. Physicians must keep in mind the wide disparity of adverse events associated with pembrolizumab, despite the reported benefit of quality of life in pembrolizumab compared to chemotherapy-treated patients.
The IMvigor 211 study randomized patients with metastatic urothelial carcinoma to atezolizumab or chemotherapy. This complicated statistical model did not demonstrate any differences in overall survival (p=0.41). However, on an intention to treat analysis, OS was improved in patients on atezolizumab compared to chemotherapy (HR 0.85 95%CI 0.73-0.99). When the specific chemotherapeutic regimen was analyzed, atezolizumab demonstrated a survival benefit compared to taxane therapy.
Multiple phase II studies have been published leading to accelerated checkpoint inhibitor approval in the United States. Overall response of these drugs for urothelial cancers post platinum therapy range from 13.4% (atezolizumab) to 21.1% (prembrolizumab). This dramatic improvement compared to the history control of chemotherapy (10% response) is a great starting point but leaves researchers hungry for more.
Finally, in cisplatin-ineligible patients, overall response of 23-24% is lower than Gem/Carbo (36%). Overall survival is longer with at atezolizumab then gem/carbo, but data for pembrolizumab is still immature. Future randomized controlled trials are needed to better understand the evidence to support treatment guidelines in the cisplatin-ineligible space.
Presented by: Elizabeth Plimack, MD, MS, Fox Chase Cancer Center, Philadelphia, PA
Written by: David B. Cahn, DO, MBS, Fox Chase Cancer Center, Philadelphia, PA, Twitter: @dbcahn at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC