Median survival after chemotherapy in metastatic disease is 12-15 months with MVAC and Gemcitabine + Cisplatinum. Cisplatinum improves survival, however 50-70% of patients are ineligible due to comorbidities. These patients are prone very poor outcomes.
Unfortunately, cisplatin based chemotherapy (MVAC in particular) is associated with significant toxicity. Cisplatin toxicity include nephrotoxicity, ototoxicity, neurotoxicity and vascular toxicity (cardiovascular, cerebrovascular, thromboembolic events in up to 20%, and Raynaud’s phenomenon).
Immune check point inhibitors (ICPI) have been introduced to the world of bladder cancer, and have been recently incorporated by FDA as first line therapy in cisplatin ineligible metastatic UC and in 2nd line metastatic UC as well. The Imvigor210 phase 2 trial analyzed Atezolizumab in metastatic UC, and has shown an overall objective response rate (ORR) of 16%. However, recently the trial investigators have published in the media that their study did not meet its primary endpoint of overall survival (OS) compared to chemotherapy.
Another ICPI trial is the Checkmate 275, assessing the role of Nivolumab in the setting of metastatic UC. The results showed an ORR of 19.6%, with better results as the PD-L1 percentage rose (<1% vs. >1%), with an OS of 8.74 months.
Another trial is the Keynote 045 assessing Pembrolizumab in the setting of UC of the renal pelvis, bladder, ureter and urethra. Patients were all after 1-2 lines of platinum based chemotherapy, and were either randomized to Pembrolizumab or to 2nd line of chemotherapy. In this phase 3 trial the ORR has been shown to be 21.1%. The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).
An additional trial is KEYNOTE 052 – examining Pembrolizumab as a 1st line therapy for cisplatin ineligible patients. This trial has demonstrated an ORR of 29%, with even better numbers, as the number of PD-L1 positive immune and tumor cells rose. Lastly, study 1108 was presented assessing dose escalation and expansion in patients with advanced solid tumors receiving Durvalumab. This study showed an ORR of 20%.
Summarizing the recent immunotherapy trial results, the ICPI are active and well tolerated and have transformed bladder cancer therapy with the most important advancement in over 30 years. The FDA has approved 5 ICPI as 2nd line chemotherapy. Their median OS rate is approximately 7-11 months, with an ORR of 15-21%. The FDA has also approved 2 ICPI as first line therapy in cisplatin ineligible patients.
Presented By: Arjun Balar, MD, NYU Langone Medical Center, New York, NY
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
at the 2017 Bladder Cancer Academy - June 9 - 10 - Schaumburg, Illinois, USA