Metastatic disease has a median survival of 12-14 months and first line treatment is cisplatin based chemotherapy with a response rate of 45-60%. However, cure rates remain low. Additionally, 50-70% of patients are ineligible due to comorbidities, and are prone to very poor outcomes. Until recently no approved second line options were available. Most commonly used agents were taxanes or vinflunine with a response rate of 10-15%. Therefore, there is a significant unmet therapeutic need in 2nd line metastatic UC.
Immunotherapy is not a new concept in bladder cancer. BCG, a type of immunotherapy, is the standard of care for high risk non-muscle invasive bladder cancer (NMIBC). Its mechanism of action is unclear and it prevents recurrence by up to 67%. The cancer immunity cycle is a series of stepwise events leading to effective killing of cancer cells. 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 urothelial carcinoma (mUC) and in 2nd line mUC as well.
The Imvigor210 phase II trial analyzed Atezolizumab in mUC, and has shown an overall objective response rate (ORR) of 16%. However, recently the trial investigators have stated that this 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 mUC. 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 advanced bladder cancer 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 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 in the chemotherapy group .ORR has been shown to be 21.1%. 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.
Looking ahead, the DANUBE study, is a planned first line combination study randomizing 1300 patients who are platinum eligible or ineligible with locally advanced/metastatic disease. The 3 arms include an ICPI alone, 2 ICPI combination, and gemcitabine + cisplatinum. This manifests the next step of immunotherapy in cancer, to see whether a combination therapy is more effective than a single agent.
Speaker: Kala S. Sridhar, MD, MSc, FRCPC, University of Toronto, Princess Margaret Hospital, Toronto, Canada
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre Twitter: @GoldbergHanan at the 72nd Canadian Urological Association Annual Meeting - June 24 - 27, 2017 - Toronto, Ontario, Canada