Most in the field are by now well-acquainted with the famous diagram of the cancer immunity cycle. This diagram continues to get more crowded with a population of newly discovered modulators that affect the cycle at different points. We currently target a small minority of these modulators; and in particular, we have FDA-approved drugs that target the PD-1/PD-L1 and CTLA-4 axes, which are both responsible for inhibiting the immune response against tumor cells.
These checkpoint inhibitors were initially studied and approved as 2nd-line therapy for metastatic bladder cancer. There are several drugs now clinically available, and response rates in Phase III trials have been around 15-20% across the board. The historic response rates to standard chemotherapy regimens is about 36%, so there may be some evidence (though difficult to analyze across studies and time periods) of lesser effectiveness of immunotherapies. That being said, it appears that checkpoint inhibition has a more durable duration of response.
The successes in 2nd line therapy have led to trials and recent approvals of these drugs in the 1st-line space. Atezolizumab, with a 23% response rate and strong response durability, was recently approved as a 1st-line agent for cisplatin-ineligible patients. There is no doubt that more of these drugs will be shown to have favorable 1st-line activity, and we should expect to see the indication for immunotherapy continue to creep forward in the treatment algorithm for high-risk and/or metastatic bladder cancer. Indeed, pembrolizumab, nivolumab, and atezolizumab all have concurrent trials underway in the neoadjuvant/adjuvant therapy space for patients undergoing curative-intent treatment for high-risk bladder cancer. These same drugs are also under clinical investigation for BCG-unresponsive nonmuscle-invasive bladder cancer (NMIBC).
A takaway point from these trials is that even though checkpoint inhibitors appear to be well tolerated, there exists a population of patients that do experience severe toxicity. The 5 main trials in this space have all reported around 15% adverse event rates. Urologists should familiarize themselves with the immune-related toxicities of these agents, such as pneumonitis and colitis. Early diagnosis and intervention is key to preventing morbidity from immunotoxicity.
Progression in the field will require improved biomarkers to provide rational care. Currently, PD-L1 immunohistochemistry is the most widely used biomarker. Unfortunately, there virtually no uniformity in how trials were designed to utilize these markers; and as such, there is no clear guidance on when or how these biomarkers should be used. As Dr. Black correctly points out, we either need better biomarkers or better consensus on how to use the ones we have.
The last step in realizing the full potential of immune modulation is by more thoroughly understanding “the immunologic synapse”. This refers to the multitude of checkpoint molecules that have been identified but still await agents to effectively target them. Combination therapies of various checkpoint inhibitors, or of checkpoint inhibitors with non-immune therapy will soon be the preferred treatment paradigm for bladder cancer.
We should take note that only about 20% of patients are responding to these treatments. We must continue to push hard to make a difference for the remaining 80%.
Presented By: Peter Black, MD, FACS, FRCSC, University of British Columbia
Written By: Shreyas Joshi, MD, Fox Chase Cancer Center
at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA