“A majority of patients that present with bladder cancer do not have muscle invasive disease. They have earlier stage, non-muscle invasive, and the NCCN guidelines have detailed guidance for providers about managing those patients,” said Thomas Flaig, MD.
In recent interview, Thomas Flaig, MD, chair of the NCCN Guidelines Panel for Bladder Cancer, discussed the latest guideline updates and explained how the field has evolved over the past few years. Flaig is a medical oncologist and vice chancellor of research for the University of Colorado Denver and the University of Colorado Anschutz Medical Campus.
Flaig: For bladder cancer, we think about it broadly and the NCCN guidelines certainly have captured this. The treatment of bladder cancer has undergone a period of very rapid change over the last 5 or more years. If you'd look back 10 years ago, we had very little development in terms of new drugs and new therapies for bladder cancer. Then 5 or 6 years ago, we had the introduction of immune checkpoint inhibitors, and more recently, the integration of those across several different disease states in bladder cancer.
More recently with the addition of antibody-drug conjugates and targeted therapies with FGFR inhibitors and so forth, it's been a period of rapid growth in the therapeutic armamentarium for bladder cancer. The NCCN guidelines have worked to assess new data and decide how the guidelines should be changed along those lines. It is a very exciting time in bladder cancer for providers, patients, and advocates.
One thing that's really defined the treatment of bladder cancer patients in the last 5 years or so has been the introduction of immune checkpoint inhibitors. These initially started out as a later-line of therapy and these agents are now being tested and integrated across different disease states. It became apparent early on that bladder cancer was going to be an area of special interest for these agents with clear activity. We saw the introduction of multiple immune checkpoint inhibitors, again, in a later-line, advanced metastatic setting.
More recently, we have seen the introduction of immune checkpoint inhibitors in the non-muscle invasive BCG-unresponsive setting. In a different clinical indication, we've seen the introduction of immune checkpoint inhibitors in the high-risk adjuvant or post-operative setting as well. We've seen broad testing of these agents and now the maturation of these results to where immune checkpoint inhibitors are applied in diverse settings across the disease spectrum.
Within the muscle invasive disease area, which is localized and extensive, we've seen rapid development of new therapies over a number of years in all areas. In the non-muscle invasive disease, we've seen the introduction of systemic immune checkpoint inhibitors, specifically for the BCG-unresponsive, high-risk patients in those ineligible for or unable to undergo cystectomy. In muscle invasive disease, we've seen the use of immune checkpoint inhibitors in the post-operative, high-risk setting. Then in the muscle invasive metastatic, so the advanced disease, we've seen again, a tremendous amount of activity with clinical trials and development.
There has been category 1 data to support the use of checkpoint inhibitors after platinum based therapies, and that's made a major impact. Also there have been 2 antibody-drug conjugates that are included in the guidelines now. For example, enfortumab vedotin-ejfv and sacituzumab govitecan [Trodelvy]. This is a relatively new class of drugs, antibody-drug conjugates, with specific antibodies that target tumor related antigens or targets. What they're looking for is an antigen on the cell surface that's selective—where it is seen with cancer cells but not in normal tissues, where there's a very high differential between these.
Then, there's a targeted payload associated with these antibodies. We've seen the use of these drugs now that are tested in maturing trials and they have been integrated into the guidelines to provide a newer class of drugs that's shown to be efficacious in advanced bladder cancer. Then there is also the realm of targeted therapies. People call this personalized medicine or targeted therapy where you assess the patient’s tumor for specific targets and look at their mutational signature. This is done frequently in lung cancer for example, but has not previously been a significant part of bladder cancer therapy. We've found that for patients that have selective FGFR mutations, it's efficacious to give an FGFR inhibitor. One of the major changes we've seen when you think about bladder cancer is the idea of looking for mutations. If certain mutations are present, then specific drugs become available for those patients.
Bladder cancer is divided into different classes, so if we think about non-muscle invasive bladder cancer, the muscle parts speak to the idea of the muscularis propria, the muscle the bladder, and is that invaded? A majority of patients that present with bladder cancer do not have muscle invasive disease. They have earlier stage, non-muscle invasive, and the NCCN guidelines have detailed guidance for providers about managing those patients with TURBT or trans urethral resection of bladder tumors, and with intravesical therapy which is given directly into the bladder via catheter using BCG and other agents in that setting. Sometimes systemic therapies such as immune checkpoint inhibitors are also used in certain refractory cases.
I think what that highlights, for example in non-muscle invasive bladder cancer, is the NCCN guideline approaches generated by a multidisciplinary group. We have as members of our committee, the bladder cancer committee, urologists, medical oncologists, radiation oncologists, and some other specialists that all contribute into the development of guidelines along that multidisciplinary approach.
For all the advancements that we've had in bladder cancer with new drugs in the last few years, antibody-drug conjugates, better standard of adjuvant therapies, and so forth, I would say that 1 areas that's the biggest unmet need would be that of predictive biomarkers.
Who are the patients that are going to most benefit from any immune checkpoint inhibitors? Which patients need upfront chemotherapy when they're eligible to receive? Again, we use biomarkers effectively to screen for FGFR mutations for specific treatments, but how about antibody-drug conjugates? What about some of the novel combinations that are now being investigated? What are the best ways to select those patients going forward?
In some disease settings like lung cancer, we have been very effective in developing predictive biomarkers. I hope that is something that we can move towards in bladder cancer so that as we continue to have more agents that are available for treatment, we can be as selective and personalized as possible for those patients who are most likely to respond to a specific drug, and perhaps who is likely to have significant adverse events and who should avoid them for that reason.
I feel privileged to be someone who's able to treat patients with bladder cancer, be involved in the investigation looking for new drugs in this setting and to be involved in the NCCN guidelines for bladder cancer. Years ago, I think there was some nihilism about looking for new therapies or our success in identifying approaches, going through clinical trials, and approving drugs. When I was starting my career, there was a nihilism around our ability to succeed in this. It was believed this wasn't a fruitful area for us to develop new therapies. But that's out the door now and it is just the opposite.
There is no question that we can be successful in finding new agents for bladder cancer, we can identify biologic pathways, we can test those in the laboratory, we successfully design and execute clinical trials that develop new drugs. It's a remarkably exciting time to being this area. For those of us that are treating bladder cancer, we've seen our treatment options expand to now be evidence-based, multi-layer, multi-line approaches to treatment. That makes it a remarkably exciting time. In fact, 1 of the most exciting things is what's next and how are we going to further improve the outcomes of our patients with bladder cancer?