A Closer Look at the Most Recent NCCN Guidelines for Bladder Cancer

Thomas Flaig, MD

The treatment landscape for patients with bladder cancer has rapidly changed with the addition of PD-1 and PD-L1 inhibitors approved for urothelial carcinoma, antibody drug conjugates like enfortumab vedotin-ejfv (Pacdev), and targeted agents such as erdafitinib (Balversa) for patients with select FGFR mutations.

With the many new advances, NCCN guidelines now include the use of avelumab (Bavencio) as maintenance therapy, and immune checkpoint inhibitors (ICIs) are also listed as a first-line treatment option for cisplatin-ineligible patients with PD-1-positive or platinum-ineligible disease.

Updates to systemic therapies include new roles for ICIs in patients with BCG-unresponsive non-muscle invasive bladder cancer as well as the adjuvant treatment of muscle-invasive bladder cancer post cystectomy.

“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. The use of these agents initially started out as a later-line of therapy and these agents are being tested across different disease states,” noted Thomas Flaig, MD, in an interview with Targeted Oncology^TM.

These areas are continuing to evolve with phase 3 trials further supporting the use of avelumab as first-line maintenance therapy for those with metastatic disease, but without progression on initial chemotherapy treatment and pembrolizumab (Keytruda) in the second-line, post-platinum setting.

“For those of us that are treating bladder cancer and have that privilege, we've seen our options from even a few years ago where they were limited and they weren't well evidenced, to now 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 we are going to further improve the outcomes of our patients with bladder cancer.” added Flaig, vice chancellor of research for the University of Colorado Denver, member, University of Colorado Cancer Center, and the University of Colorado Anschutz Medical Campus, Chair of the NCCN Guidelines Panel for Bladder Cancer.

In the interview with Targeted Oncology^TM, Flaig further discussed the updates to the 2022 NCCN guidelines for patients with bladder cancer and explained how the field has evolved over the past few years.

Targeted Oncology: Can you discuss some of the current NCCN guidelines in bladder cancer?

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.

What in this space has led to these impactful changes for guidelines?

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've 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.

What treatment options are currently available for non-muscle invasive and muscle invasive bladder cancer?

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 sytemic 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 cancercellsbut 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.

What is it important to keep in mind when examining these NCCN guidelines?

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 contributeinto the development of guidelines along that multidisciplinary approach.

What unmet needs still exist in the bladder cancer space?

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 FGFRmutations 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.

For community oncologists, what would you say are the key recommendations to take away from these guidelines?

Whenever I get a chance to speak about the treatment of bladder cancer and our current approaches, it's a time of optimism, I would say. When I have trainees with me in clinic, including fellows or medical residents, I say that you have to do update yourself with bladder cancer, because whatever you learned a few years ago is rapidly changing. I think for any of us that have the privilege of treating patients with bladder cancer and the guidelines are a great and comprehensive resources in a time of rapid change.

There's a couple of things to take away from this. One is that there is an importance to mutational assessment in bladder cancer. We now have targeted therapy, we have approved therapies for patients that have specific FGFR mutations, that's been a recent development. For patients that undergo surgery, new adjuvant therapy has now been defined through recent clinical trials, for example, immune checkpoint inhibitors in that setting, depending on the pathological risk or the residual tumor that might exist at the time of resection. It's important to think about those patients who are undergoing surgery and have residual disease found at the time of surgery and cystectomy.

In terms of advanced bladder cancer patients and patients that are metastatic, it has become a lot more complicated in the last few years. That's a good thing since we have more options to integrated into our care plans. But I would encourage providers who don't see many patients and maybe aren't doing this every day to keep abreast of what those changes are and the integration of antibody drug conjugates. The use of new checkpoint inhibitors has also become a more complex considedation, depending on the patient's cisplatin eligibility, platinum eligibility, or and previous treatment. I would encourage all providers that are treating advanced patients to review the guidelines, review the changes and implement the best regimen based on this rapidly changing area.

With all of the advancements in the field, what are you most excited for in the future?

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 bein 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?