Bladder Cancer Guidelines Highlight Arrival of Immunotherapy

Thomas W. Flaig, MD

Thomas W. Flaig, MD

Recent therapeutic updates incorporated into the National Comprehensive Cancer Network (NCCN) guidelines for patients with urothelial cancer showcase the evolution of a field that had seen little change for more than 30 years.

For example, recommendations for muscle-invasive bladder cancer now include cisplatin-based combination chemotherapy, as well as chemotherapy plus radiation therapy.

Moreover, for those with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, there has been the addition of 5 checkpoint inhibitors to the space.

“The biggest change in data in the bladder cancer guidelines occurred last year with the advent of checkpoint inhibitors,” said Thomas W. Flaig, MD. “Those have been integrated, and there have been multiple drugs approved.”

One of these approvals includes the PD-1 inhibitor pembrolizumab (Keytruda), which was approved as a treatment for these patients following a prior line of cisplatin or carboplatin. While many other checkpoint inhibitors are being investigated in clinical trials, the only category 1 designation currently available in bladder cancer is for pembrolizumab.

At the 2019 NCCN Annual Conference, Flaig updated the audience on the latest changes and additions to the National Comprehensive Cancer Network (NCCN) guidelines for bladder cancer, including the role of checkpoint inhibitors and in which patient populations these agents could be most beneficial.

In an interview withTargeted Oncology, Flaig, professor, associate dean for clinical research, Genitourinary Cancer Program, Division of Medical Oncology, University of Colorado, Denver, discussed the latest updates to the NCCN guidelines for the treatment of patients with muscle-invasive bladder cancer. In addition, he highlights the latest approvals of checkpoint inhibitors in this patient population.

TARGETED ONCOLOGY:What are the recent updates to the NCCN guidelines for muscle-invasive bladder cancer?

Flaig: The NCCN bladder cancer guidelines have been quite active over the last several years. Traditionally, if you go back 30 years, there was very little therapeutic development in bladder cancer. In the last 3 or 4 years, there have been 5 new checkpoint inhibitors added to the guidelines. In addition to that, we’ve recently looked at the treatment of muscle-invasive disease. These are patients with invasions to T2 to T4A and are treated with curative, radical approaches. The 2 category 1 designations for muscle-invasive bladder cancer is cisplatin-based chemotherapy followed by surgery versus a combination of chemotherapy and radiation therapy, of which both are category 1.

TARGETED ONCOLOGY:How are these updates being integrated into clinical practice?

There are a couple of major ways the guidelines have been integrated into clinical practice in the last year. One is, again, the inclusion of both cisplatin-based combination chemotherapy for muscle-invasive disease, as well as chemotherapy/radiation therapy as a category 1 [recommendation] for muscle-invasive disease.

In addition, the American Joint Committee on Cancer staging guidelines have changed. The NCCN guidelines panel was essentially confronted with new guidelines in which we had to apply data that were generated under old guidelines and see how they best fit. For example, the new category of stage IIIA disease, which is minimal lymph node involvement, or IIIB, which is more extensive regional involvement, is now incorporated into the guidelines. For these patients, you use aggressive chemotherapy upfront and then use more aggressive local therapy for those patients who have great responses as a part of the guidelines. If a patient has lymph node disease, receives down-staging chemotherapy and has a great response, you could consider radiation therapy or consolidative surgery in those patients, and that is a change.

TARGETED ONCOLOGY:Could you discuss some of the data supporting these updates?

The biggest change in data in the bladder cancer guidelines occurred last year with the advent of checkpoint inhibitors. Those have been integrated, and there have been multiple drugs approved. One of those, pembrolizumab, [was approved] in the post-platinum setting, so for patients who received cisplatin or carboplatin in the first-line setting, progressed, they then received pembrolizumab. That is a category 1 designation. Amongst immune checkpoint inhibitors, it is the only category 1 we have right now.

The major change has been the staging guidelines, which were altered and updated in 2017. Based on the data we have for staging, based on the lymph node-only disease, those patients previously categorized as stage IV disease could have a better prognosis, and in most cases, have a more aggressive therapy approach. It would be appropriate if they respond well to chemotherapy.

TARGETED ONCOLOGY:How can these updates impact quality of life in this patient population?

The dramatic change I have seen in bladder cancer over the last several years, particularly in patients with advanced bladder cancer, is the approval of 5 checkpoint inhibitors for bladder cancer. We finally have our foot in the door. We would be hard pressed to say what the developments were before that. Really, we would have said that we moved chemotherapies into different combinations, so this is a new class of highly effective drugs.

For patients in the clinic, we are looking for high response rates. Right now, response rates are in the 20% to 25% range with monotherapy checkpoint inhibitors. What we would like to see would be much higher response rates. What patients and the providers clearly want is durable responses that are well tolerated. We are seeing that now with checkpoint inhibitors, but the clinical trials that are underway right now looking at combining checkpoint inhibitors, such as PD-1/PD-L1 inhibitors with CTLA-4 inhibitors or checkpoint inhibitors with chemotherapy. Those trials are underway, and many of us hope that they can give us a high response rate with similar durability over time.

TARGETED ONCOLOGY:What criteria do you use to decide patient selection for some of these therapies?

Patients with muscle-invasive bladder cancer are candidates for surgery/radiation, and it should be offered. For the checkpoint inhibitors, there are rare patients who should receive that upfront, but most patients should receive chemotherapy first and then the checkpoint inhibitors in the second-line setting.

TARGETED ONCOLOGY:What is your take-home message from these updates?

It is an optimistic time in bladder cancer right now. For those of us who have been focused on this disease for a long time, we have been a bit discouraged by the lack of therapeutic progress overtime. Really, for 30 years, there was almost nothing new. By the same light, we are now void in seeing multiple drugs being approved and multiple clinical trials.

The biggest problem we have right now in terms of drug development for bladder cancer is simply selecting the trials that we can complete and get readout to benefit patients.