NCCN Update in Urothelial Bladder Cancer Highlights Checkpoint Inhibitors, Maintenance Therapy

Add urothelial bladder cancer to the list of cancer types that are seeing success with immunotherapy, despite some early failures.

The advent of checkpoint inhibitors has altered the treatment landscape in this disease, said Arlene O. Siefker-Radtke, MD, of The University of Texas MD Anderson Cancer Center, during last week’s National Comprehensive Cancer Network (NCCN) Virtual Annual Conference.

The NCCN Conference has grown in importance in recent years, as payers consider the group’s guidelines the gold standard for making decisions on whether to cover a therapy. Being added to the recommendations is a signal to the major national payers that a panel of independent experts has reviewed peer-reviewed evidence published at recent scientific meetings and deemed a therapy worthy of adding to the guidelines.

Radtke’s review focused on the immunotherapy landscape and offered updates on maintenance, combinations, and sequencing of therapy in urothelial bladder cancer, based on NCCN updates released March 22, 2021.

Gemcitabine plus cisplatin and the combination of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) remain typical frontline standards in urothelial cancer treatment, but immunotherapy agents are gaining interest—and chemotherapy and immunotherapy have the potential to be great together, Siefker-Radtke said. Research on single-agent immunotherapy in node-only disease, for example, has shown an improved response rates, but that rate diminishes in the metastatic setting, especially liver metastases.

“When we look at some of the randomized trials, we also see this potential evidence suggesting there's a group that do better initially with chemotherapy,” she said. “But it's the durability of immunotherapy in the long term that makes immunotherapy quite attractive. This may impact as well how we combine or how we incorporate the immune checkpoint inhibitors with systemic chemotherapy.”

Chemotherapy may affect antigen presentation and help enhance immune response in urothelial tumors. It may also increase PD-L1 expression, as it has in some non-small cell lung cancer patients; this could mean targeting PD-L1 may help improve outcomes in those tumors with high PD-L1 expression, a potential resistance mechanism.

While the potential benefits of combining immunotherapy chemotherapy are great, Siefker-Radtke said there are arguments against this option. Chemotherapy is immunosuppressive, and there is increased risk of neutropenia and lymphopenia, especially with gemcitabine, she said.

Early studies combining checkpoint inhibitors and chemotherapy also showed evidence of immune toxicity, without any survival benefit. What’s more, chemotherapy may promote tolerance to the immune response.

“As we think about 2 grade standards and how to incorporate them together, the question arose: ‘Which is best: combinations of chemotherapy with immunotherapy, maintenance strategies, or sequencing of the immune checkpoint inhibitor following response to therapy?’ And we have trials that have been presented in all 3 strategies in the setting of urothelial cancer,” she said.

Maintenance Therapy

One important update for 2021 involved maintenance: the guidelines include avelumab as a Category 1 recommendation for maintenance therapy. This is based on a trial that showed avelumab after platinum-based chemotherapy showed an improvement in overall survival compared with patients who did not receive avelumab.

Another approach is evaluating putting patients on a regimen of immune checkpoint inhibitors after they have received frontline chemotherapy but while disease is stable or better. Pembrolizumab is being studied; there has been benefit in PFS with this regimen in studies, but it did not translate to overall survival.

Combination Therapy

For combination therapy, Siefker-Radtke highlighted a study of neoadjuvant gemcitabine and cisplatin plus pembrolizumab, with results presented at the European Society of Medical Oncology (ESMO) 2018. The abstract showed promising results compared with those seen with cisplatin chemotherapy, but it was a small subset of patients. Trials are ongoing.

The combination strategy has also been examined in metastatic disease, with the IMvigor 130 trial looking at gemcitabine with atezolizumab vs atezolizumab alone. An interim analysis showed improvement in progression-free survival (PFS), but more work is needed to determine overall survival (OS).

Because these combination strategies have not yet shown an impact on OS, they are not reflected in NCCN guidelines.

The combination of enfortumab vedotin and pembrolizumab is another strategy being studied. “Keep in mind this frontline strategy is based on a small number of patients, and as a result, it is not FDA approved or on the NCCN guidelines,” she said. “But we are awaiting results for frontline trials combining these agents together in patients who are cisplatin ineligible, given the early promising results that have been published today.”

Sequencing Therapy

Siefker-Radtke described the sequencing approach as giving frontline chemotherapy, then waiting until disease progression to give the immune checkpoint inhibitor.

A study of patients who had failed prior platinum chemotherapy for metastatic disease and those who had progressed within 12 months of neoadjuvant or adjuvant treatment looked at pembrolizumab versus single-agent therapy with either paclitaxel, docetaxel, or vinflunine, the immune checkpoint addition improved response rated and OS with an improved toxicity profile compared to single-agent therapy.

In the NCCN Guidelines, pembrolizumab is the preferred regimen for urothelial cancer patients who have progressed following frontline chemotherapy. Where alternative preferred regimens are concerned, one recent change has been the removal of durvalumab from the recommended regimens following its voluntary withdrawal as a urothelial cancer indication after a negative trial.

“So what would you choose in the treatment of urothelial cancer patients? Would you combine chemotherapy with immunotherapy? I would argue the answer is not yet,” Siefker-Radtke said.

How to Proceed?

As investigators wait for results in atezolizumab--and pembrolizumab having negative results—a combination treatment with these 2 or other agents with an immune checkpoint inhibitor is not yet approved; thus, this combination shouldn’t be a regular choice in urothelial cancer, she said. Where maintenance therapy is concerned, there has been evidence of survival benefits; avelumab is the only agent approved in this setting.

In the sequencing strategy, pembrolizumab, nivolumab, atezolizumab, and avelumab are the currently approved and recommended agents following durvalumab’s recent voluntary withdrawal.