The Expanding Landscape of Immunotherapy in Urothelial Bladder Cancer

Immunotherapy agents have seen widespread use across cancer types in recent years, changing the game for several disease types. At the National Comprehensive Cancer Network (NCCN) Virtual Annual Conference, Arlene O. Siefker-Radtke, MD, discussed immune checkpoint inhibitors and their potential in urothelial bladder cancer.

While gemcitabine plus cisplatin and the combination of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) are typical frontline standards in urothelial cancer treatment, immunotherapy agents have been of interest in this disease type for some time. And despite early failures in immunotherapy plus chemotherapy in urothelial cancers, approvals and advances in treatment—namely the advent of immune checkpoint inhibitors—have altered the treatment landscape.

Chemotherapy and immunotherapy are both great standards, and they have potential to be even better 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.”

She added that chemotherapy may impact 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, meaning that 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 also noted that there are reasons not to do so. 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 and no apparent impact on overall survival. There has also been evidence that chemotherapy may promote tolerance to the immune response, she explained, which is another reason why giving chemotherapy with immunotherapy may have a negative impact.

“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.

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. More trials are ongoing in this area.

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 has seen improvement in progression-free survival (PFS), but further research is needed to determine overall survival (OS).

Because these combination strategies are yet to be proven to impact OS, these strategies combining chemotherapy with a checkpoint inhibitor are not yet FDA approved or included 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.”

Maintenance Therapy

A maintenance approach, putting patients on a regimen of immune checkpoint inhibitors after they have received frontline chemotherapy but while disease is stable or better, is also being evaluated.

A trial of maintenance avelumab after platinum-based chemotherapy showed an improvement in OS compared with patients who did not receive avelumab. This year's NCCN guidelines include avelumab as maintenance therapy.

Pembrolizumab as maintenance therapy is not FDA approved but is being studied. There has been benefit in PFS with this regimen in studies, but it did not translate to overall survival.

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?

With results still awaited in atezolizumab and pembrolizumab having a negative trial, combination treatment with these 2 or other agents with an immune checkpoint inhibitor is not yet approved and shouldn’t be used regularly to treat urothelial cancer, she said.

Where maintenance therapy is concerned, there has been evidence of survival benefits, and it is FDA approved and included in the NCCN guidelines. Avelumab is the only agent approved in this setting, she noted.

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

Other settings where there is potential for immunotherapy in urothelial cancer are superficial urothelial cancer, particularly patients with carcinoma in situ who have progressed following BCG intravesical therapy. Pembrolizumab is approved in this population and included in the NCCN guidelines.

The combination of immunotherapy with adjuvant therapy is also being explored. Promising research in high-risk patients and in those with PD-L1 high tumors was presented at ASCO GU this year. The PD-L1–high cohort in particular appeared to benefit. “We do have a sense of a potential plateau arising that perhaps we are impacting the long-term outcome, which may possibly translate to improve to cure in these patients.” Siefker-Radtke said. Still, OS benefit has not been confirmed and this strategy is not yet approved.

Overall, the treatment landscape for urothelial cancers is diversifying with the addition of immune checkpoint inhibitors, with hope for more in the future, she said.

“There's multiple other settings where immune checkpoint inhibitors are currently under study and are showing promise,” she said. “So we hope to be able to add to the FDA approval list with the use of immune checkpoint inhibitor.”