Immune Checkpoint Inhibitors, Expanding Trials Signal Progress in Advanced Urothelial Carcinoma

Following decades of little progress, the treatment landscape in advanced urothelial carcinoma is enjoying a period of growth in treatment options thanks the introduction of several novel drugs, including immune checkpoint inhibitors, according to Matthew Galsky, MD. He added that the publication of multiple phase 3 trials is a sign that the field heading in the right direction.

“Urothelial cancer has historically been an underfunded and understudied disease for a variety of reasons. That's really started to change, and we see the tide turning with a number of new developments in the field in terms of new therapies that are available,” he said. “The number of large clinical trials that have read out in the past few years is greater than the number of trials that have been done over the past several decades. The progress is palpable, and this momentum needs to continue to better serve our patients.”

In an interview with OncLive^®, Galsky; professor, Medicine, Hematology and Medical Oncology, and Urology, as well as director, Genitourinary Medical Oncology, Mount Sinai Hospital; discussed the impact of recent developments in the advanced urothelial carcinoma treatment paradigm.

OncLive^®: Can you briefly speak to the speak to treatment landscape of advanced urothelial carcinoma?

Galsky: This field has changed dramatically in the past several years, from the introduction of immune checkpoint blockade for the treatment of patients with metastatic urothelial cancer based on single-arm phase 2 studies in a few different disease states to multiple randomized clinical trials trying to refine the use of these treatments and trying to define optimal disease states to apply these treatments.

What are the pivotal trials in this patient population?

[There are] several large, randomized phase 3 studies that have read out in the past few years, which address 3 major sets of clinical questions. The first question has been, should we give chemotherapy plus immune checkpoint blockade together for the treatment of metastatic urothelial cancer? That question was tackled by the phase 3 IMvigor130 trial [NCT02807636] and the phase 3 KEYNOTE-361 trial [NCT02853305].

The next question is whether we should give immune checkpoint blockade alone vs chemotherapy alone to patients with metastatic urothelial cancer. That question was tackled by three studies: the IMvigor130 trial, the KEYNOTE-361 trial, and the phase 3 DANUBE trial [NCT02516241].

The next question is whether we should give doublet immune checkpoint blockade, [which] is PD-L1 blockade plus CTLA-4 blockade. That question has been addressed by the DANUBE study.

The final question looks at whether we should give switch maintenance immune checkpoint blockade. Should we give chemotherapy up front and, in patients who have at least stable cancer after chemotherapy, immediately use immune checkpoint blockade? That question was addressed by the phase 3 JAVELIN Bladder 100 [NCT02603432].

What is the current standard of care for this patient population?

Based on the culmination of randomized phase 3 studies that have been done over the past few years in patients with metastatic urothelial cancer who are treatment-naive, upfront platinum-based chemotherapy still remains the standard of care. But, now after patients have at least 4 cycles of treatment, if there is at least stable disease on imaging, then switching to maintenance immune checkpoint blockade has become a standard treatment supported by level 1 evidence demonstrating survival benefit in the setting of phase 3 randomized studies.

Are there still unmet needs to be addressed?

There are a number of unmet needs in this patient population. Immune checkpoint blockade, when it works, really works quite well. Unfortunately, only a subset of patients respond to treatment. We need to understand why that is and we need to develop combination regimens to overcome intrinsic or acquired resistance.

There are a number of combination strategies that have been demonstrated to be active in patients with metastatic urothelial cancer and now have advanced to late-stage clinical testing. We expect to see some of those regimens integrated into our standard treatment approaches within the next few years.

What does the future look like in this space? Are there any roadblocks or challenges that you foresee?

The field has really exploded with a number of new treatment options for urothelial cancer. This is a field where for decades, we really had only chemotherapy, and we really had only a few chemotherapy regimens that were considered standard care. Now, we have a number of new approvals spanning different drug classes, spanning different clinical disease states. So, a number of new treatments [are] available.

Of course, the key is going to be to define how to best use the current treatments that we have to optimize individual outcomes for patients. Even with all these advances, we still need better and safer treatments. Drug development in this disease remains a priority.