Recent Developments Solidify Role of Immunotherapy in Advanced Urothelial Carcinoma

Matthew Galsky, MD

Platinum-based chemotherapy has long been the standard-of-care treatment for patients with advanced urothelial carcinoma. However, data from several recent clinical trials have shown that immunotherapy, both alone and in combination, may have a role in the treatment of this population, according to Matthew Galsky, MD.

“Based on the culmination of randomized phase 3 studies that have been done over the past few years in patients with metastatic urothelial carcinoma who are treatment naïve, upfront platinum-based chemotherapy remains the standard of care,” Galsky said. “However, after patients have at least 4 cycles of treatment, if there is stable disease on imaging, then switch maintenance immune checkpoint blockade has become a standard treatment, supported by level 1 evidence that has demonstrated survival benefit in the set- ting of phase 3 randomized studies.”

In an interview with OncLive^® ahead of his presentation, Galsky, a professor of medicine, hematology, and medical oncology, director of genitourinary medical oncology at Mount Sinai, and codirector of the Center of Excellence for Bladder Cancer, and associate director for translational research at the Tisch Cancer Institute, both in New York, New York, discussed the role of immunotherapy in urothelial cancer, as well as unmet needs and future research directions for this patient population.

OncLive^®: Your presentation will focus on state-of-the-art use of immunotherapy. Please provide an overview of some of the main points you will be highlighting.

Galsky: I will be speaking about the use of immunotherapy in urothelial cancer. 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—which was based on single-arm phase 2 studies in a few different disease states—to now multiple randomized clinical trials which are trying to refine the use of these treatments and define optimal disease states in which to apply them.

What are some of the pivotal trials you will be touching on in your presentation?

I will be speaking about several large, randomized phase 3 studies that have read out in the past few years, which address 4 major sets of clinical questions [TABLE].

The first question is, should we give chemotherapy plus immune checkpoint blockade together for the treatment of metastatic urothelial cancer? That question was tackled in the phase 3 IMvigor130 [NCT02807636] and KEYNOTE-361 [NCT02853305] trials.

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

Another question is whether we should give doublet immune checkpoint block- ade, such as PD-L1 blockade plus CTLA-4 blockade, and the question was addressed by the DANUBE study as well.

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

TABLE. Phase 3 Immunotherapy Trials in Urothelial Carcinoma

What are some unmet needs, or questions that remain to be answered for this population?

There are several unmet needs in this patient population. When immune checkpoint blockade works, it really works quite well, but unfortunately only a subset of patients respond to treatment. We need to understand why that is.

Additionally, we need to develop combination regimens to overcome intrinsic or acquired resistance. There are a number of combination strategies that have been 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 you foresee?

The field has really exploded with several new treatment options for urothelial cancer. This is a field where, for decades, we only had chemotherapy, and only had a few chemo- therapy regimens that were considered standard of care. Now we have a number of new approvals spanning different drug classes and spanning different clinical disease states. There are several new treatments available, and 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 of these advances, we still need better and safer treatments, so drug development in this disease remains a priority.

What is your take-home message?

The most important takeaway is the progress that has been made in this field. Urothelial cancer has historically been an underfunded and under-studied disease for a variety of reasons, and that has really started to change. We see the tide turning with several new developments in the field, in terms of new therapies that are available. 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, so the progress is palpable. This momentum needs to continue to better serve our patients.