Assessing Long-Anticipated Treatment Advances in Metastatic Urothelial Cancer

Nancy B. Davis, MD

Checkpoint inhibitors and novel agents, such as erdafitinib (Balversa), enfortumab vedotin-ejfv (Padcev), and sacituzumab govitecan have shown encouraging single-agent activity in patients with advanced urothelial cancer, said Nancy B. Davis, MD. Now, the next steps are to evaluate these agents both in combination and in earlier lines of therapy.

“We’re going to see more combinations [emerge]. Thus far, we've seen chemotherapy combined with immunotherapy. We're going to see erdafitinib or other FGFR inhibitors combined with immunotherapy, as well,” said Davis. “We’re also anxiously awaiting neoadjuvant data for immunotherapies in patients who are platinum-ineligible.”

The most recent advancement in the paradigm is the accelerated approval of enfortumab vedotin for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy. The approval is based on results from the first cohort of patients in the phase II EV-201 trial, which showed that enfortumab vedotin elicited an overall response rate of 44% in patients with locally advanced or metastatic urothelial cancer.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Davis, associate professor of medicine, Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, discussed the excitement with targeted therapies as well as anticipated combination strategies under investigation in advanced urothelial cancer.

OncLive: Could you highlight some of the targeted therapies that have emerged in advanced urothelial cancer?

Davis: Erdafitinib is a targeted therapy that has been approved for use in patients with FGFR mutations. It's really an exciting time in urothelial cancer. We now have many options for patients and many trials are going to lead to even more of them.

Could you discuss the impact of erdafitinib’s approval on the treatment paradigm?

The agent is approved for use in a small population of patients. However, it’s very exciting for patients who have the [FGFR] mutation. The mutation tends to occur earlier in the development of disease. Currently, erdafitinib is approved in the second- or later-line setting for patients with this mutation. In ongoing studies, [investigators] are trying to move the agent up front. These patients don't tend to respond as well to platinum-based therapies or immunotherapy, so getting the right drug for the right patient in the right setting is very important. We're expanding the treatment armamentarium for [our patients with urothelial cancer], which hasn't happened in a long time.

Is there rationale to evaluate the agent in combination with immunotherapy?

I believe so. Studies are being designed and others are ongoing that are looking at combining erdafitinib with immunotherapy in earlier settings in this patient population.

How prevalent are FGFR mutations in patients with urothelial cancer?

Somewhere between 10% and 15% of patients [with urothelial cancer have FGFR mutations]. It's a select population, but as we know in ALK-positive lung cancer, [targeted agents] were groundbreaking and have led to better overall outcomes. I expect [FGFR inhibitors] to do the same in urothelial cancer.

Do you expect to see a rise in genetic testing as more targeted agents enter the space?

[I do]. We're currently [sending genetic testing] for every patient with metastatic disease. It probably needs to be done earlier for patients with muscle-invasive disease as we learn more about these drugs. In oncology, we always [test agents in the] metastatic setting [and evaluate them in the] first-line setting. In urothelial cancer, the next question will be whether [erdafitinib] [is effective] in the frontline setting, and if so, whether it will work in the neoadjuvant setting.

Could enfortumab vedotin be the next targeted therapy to receive approval in urothelial cancer?

We certainly hope so. [Enfortumab vedotin is] an exciting development. A cohort from the [EV-201] trial was presented at the 2019 ASCO Annual Meeting. Enfortumab vedotin is a targeted agent to Nectin-4. Every patient in the subset that was presented expressed Nectin-4. [Nectin-4] seems to be much more prevalent in patients with urothelial cancer. [If the agent is approved], it too will be tested in earlier settings to see whether it provides more benefit than our traditional platinum-based regimens. [The agent may] also show benefit in [earlier lines of therapy in] platinum-ineligible patients.

Could you shed light on the data that were presented on sacituzumab govitecan at the 2019 ESMO Congress?

It was a phase I/II trial. [The agent is being examined in an] ongoing phase II trial with 2 separate cohorts of patients who had immune-oncology (IO)—based therapies and were platinum ineligible, and those who received platinum as well as IO-based therapies. The data are early, but they’re exciting. The agent is more chemotherapy-like, so it carries more chemotherapy-like AEs.

What are your thoughts on the data from the IMvigor130 trial with atezolizumab (Tecentriq)?

[We saw an improvement in] progression-free survival [with the combination of atezolizumab and chemotherapy], but it’s too early [to see if there was an] overall survival [benefit]. The PFS data with atezolizumab were very exciting and showed a substantial improvement versus chemotherapy alone.

With these novel agents, how are you approaching sequencing?

We always worry about sequencing. Having many agents is a luxury. Patients who have FGFR2/3 mutations are eligible for erdafitinib after first-line therapy, but we'll see if that agent can be moved up and provide more benefit to that subgroup of patients.

Editor’s Note: This interview took place prior to the December 2019 FDA approval of enfortumab vedotin-ejfv for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.

Petrylak DP, Balar AV, O'Donnell PH, et al. EV-201: results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol. 2019;37(suppl; abstr LBA4505). doi: 10.1200/JCO.2019.37.18_suppl.LBA4505.