IO/Targeted Combos Poised to Enter Metastatic Urothelial Carcinoma Paradigm

Daniel P. Petrylak, MD, professor of Medicine and Urology, co-director, Signal Transduction Research Program, Yale School of Medicine

Daniel P. Petrylak, MD

The rapid influx of immunotherapy and targeted therapy approvals in metastatic urothelial carcinoma has led research efforts to pivot toward potentially enhancing response rates with combination regimens, said Daniel P. Petrylak, MD.

"We have more options available for the treatment of metastatic disease," said Petrylak. "Back 6 or 7 years ago, we did not have checkpoint inhibitor therapies or targeted agents approved."

Regarding immunotherapy, atezolizumab (Tecentriq) and pembrolizumab (Keytruda) have been approved by the FDA to treat patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy and whose tumors express PD-L1.

In the second-line setting, the checkpoint inhibitors pembrolizumab, atezolizumab, durvalumab (Imfinzi), nivolumab (Opdivo), and avelumab (Bavencio) are approved for patients who progress on or following cisplatin-based chemotherapy.

The targeted therapy erdafitinib (Balversa), an FGFR3/FGFR2 inhibitor, received an accelerated approval in April 2019 for the treatment of patients with locally advanced or metastatic bladder cancer with an FGFR3 or FGFR2 alteration that have progressed on platinum-containing chemotherapy.

Most recently, in December 2019, enfortumab vedotin-ejfv (Padcev), a Nectin-4—directed antibody–drug conjugate, also received accelerated approval for the treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting.

With the influx of approved agents, combination strategies have become a relevant avenue to investigate with the goal of enhancing response rates, said Petrylak.

For example, at the 2019 ESMO Congress, data from the phase Ib/II EV-103 trial demonstrated an objective response rate (ORR) of over 70% with the combination of enfortumab vedotin and pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer.

Updated results presented at the 2020 Genitourinary Cancers Symposium reported an ORR of 73% including a 15.6% complete response (CR) rate and 57.8% partial response rate with the combination at a median follow-up of 11.5 months. Median duration of response had not been reached, suggesting the responses are durable.

As a result, the FDA granted a breakthrough designation to the combination as first-line treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are ineligible to receive cisplatin-based chemotherapy.

In an interview with OncLive, Petrylak, a professor of medicine and urology at Yale Cancer Center, and a 2017 Giant of Cancer Care^® in Genitourinary Cancer, discussed the current treatment landscape of metastatic urothelial carcinoma and exciting strategies in the pipeline.

OncLive: What is the state of immunologic and targeted therapy in metastatic bladder cancer?

Petrylak: The role of immune therapy and targeted therapy is evolving in metastatic disease.

As far as immunotherapy, atezolizumab and pembrolizumab are approved as frontline therapy for patients who are not eligible to receive cisplatin-based chemotherapy and are PD-L1—positive.

As frontline therapy, atezolizumab was shown to be better than chemotherapy in [the IMvigor210] randomized trial. Now, that is our standard first-line treatment.

In the second-line setting, there are 5 checkpoint inhibitors approved for use in metastatic bladder cancer. There is no way to distinguish between these except for the fact that only pembrolizumab has positive phase III data.

[The KEYNOTE-045] trial showed an overall survival (OS) benefit with pembrolizumab over dealer's choice of chemotherapy in that setting.

As far as targeted therapy is concerned, we have 2 agents currently approved. Erdafitinib should be used for patients who are FGFR2/FGFR3 positive and have had prior platinum-based chemotherapy. That can also include patients who have had prior checkpoint inhibitor therapy. This accounts for about 10% to 20% of all patients with metastatic urothelial carcinoma.

Enfortumab vedotin, which targets Nectin-4, is also approved by the FDA for patients who received platinum-containing chemotherapy and 1 prior checkpoint inhibitor therapy.

Regarding the 5 checkpoint inhibitors, is pembrolizumab the preferred agent as it has phase III data or are other agents like durvalumab still relevant?

They are all relevant drugs, but the agent that does have phase III data is pembrolizumab. If you are being a strict clinical trial purist, that is the one that shows a positive survival benefit.

In your opinion, what were some of the most compelling data you saw at the 2020 Genitourinary Cancers Symposium?

The most compelling data is [from EV-103], the combination study of enfortumab vedotin and pembrolizumab in patients who are platinum-ineligible. We saw almost a 90% tumor shrinkage rate, which is very similar to the rate that we saw presented at the 2019 ESMO Congress.

This is an exciting combination, but the data are still evolving. Certainly, this response rate with a high CR rate of about 14% is impressive.

Do you think it could extend to patients who are platinum-eligible or is platinum established?

We have to look at the platinum-ineligible data carefully to see if enfortumab vedotin/pembrolizumab shows a better survival than what you would see from historical controls with cisplatin-based chemotherapy.

We need a clinical trial in order to identify whether this is going to be equivalent to or better than cisplatin-based chemotherapy.

What are your thoughts on the NEODURVARIB trial data looking at the combination of durvalumab and olaparib (Lynparza) prior to surgery in resectable urothelial bladder cancer?

It is interesting to see complete responses with this because that correlates with OS. This needs to be evaluated in randomized trials later on, but certainly the data are intriguing.

What is your take-home message to colleagues?

Going forward, we need to make sure patients receive next-generation sequencing early in their metastatic disease course. If a patient progresses, you want to be ready. If they have an FGFR3 mutation, they should go on erdafitinib. If they also progressed on these other agents, enfortumab vedotin is a standard of care.

We have multiple options which can be used, but the question is what is the optimal sequence? Of course, should we start thinking about erdafitinib combined with enfortumab vedotin in an FGFR-positive patient.

It would be interesting to see a triplet with checkpoint therapy, as well. We've got a lot of work to do as we have yet to hit the ball out of the park.

Rosenberg JE, Flaig TW, Friedlander TW, et al. Study EV-103: preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2020;38(suppl; abstr 441).