Petrylak Previews Shift in Sequencing Paradigm in Urothelial Cancer

Daniel P. Petrylak, MD, highlights the use of checkpoint inhibitors, antibody-drug conjugates, and FGFR inhibitors in urothelial cancer and the current sequencing hurdles in the paradigm.

The addition of checkpoint inhibitors, antibody-drug conjugates, and FGFR inhibitors to the urothelial cancer armamentarium has been a welcome one, but has lent itself to a pile of sequencing questions for both platinum-eligible and -ineligible patients, according to Daniel P. Petrylak, MD.

Determining the optimal course of action prior to erdafitinib (Balversa), when or if to give a patient maintenance avelumab (Bavencio), and decision-making in the fourth-line setting are all questions investigators are seeking to answer to optimize outcomes. Further, ongoing clinical trials that are exploring these drug classes in the localized settings will be key to determining how select agents perform for those with earlier-stage disease.

“[It is important to note that] any chance you can enter a patient in a clinical trial may help us answer these particular questions about sequencing and about how to best use our drugs,” Petrylak said.

Petrylak will give the presentation, “Sequencing Therapy Throughout the Urothelial Carcinoma Treatment Continuum” on Friday, November 11 during the 40th Annual Chemotherapy Foundation Symposium® (CFS®). In an interview with OncLive®, Petrylak, professor of medicine (medical oncology) and of urology and coleader of Cancer Signaling Networks at Yale Cancer Center in New Haven, Connecticut, highlighted the use of these agents in urothelial cancer and the current sequencing hurdles in the paradigm.

OncLive®: You are discussing bladder cancer treatment at this year’s CFS®. What are some notable changes in the armamentarium that will be highlighted?

Petrylak: I will highlight the various options that we do have for treatment of patients with urothelial carcinoma and focus on both platinum-eligible and -ineligible patients [Table1]. The sequences [for each of these subsets] are different and why they can be different for these tumors [will be covered, as well].

For example, in a platinum-ineligible patient, drugs such as pembrolizumab [Keytruda] or atezolizumab [Tecentriq] are FDA approved and they are used in those patients who have positive PD-L1 staining. Chemotherapy can be administered afterwards.

However, I think a lot of us are thinking about how we sequence these treatments. For example, the JAVELIN Bladder 100 study [NCT02603432] looks at the combination of those patients who have responded to chemotherapy. It looks at giving maintenance avelumab in this group of patients, which is standard of care.

Irrespective of PD-L1 status, [patients] could receive maintenance avelumab [after either] immunotherapy followed by chemotherapy or chemotherapy followed by immunotherapy. PD-L1 is a selection factor, but I also like to look at the patient’s need to get their disease under control. That’s certainly an issue with patients who have rapid progression, particularly with visceral disease.

When we start looking at [sequencing] second-line and third-line therapies, there are 3 checkpoint [inhibitors] approved for second-line therapy in the United States: pembrolizumab, avelumab, and nivolumab [Opdivo].

Enfortumab vedotin-ejfv [Padcev] is [an antibody-drug conjugate that is] approved for patients who have progressed on chemotherapy and checkpoint inhibitor therapy.

What do you do in a patient who [harbors] an FGFR3? Erdafitinib is approved for these patients [and] there are no randomized data that tell us which drugs should be selected beforehand. In the fourth-line setting, where you could have sacituzumab govitecan-hziy [Trodelvy] you may have a patient with FGFR3-positive [disease and] there are no data comparing FGFR3-targeted therapy with erdafitinib with sacituzumab govitecan. I think it’s important to think about that and do trials in that [setting].

What clinical trials have had a hand in revolutionizing sequencing strategies for these patient populations?

[Many] trials are moving these therapies up earlier. For example, the CheckMate 274 study [NCT02632409] [looked] at nivolumab as adjuvant therapy after cystectomy for patients with muscle-invasive bladder cancer.

There are [ongoing] neoadjuvant trials looking to move checkpoint inhibitors up even earlier. This is going to compose a very important question as to whether a patient—if they have developed metastatic disease after one of these trials—whether they should [receive retreatment with a] checkpoint inhibitor? Can they potentially respond? What’s the optimal duration of time after that response that checkpoint therapy may or may not work? We don't have any data for that.

With the EV-302 [NCT04223856] and EV-103 [NCT03288545] trials with enfortumab vedotin, investigators are moving enfortumab vedotin up earlier. Is that going to shuffle the deck again? Should we use chemotherapy as a second-line agent after enfortumab vedotin? How long do you need to continue enfortumab vedotin? These are all very relevant, important questions.

How are you hoping to see urothelial cancer treatment progress in the future?

What we need are better molecular markers, we don’t have them at this point. Except for FGFR3, we don’t have a marker that will help us understand whether a patient responds to enfortumab vedotin, chemotherapy, or sacituzumab govitecan. We have some clues, but we just need more prospective confirmation.

What unmet needs in this patient population is the bladder cancer community aiming to address?

An unmet need is that we still need a curative agent. We are seeing some very remarkable long-term responses with enfortumab vedotin [alone or with] pembrolizumab in the early phase 1/2 experience. The real question is: Will that translate to a phase 3 trial? I’m excited about the fact that we have new drugs, and we’re clearly seeing our patients living longer than they did before.


Flaig TW, Spiess PE, Abern M, et al. NCCN guidelines insights: bladder cancer, version 2.2022. J Nat Comp Cancer Network. 2022;20(8):866-878. doi:10.6004/jnccn.2022.0041