Navigating a “Sea Change” in Frontline Urothelial Carcinoma Treatment

With what one expert described as a “sea change” having occurred in the frontline treatment of urothelial carcinoma, providers are facing the issue of how to best tailor therapy for individual patients.

“Now we have two very potent combination entities that are FDA approved in the frontline setting, and the question is, ‘How do we personalize and improve patient selection for frontline treatment now that patients are living, on average, more than 2 years with this aggressive cancer?’” said David H. Aggen, MD, PhD, a genitourinary medical oncologist and cellular therapist with Memorial Sloan Kettering Cancer Center in New York, New York during a talk at the 2024 Chemotherapy Foundation Symposium (CFS), hosted by Physicians’ Education Resource, LLC.¹

The last 18 months have seen the FDA approvals of both enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial cancer in December 2023, and nivolumab (Opdivo) plus cisplatin and gemcitabine for patients with unresectable or metastatic urothelial carcinoma in March 2024, as Aggen recounted during his presentation.

Referencing the findings of the randomized, open-label, phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) that led to the approval of enfortumab vedotin and pembrolizumab in this patient population, Aggen noted that “what happens for most patients is they respond and their tumor burden decreases, but there's a cumulative toxicity that's a task for patients.”

In EV-302, treatment-related adverse effects (TRAEs) that led to dose reductions of either drug occurred in 40.7% and 37.9% of patients on the enfortumab vedotin/pembrolizumab and chemotherapy arms, respectively; TRAEs that led to treatment discontinuation occurred in 35.0% and 18.5% of patients, respectively. In the enfortumab vedotin arm, the TRAEs that led to treatment discontinuation in more than 1% of patients included peripheral sensory neuropathy (10.7%), pneumonitis (2.0%), maculopapular rash (1.6%), immune-mediated lung disease (1.4%), and paresthesia (1.4%).²

“So, we know that at a year, about 50% of patients are still on therapy or have completed therapy and have not had progression of disease. Yet it's only about 25% of patients within the first 6 months that have progression, and it's in this other 75% of patients with stable disease or better that I think [we] need to be better about adapting the dosing to maximize efficacy and minimize toxicity.”

One factor that can potentially be used to guide treatment, Aggen noted, is circulating tumor DNA (ctDNA).

“The standard of care is to continue enfortumab vedotin and pembrolizumab as long as patients are tolerating and benefiting clinically,” he explained. “But for patients with concerns about toxicity, ctDNA may be another tool that you can use to help tailor treatment.”

For example, a patient treated with EV and pembrolizumab who attains a complete response may be able to deescalate therapy comfortably if they reach and maintain ctDNA negativity, Aggen said.

Aggen also recounted the findings of the phase 3 CheckMate 901 study (NCT03036098) which was the basis for the FDA approval of nivolumab plus cisplatin and gemcitabine in the frontline setting.³ Here, the median overall survival (OS) with the nivolumab plus chemotherapy combination was 21.7 months (95% CI, 18.6-26.4) vs 18.9 months (95% CI, 14.7-22.4) with chemotherapy, demonstrating a 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.63-0.96). The median progression-free survival (PFS) with nivolumab and chemotherapy was 7.9 months (95% CI, 7.6-9.5) and was 7.6 months (95% CI, 6.0-7.8) with chemotherapy alone (HR, 0.72; 95% CI, 0.59-0.88).

In addition, the objective response rate (ORR) from nivolumab plus chemotherapy was 57.6% (95% CI, 51.8%-63.2%) vs 43.1% (95% CI, 37.5%-48.9%) with chemotherapy.

Discussing the current treatment paradigm for frontline treatment of metastatic urothelial carcinoma, Aggen said that most patients in the US are currently receiving treatment with enfortumab vedotin plus pembrolizumab, and upon progression are moving to erdafitinib (Balversa) if their disease is FGFR-mutated, to fam-trastuzumab deruxtecan-nxki (Enhertu) if their disease is HER2 3+ or to platinum-based chemotherapy.

“And there's not really data at the moment to guide which is best in terms of overall survival,” he said.

Regarding current research, Aggen noted examples such as the phase I Double Antibody Drug Conjugate (DAD; NCT04724018) trial evaluating sacituzumab govitecan-hziy (Trodelvy) and enfortumab vedotin among patients with treatment-resistant metastatic urothelial cancer and its currently enrolling phase I/II extension, DAD-IO, examining combinations of sacituzumab govitecan plus enfortumab vedotin and pembrolizumab for metastatic urothelial carcinoma.⁴

Of note, it was announced last month that manufacturer Gilead Sciences had voluntarily withdrawn the FDA’s accelerated approval of sacituzumab govitecan for the treatment of locally advanced or metastatic urothelial cancer previously treated with platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.⁵

“It may be that sacituzumab is not the right partner here, but there are several other ADCs that are in development that may be additive,” Aggen said. “The question is, how do you mitigate toxicity with a triplet regimen in the frontline setting?”

In summary, Aggen said, urothelial carcinoma is a rapidly evolving treatment landscape.

“[Enfortumab vedotin] plus [pembrolizumab] is approved regardless of platinum eligibility, based on unprecedented PFS and OS benefits, nivolumab plus [gemcitabine and cisplatin] is also approved for [cisplatin]-platinum eligible patients and for patients ineligible for platinum pembrolizumab monotherapy is a standard of care. We really need more biomarker work from these large phase 3 studies to guide treatment selection. If we knew who the patients were that were CRs to nivolumab [plus gemcitabine and cisplatin], it would make that a much more attractive frontline option. And I think future trials now are just beginning to build on [enfortumab vedotin] plus [pembrolizumab] as the treatment backbone.”

References

1. Aggen, D. Urothelial Carcinoma: Biologic Factors That Drive Treatment. Presented at: Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Conference; on November 13-15, 2024; New York, New York.
2. Powles TB, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Eng J Med. 2024;390(10):875-888. doi: 10.1056/NEJMoa2312117
3. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. Accessed Nov. 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-cisplatin-and-gemcitabine-unresectable-or-metastatic-urothelial
4. McGregor BA, Kwak L, Sonpavde GP, et al. Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) for metastatic urothelial carcinoma (mUC) treatment-experienced (DAD) and with pembrolizumab (P) in treatment naïve UC (DAD-IO). J Clin Oncol. 2024;42(16). doi10.1200/JCO.2024.42.16_suppl.TPS46
5. Gilead Provides Update on U.S. Indication for Trodelvy® in Metastatic Urothelial Cancer. Gilead Sciences. Oct. 18, 2024. https://www.gilead.com/company/company-statements/2024/gilead-provides-update-on-us-indication-for-trodelvy-in-metastatic-urothelial-cancer