Novel Frontline Treatments Add Layer of Complexity in Urothelial Carcinoma
The past 12 months have seen the FDA approvals of enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial cancer and nivolumab plus cisplatin and gemcitabine for patients with unresectable or metastatic urothelial carcinoma.
The addition of novel frontline therapies in urothelial carcinoma has led to a “sea change” for providers who are faced with how to best tailor therapy for individual patients, according to David H. Aggen, MD, PhD.
“Now we have 2 very potent combination entities that are FDA approved in the front- line 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 Aggen, a genitouri- nary medical oncologist and cellular therapist at Memorial Sloan Kettering Cancer Center in New York, New York, during the 42nd Annual CFS, an event sponsored by Physicians’ Education Resource, LLC.1
The past 12 months have seen the FDA approvals of 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 gemcit- abine for patients with unresectable or metastatic urothelial carcinoma in March 2024,
Aggen noted during his presentation. Referencing findings from the randomized, open-label, phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), which led to the approval of enfortumab vedotin and pembrolizumab in this patient population, Aggen noted, “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 the EV-302 trial, 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
“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 [who] 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.”
Aggen also recounted the findings of the phase 3 CheckMate901 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 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 receiving treatment with enfortumab vedotin plus pembrolizumab, and upon progression are moving to erdafitinib (Balversa) if they have FGFR- mutated disease, to fam-trastuzumab deruxtecan-nxki (Enhertu) if their disease is HER2 3+, or to platinum-based chemotherapy. “There are 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 trial (DAD; NCT04724018), which is evaluating sacituzumab govitecan-hziy (Trodelvy) and enfortumab vedotin in patients with treatment-resistant metastatic urothelial cancer, and its currently enrolling phase I/ II extension, DAD-IO, which is examining combinations of sacituzumab govitecan plus enfortumab vedotin and pembrolizumab for patients with metastatic urothelial carcinoma.4
Of note, it was announced in October 2024 that manufacturer Gilead Sciences had voluntarily withdrawn the FDA’s accelerated approval of sacituzumab govitecan for the treatment of patients with locally advanced or metastatic urothelial cancer previously treated with platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.5
“[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. I think future trials now are just beginning to build on [enfortumab vedotin] plus [pembrolizumab] as the treatment backbone.”
