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New data support the recent approval of enfortumab vedotin (EV, Padcev) and pembrolizumab (Pembro, Keytruda) as a first-line option for cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer, researchers reported.

In "Cohort K" of the EV-103 phase Ib/II study, 149 patients were randomized to first-line EV plus Pembro or EV monotherapy. The median follow-up was approximately 15 months, Jonathan Rosenberg, MD, of Memorial Sloan-Kettering Cancer Center in New York City, and colleagues reported.

As they noted in the , the confirmed objective response rate, the study's primary endpoint, was 64.5% in the combination group and 45.2% for patients on monotherapy. The 12-month response rate was also higher for the combination (65.4% vs 56.3%), as was the median duration of response (not reached vs 13.2 months).

"In the first-line cisplatin-ineligible patient population with high unmet need, EV + Pembro had a manageable safety profile and resulted in a high objective response rate with durable responses and encouraging progression-free survival and overall survival results, which will evolve with follow-up," the researchers concluded.

In the following interview, first author Peter H. O'Donnell, MD, of the University of Chicago, discussed the treatment options for this patient population.

What are the current first-line treatment possibilities for these patients?

O'Donnell: In the current FDA-approved treatment landscape for advanced/unresectable metastatic urothelial cancer, three options are considered: gemcitabine with platinum (potentially followed by avelumab maintenance), EV + Pembro, and pembrolizumab alone.

What are the limitations of gemcitabine with platinum?

O'Donnell: For patients who are cisplatin-ineligible, carboplatin/gemcitabine (objective response rate [ORR] ~40%) has historically been substituted for cisplatin/gemcitabine, but more recent treatment trends are moving away from this carboplatin-based paradigm. Classic cytotoxic chemotherapy toxicities, and few complete responses along with lack of durability of response, are the major limitations of carboplatin-based therapy.

And for pembrolizumab monotherapy?

O'Donnell: Pembrolizumab is FDA approved in the front-line setting for patients who are entirely platinum-ineligible. The use of pembrolizumab monotherapy in our practice is considered only for selected patients who might be predicted to have high ORR along with durability from immunotherapy alone -- findings that have been shown based on the KEYNOTE-052 long-term data.

However, pembrolizumab alone is not an optimal choice, in our opinion, for patients with rapidly progressive urothelial cancer or symptomatic disease, and in all-comers, it has a modest ORR (29%). It would also not be appropriate for most patients with pre-existing auto-immune diseases.

What are the clinical implications of your study?

O'Donnell: These data supported the 2023 accelerated FDA approval of this therapy combination as a new option for metastatic urothelial cancer. EV + Pembro is an attractive new therapy option. EV + Pembro has the highest ORR of known front-line therapies, although formal comparisons across therapies have not been completed.

EV has known toxicities including especially skin toxicities, neuropathy, and hyperglycemia, and skin toxicity rates appear higher when EV is combined with pembrolizumab, although the combination was still quite tolerable.

What additional research do you have planned or ongoing?

O'Donnell: The ongoing EV-302 study evaluating EV + pembrolizumab against platinum-based therapy in the front-line setting will hope to confirm these data and affirm this combination as a new treatment paradigm for this disease.

Read the study here and expert commentary about it here.