UC Trials Get Standing Ovation

For decades, platinum-based chemotherapy has been the standard first-line treatment for patients with urothelial carcinoma (UC), but their prognosis is poor and efforts to boost median overall survival (OS) beyond 12 to 14 months have failed. However, results of two studies presented at the 2023 ESMO Congress in Madrid, Spain, October 20–24, demonstrated dramatically improved OS, prompting cheers and sustained applause from conference-goers.

“It's a big day for us in bladder cancer,” declared Thomas Powles, MD, MBBS, of the University of London and director of Barts Cancer Institute, also in London, UK.

Earlier this year, the FDA greenlighted the nectin-4 directed antibody–drug conjugate enfortumab vedotin (EV; Padcev; Astellas/Seagen) combined with the PD-1 inhibitor pembrolizumab (Keytruda; Merck) to treat patients with newly diagnosed locally advanced or metastatic UC who cannot take cisplatin. Based on research supporting that approval, as well as studies showing a survival benefit for enfortumab vedotin and pembrolizumab as monotherapies for previously treated disease, investigators have been testing the combination as a first-line therapy for these patients.

For the EV-302/KEYNOTE-A39 trial, researchers enrolled 886 patients—regardless of PD-L1 expression or cisplatin eligibility—and randomly assigned them to receive EV plus pembrolizumab or chemotherapy (either cisplatin or carboplatin) plus gemcitabine.

Powles, who presented the findings, said the risk of disease progression or death was reduced by 55% in patients who received EV plus pembrolizumab instead of chemotherapy, and that their median progression-free survival (PFS) was nearly twice as long—12.5 months versus 6.3 months.

Further, after a median follow-up of 17.2 months, the median OS was 31.5 months for EV plus pembrolizumab compared with 16.1 months for chemotherapy. The PFS and OS benefits favored the experimental arm in every prespecified subgroup, including age, presence of liver metastases, PD-L1 expression, and cisplatin eligibility. At the time of the data analysis, 144 patients (33%) who received EV were continuing to respond to treatment, compared with none in the chemotherapy group.

“As you know, we've not seen a survival benefit in urothelial cancer before this. We've never beaten chemotherapy in the first-line setting. This is the first time we've achieved that goal,” announced Powles, who received a standing ovation.

Adverse events of grade 3 or higher occurred in 56% of patients in the experimental arm and 70% of patients in the control arm—and led to the death of eight patients, four in each arm. For patients who received EV plus pembrolizumab, the most common adverse events were peripheral sensory neuropathy, skin reactions, and hyperglycemia, as well as ocular disorders. For those who received chemotherapy, fatigue, nausea, anemia, neutropenia, and thrombocytopenia predominated.

Separately, the phase III CheckMate 901 trial pitted the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb) plus gemcitabine–cisplatin chemotherapy against gemcitabine–cisplatin chemotherapy alone in a similar population of patients, with 304 randomly assigned to each group.

Patients who received nivolumab experienced longer survival than those who didn't, said Michiel van der Heijden, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, who presented the findings, which were simultaneously published (N Engl J Med 2023;389:1778–89). After a median follow-up of 33.6 months, the 12-month PFS rates were 34.2% and 21.8%, respectively; the 24-month PFS rates were 23.5% and 9.6%, respectively.

As well, van der Heijden reported, compared with the chemotherapy monotherapy group, those in the nivolumab trial arm had a 22% improvement in survival. The 12-month OS rates were 70.2% for the nivolumab group versus 62.7% for the chemotherapy group; the 24-month OS rates were 46.9% and 40.7%, respectively.

Complete response rates and median duration of response (DOR) were 21.7% and 9.5 months among those who received nivolumab, compared with 11.8% and 7.3 months, respectively, among those who received only chemotherapy. Notably, said van der Heijden, the median DOR was nearly three times longer among the complete responders in the experimental group than in the control group—37.1 months versus 13.2 months.

The most common adverse events in each arm were anemia, nausea, and neutropenia. More adverse events—and more deemed grade 3 or higher—occurred in the experimental arm.

This is the only time that using an immune checkpoint inhibitor (ICI) with first-line chemotherapy has been shown to improve survival, with the results supporting nivolumab plus cisplatin-based chemotherapy as a new treatment option, said van der Heijden.

Discussant Andrea Apolo, MD, of the NCI noted that two other phase III trials assessing ICIs as a first-line treatments for metastatic UC—the PD-L1 inhibitor atezolizumab (Tecentriq; Roche/Genentech) as a single agent in IMvigor130 and pembrolizumab monotherapy in KEYNOTE-361—were negative, so having positive OS results in the two new trials “is monumental for our field.”

Acknowledging that cross-trial comparisons should be made with caution, Apolo noted that the median OS for EV was higher than for nivolumab—31.5 months versus 21.7 months, respectively—meaning that “EV plus pembro takes first place as the best first-line treatment in urothelial carcinoma.”

But questions remain, Apolo said. For example, what becomes second-line therapy? In addition, what's the best way to handle the unique toxicity profile of EV? Biologically, why is the OS response so dramatic with EV?

Further, “it is still unclear what the role would be for the combination of [nivolumab plus gemcitabine/cisplatin] in the landscape right now,” she added.

Regardless, she said, “the future looks bright for our patients with urothelial carcinoma.” –Suzanne Rose