EV-302 heralds practice change for advanced urothelial cancer

medwireNews: Combined treatment with enfortumab vedotin (EV) plus pembrolizumab significantly improves the survival of patients with previously untreated locally advanced or metastatic urothelial cancer relative to chemotherapy, show phase 3 data presented at the ESMO Congress 2023. Speaking in Madrid, Spain, presenting author Thomas Powles (Barts Cancer Centre, London, UK) highlighted that this “is the first time that platinum-based chemotherapy has been surpassed in OS [overall survival]” in this patient population. He added that these results support EV plus pembrolizumab “as a standard of care in this setting.” Powles explained that the combination of the Nectin-4-directed antibody–drug conjugate and the PD-1 inhibitor is approved in the USA for advanced urothelial cancer patients who are ineligible for cisplatin therapy, but the current EV-302/KEYNOTE-A39 study evaluated the regimen in the first-line regardless of cisplatin eligibility and PD-L1 expression status. A total of 886 patients were randomly assigned to receive 3-week cycles of EV 1.25 mg/kg on days 1 and 8 (no maximum number of cycles specified) together with pembrolizumab 200 mg on day 1 (maximum 35 cycles) or up to six cycles of cisplatin or carboplatin plus gemcitabine. At a median follow-up of 17.2 months, treatment with EV plus pembrolizumab almost doubled the median duration of the co-primary endpoint of independently assessed progression-free survival (PFS) relative to chemotherapy, at 12.5 versus 6.3 months. The risk for disease progression or death was a significant 55% lower with the combination. The PFS rate at 12 months was 50.7% in the EV plus pembrolizumab arm and 21.6% in the chemotherapy arm, while the respective 18-month rates were 43.9% and 11.7%. Median OS – the other primary endpoint – was also nearly doubled with EV–pembrolizumab, at 31.5 months versus 16.1 months with chemotherapy, and was associated with a significant 53% reduction in the risk for death. At the 12-month mark, 78.2% of patients in the EV plus pembrolizumab group were still alive compared with 61.4% of those in the chemotherapy group; the corresponding rates at 18 months were 69.5% and 44.7%. Of note, subgroup analysis showed a significant PFS and OS benefit of the combination in all evaluated prespecified subgroups, said the presenter. For instance, the hazard ratio (HR) for death was 0.53 in favor of EV plus pembrolizumab in cisplatin-eligible patients and 0.43 in those who were cisplatin-ineligible. And the HRs for death in the PD-L1 high and low subgroups were 0.49 and 0.44, respectively. The objective response rate was also significantly higher with EV plus pembrolizumab than chemotherapy, at 67.7% versus 44.4%, and the median duration was not reached and 7 months, respectively. The complete response rate in the combination group was 29.1%, which Powles said “is not something we have seen before,” and 12.5% in the chemotherapy group. Moving onto the toxicity data, he commented that the safety profile of EV plus pembrolizumab “was in line with what we saw in phase 1 and phase 2, and in line with my expectations and clinical experience, and is manageable.” Treatment-related adverse events (TRAEs) of at least grade 3 were experienced by 55.9% of participants treated with EV–pembrolizumab and 69.5% of those given chemotherapy. The most frequent events of this severity with the combination were maculopapular rash (7.7%), neutropenia (4.8%), peripheral sensory neuropathy (3.6%), and diarrhea (3.6%), whereas anemia (31.4%), neutropenia (30.0%), and thrombocytopenia (19.4%) were most common with chemotherapy. There were four fatal TRAEs in each group. The majority of AEs of special interest related to EV were low grade, reported Powles, with skin reactions the most commonly occurring event of grade 3 or worse, in 15.5%. And “there was nothing new” with regard to AEs of special interest related to pembrolizumab, he added. Discussant Andrea Apolo (National Cancer Institute, Bethesda, Maryland, USA) said that EV plus pembrolizumab “has raised the bar for OS in metastatic urothelial carcinoma” and “we welcome a new standard of care” in the management of patients with locally advanced or metastatic urothelial carcinoma. “But with new standards of care come questions and challenges,” she continued, such as what treatment now becomes the best second-line option, is it feasible to de-escalate the dose of EV in the combination, and what is the efficacy of this combination in earlier stages of disease? Finally, Apolo stressed that “we must discuss the cost.” The combination of EV plus pembrolizumab “is expensive,” and “will patients, insurance, and public systems be able to afford this treatment?” she asked. Nevertheless, she concluded that “the future looks bright for our patients with urothelial carcinoma.” medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group ESMO Congress 2023; Madrid, Spain: 20–24 October

At a glance: The STEP trials

Springer Medicine

EV-302 heralds practice change for advanced urothelial cancer

Related topics

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

At a glance: The STEP trials

Springer Medicine

Please log in to get access to this content

Related topics

Keynote webinar | Spotlight on antibody–drug conjugates in cancer