Literature
Clinical Pearls & Morning Reports
Published March 6, 2024
In the trial by Powles et al., did enfortumab vedotin plus pembrolizumab prolong survival as compared with chemotherapy?
Powles et al. conducted a phase 3, open-label, randomized trial comparing the efficacy and safety of enfortumab vedotin plus pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Read the NEJM Original Article here.
Clinical Pearls
Q: Why are new therapies needed for locally advanced or metastatic urothelial cancer?
A: For decades, platinum-based chemotherapy has been the first-line standard therapy for locally advanced or metastatic urothelial carcinoma; however, treatment outcomes remain poor, with a relatively low 5-year survival rate. Maintenance therapy with avelumab has been shown to result in longer overall survival than best supportive care alone, but a notable proportion of patients do not receive maintenance therapy owing to disease progression or death.
Q: What is enfortumab vedotin?
A: Enfortumab vedotin is an antibody–drug conjugate directed against nectin-4. Both enfortumab vedotin and pembrolizumab, a programmed death 1 (PD-1) inhibitor, have individually been associated with a survival benefit in patients with previously treated locally advanced or metastatic urothelial carcinoma. In preclinical studies, the combination of enfortumab vedotin and a PD-1 inhibitor showed enhanced antitumor activity with lasting antitumor immunity, findings that suggest complementary mechanisms of action. Enfortumab vedotin in combination with pembrolizumab received accelerated approval in the United States for use in patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.
Morning Report Questions
Q: In the trial by Powles et al., did enfortumab vedotin plus pembrolizumab prolong survival as compared with chemotherapy?
A: The trial showed a significant and clinically meaningful benefit of enfortumab vedotin and pembrolizumab over chemotherapy with respect to progression-free survival and overall survival. Treatment with enfortumab vedotin and pembrolizumab resulted in median durations of progression-free and overall survival that were nearly double those observed with chemotherapy. The percentages of patients who had an overall response were also significantly higher with enfortumab vedotin and pembrolizumab than with chemotherapy. The efficacy benefits were seen across all the prespecified subgroups, such as those defined according to the presence or absence of liver metastases, cisplatin eligibility status, and PD-L1 expression status.
Q: Did any unanticipated safety concerns arise with the use of enfortumab vedotin plus pembrolizumab in this trial?
A: The safety profile of the combination of enfortumab vedotin and pembrolizumab was consistent with that seen previously for this combination, with no new safety signals identified. The most common adverse events of special interest of grade 3 or higher that have previously been associated with enfortumab vedotin were skin reactions, peripheral neuropathy, and hyperglycemia. The most common adverse events of special interest of grade 3 or higher that have previously been associated with pembrolizumab included severe skin reactions, pneumonitis, and hepatitis.