乌鸦传媒

Enfortumab vedotin (EV) is an antibody-drug conjugate targeted at nicotine-4 expressing tumor cells. By delivering mono methyl auristatin E (MMAE), EV induces cell cycle arrest, ultimately causing cell death. On the other hand, pembrolizumab is an anti-PD-1 antibody that utilizes the PD-1 receptor to block immune checkpoint mechanisms, allowing host T cells to eliminate tumor cells.

The explored the combination of EV and pembrolizumab based on . Cohort A demonstrated substantial antitumor activity, durable responses, and encouraging survival outcomes with a . This success prompted further investigation in Cohort K, where patients were randomized to receive either EV alone or EV in combination with pembrolizumab.

The primary endpoint of the study was the confirmed objective response rate, with secondary endpoints including duration of response and safety. Among the 149 enrolled patients, 76 received EV plus pembrolizumab, while 73 received EV monotherapy. Encouragingly, the combination arm showed a 65% confirmed response rate compared with 45% in the monotherapy arm.

The median duration of response was not reached for the combination, while it was 13.2 months for monotherapy. The toxicity profile mirrored what has been observed with enfortumab and pembrolizumab individually.

Notable side effects included fatigue (56%), peripheral sensory neuropathy (51%), alopecia (46%), and rash (46%). Expected toxicities like diarrhea (28%), cytopenias (30%), hyperglycemia (13%), and pneumonitis (9%) were also present, mostly at low grades (< Grade 2), but still significant for patients. Notably, the from the original EV approval schedule, with EV administered at 1.25 mg/kg on days 1 and 8 of a 21-day cycle, alongside pembrolizumab (fixed dose of 2,000 mg) every 3 weeks.

Recently, the combination of enfortumab vedotin and pembrolizumab received accelerated approval from the Food and Drug Administration as a first-line therapy for metastatic urothelial carcinoma in cisplatin-ineligible patients, pending further phase III studies. Enfortumab itself had already proven transformative for patients who progressed on platinum-based combinations, and this study solidifies its effectiveness while indicating that the combination with pembrolizumab achieves even higher response rates compared with historical platinum-based therapies.

Contrastingly, to combine pembrolizumab with traditional platinum-based chemotherapy and atezolizumab with platinum-based combinations failed to improve overall survival, despite some .

While these outcomes are promising and reflected in clinical practice, they must be substantiated by a large-scale phase III randomized trial. Notably, a recent press release from the CheckMate 901 study team suggests positive results for nivolumab in combination with cisplatin-based chemotherapy, meeting both overall survival and progression-free survival endpoints. Full results will be unveiled at the ESMO 2023 annual meeting in Madrid in October.

Parminder Singh, MD, is Associate Professor of Medicine in the Genito-urinary Oncology Program at Mayo Clinic Arizona, Phoenix.

Read the study here and an interview about it here.