A New Promising Option for Cisplatin-Ineligible Advanced Urothelial Cancer

A significant proportion of patients with locally advanced or metastatic urothelial carcinoma (UC) are not eligible for standard cisplatin-based treatment or for any platinum-based regimens. For cisplatin-ineligible patients with high PD-L1-positive tumors, and carboplatin-ineligible patients regardless of PD-L1 status, treatment with an immune checkpoint inhibitor (ICI), atezolizumab or pembrolizumab, is an option. However, less than one-third of unselected patients respond to first-line immunotherapy, and there is a clear need for novel therapies in this patient population.

Enfortumab vedotin, an antibody–drug conjugate (ADC) directed towards nectin-4, a protein that is highly expressed in UC, has shown activity in pretreated UC. The pivotal single-arm, two-cohort, phase II EV-201 study evaluated the efficacy and safety of enfortumab vedotin in patients with locally advanced or metastatic UC who had received prior treatment with anti-PD-1/PD-L1 therapy. Results from the first cohort of patients, who had previously received both platinum-based chemotherapy and ICI therapy, showed an objective response rate (ORR) of 44% and a tolerable safety profile. Based on these results, enfortumab vedotin was granted accelerated FDA approval for patients with advanced UC who were previously treated with platinum-based therapy and ICIs.

Results from Cohort 2 of the EV-201 study were reported recently and included 89 cisplatin-ineligible patients with UC (88 with metastatic disease and 1 with locally advanced disease). All patients previously received anti-PD-1/PD-L1 therapy but no platinum-containing chemotherapy. Patients were considered cisplatin-ineligible if they had an Eastern Cooperative Oncology Group (ECOG) PS score of 2, impaired renal function, or grade 2 or worse hearing loss. Enfortumab vedotin was administered at a dose of 1.25 mg/kg as an intravenous infusion on days 1, 8, and 15 of each 28-day cycle. The median age of patients was 75 years, 12% had ECOG PS 2, and 79% had visceral metastases. Median follow-up was 13.4 months. The confirmed ORR was 52%, with 20% achieving complete response. The median duration of response was 10.9 months. Response rates in prespecified subgroups, including patients with primary upper tract tumors (61%) and those with liver metastases (48%), were consistent with the overall study population. The benefit was seen regardless of PD-L1 status and response to previous immunotherapy. Observed median progression-free survival was 5.8 months, and median overall survival was 14.7 months.

In general, the treatment was relatively well tolerated despite the majority of patients being elderly. Around half of the patients experienced grade ≥3 treatment-related adverse events (TRAEs), with the most common being neutropenia (9%), maculopapular rash (8%), fatigue (7%), and 6% of patients experienced anemia, diarrhea, hyperglycemia, increased lipase, and decreased appetite. TRAEs led to dose reductions in 46% of patients and discontinuation in 16% of patients, with peripheral sensory neuropathy contributing to 17% and 4% of these, respectively. TRAEs of special interest (any grade) included skin reactions (61%), peripheral neuropathy (54%), and hyperglycemia (10%). Four patients died due to TRAEs, albeit patients aged 75 years or older with multiple comorbidities, with three deaths occurring within the first 30 days of treatment. Therefore, careful monitoring of patients during the early stages of treatment is important.

The investigators conclude that treatment with enfortumab vedotin was tolerable and resulted in a clinically meaningful response in cisplatin-ineligible advanced UC patients following anti-PD-1/PD-L1 therapy. Thus, enfortumab vedotin may represent a new standard of care for these patients, who have limited therapeutic options post-immunotherapy. The author of an accompanying editorial highlighted that the impressive ORR reported in this study is the highest for any single-agent treatment for patients with locally advanced or metastatic UC, regardless of cisplatin eligibility or line of therapy. Therefore, enfortumab vedotin will probably be considered earlier in the therapeutic strategy.


Yu EY, et al. Lancet Oncol. 2021 May 12. [Online ahead of print].

Pignot G. Lancet Oncol. 2021 May 12. [Online ahead of print].