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Enfortumab vedotin induces a complete response in one out of five patients with cisplatin-ineligible, advanced urothelial carcinoma with previous PD-1/L1 exposure

Treatment options for cisplatin-ineligible advanced urothelial carcinoma (UC) patients with previous immunotherapy exposure are limited. Results of a phase II trial presented at ASCO GU 2021 indicate that the antibody drug conjugate enfortumab vedotin (EV) adequately addresses this medical need by inducing an overall response rate of 52% with a fifth of patients obtaining a complete response to the therapy. Responses to EV were durable and were seen irrespective of the primary tumour site, the presence of liver metastases an the prior immunotherapy response.


Cisplatin-based chemotherapy is the current, first-line, standard-of-care (SoC) treatment option for advanced urothelial carcinoma (UC). However, a substantial proportion of patients are ineligible for such an intensive treatment. For these patients, PD-1/PD-L1 inhibitors are approved as an alternative first-line treatment. Unfortunately, patients with disease progression after first line immune checkpoint inhibition have very limited treatment options. The antibody-drug-conjugate Enfortumab vedotin (EV) represents a potential new treatment for these patients and works by targeting Nectin-4, an immunoglobulin-like cell adhesion molecule that is highly expressed on UC tumour cells. EV has already shown efficacy in advanced UC patients who had previously received a PD-1/L1 inhibitor and platinum-based chemotherapy, in the phase II EV 201 trial. Presented at ASCO GU 2021, results of cohort 2 from the same trial were presented. In cohort 2, 89 locally advanced or metastatic, cisplatin-ineligible, platinum-naïve, UC patients previously treated with PD-1/L1 inhibitors received EV (1.25 mg/kg IV days 1, 8 and 15 of each 28-day cycle). The primary endpoint of this study was objective response rate (ORR), with key duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety as key secondary objectives.

Objective response rate of 52%, including 20% complete responders

The median age of this cohort was 75 years-old, 74% of patients was male and 43% and 57% of patients had a primary tumour in the upper tract and bladder, respectively. Finally, 79% of patients had visceral metastatic disease at study entry. At the time of the presented analysis 18% of patients remained on-treatment. The most common reasons for treatment discontinuation were disease progression (51%) and the occurrence of adverse events (24%). The median time on treatment was 6 months. The reported ORR with EV was 52%, with 20% and 32% of patients having a complete (CR) or partial response (PR), respectively. In addition to this, a further 30% of patients experienced disease stabilization. Comparable response rates were observed across all prespecified subgroups, including patients with an upper tract primary tumour site (61%), with liver metastasis (48%), and patients who did not respond to prior PD-1/L1 treatment (48%). At a median follow-up time of 13.4 months, the median PFS was reported at 5.8 months, with a median OS of 14.7 months. Importantly, responses to EV also proved to be durable, with a median DoR of 10.9 months.

Treatment-related adverse events (TRAEs) that lead to treatment discontinuation occurred in 16% of patients. The most common any-grade TRAEs were alopecia (51%), peripheral sensory neuropathy (47%), fatigue (34%). Grade ≥3 TRAEs of special interest included skin reactions (17%), peripheral neuropathy (8%) and hyperglycaemia (6%). In total, 4 deaths occurred that were believed to be treatment-related (i.e. acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome and pneumonitis). Three of these deaths occurred within 30 days of the first dose of EV in patients with a BMI ≥30 kg/m2. All 4 deaths occurred in patients ≥75 years of age.


With an ORR of 52% and a CR rate of 20%, this study demonstrated that EV has the highest observed response rate of any regimen in cisplatin-ineligible patients with advanced urothelial carcinoma. These results also provide further evidence to the activity seen in cohort 1 of this trial. Response rates were consistent across all pre-specified subgroups, and combined with a tolerable safety profile, these results support the continued investigation of EV across the spectrum of urothelial carcinoma patients.


Balar AV et al., EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. Presented at ASCO GU 2021; Abstract 394.

Speaker Arjun Vasant Balar

Arjun Vasant Balar

Arjun Vasant Balar, MD, NYU Langone Health, New York, United States


See: Keyslides

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