Enfortumab vedotin (EV) is an antibody-drug conjugate, that is directed against Nectin-4, an immunoglobulin-like cell adhesion molecules, highly expressed in urothelial carcinoma
EV-201 (NCT03219333) is a single-arm, two-cohort trial that assesses enfortumab vedotin (EV) in the treatment of locally advanced or metastatic urothelial carcinoma. Data from cohort 1 led to accelerated approval of EV by the FDA for this population of patients who previously received anti-PD-1/L1 and platinum-based chemotherapy, in the neoadjuvant or adjuvant setting. During the 2021 Genitourinary Cancers Symposium, primary analysis of cohort 2 was presented, which included patients ineligible for cisplatin, with prior exposure to anti-PD-1/L1, and individuals who had not previously received platinum.
In this multicenter, multinational, open-label trial, patients received 1.25 mg/kg of EV on days 1, 8, and 15 of each 28-day cycle. The primary outcome was the objective response rate (ORR) by RECIST 1.1, assessed by blinded independent central review (BICR). Secondary outcomes included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.
On September 8, 2020 (data cutoff), 91 individuals were enrolled and 89 treated in cohort 2. Patients were elderly (mean age 75 years), with comorbidities, including moderate or severe renal failure. They were also ineligible for cisplatin, at the beginning of the trial, due to creatinine clearance <60 mL/min (66%), grade ≥ 2 hearing loss (15%) or ECOG 2 (7%); an additional 12% met the criterion ≥ 1.
The primary tumor location was the upper tract in 43%; 79% had visceral metastases, including 24% with secondary liver involvement. The median duration of treatment was six months.
TRO confirmed by BICR was 52%, including 20% of complete response among treated patients. The median for DoR was 10.9 months. The medians for PFS and OS were 5.8 and 14.7 months, respectively.
The most common adverse events related to treatment in all grades were alopecia (51%), peripheral sensory neuropathy (47%), and fatigue (34%). Adverse events of interest related to treatment included rash (61% all grades, 17% ≥ grade 3), peripheral neuropathy (54% all grades, 8% ≥ grade 3), and hyperglycemia (10% all grades, 6% ≥ grade 3). Four deaths were reported as therapy-related by the investigators, all in individuals ≥75 years with multiple comorbidities: three events ≤30 days from the first dose of EV in patients with ≥ 30 BMI (acute kidney injury, metabolic acidosis, and multiple–organ dysfunction syndrome) and an event (pneumonitis) > 30 days after the last dose.
The authors conclude that, in EV-201 cohort 2, most patients with locally advanced or metastatic urothelial carcinoma, not eligible for platinum or cisplatin, who progressed during or after prior exposure to anti-PD-1/L1, reached long-term responses with EV, with 1/5 achieving a complete response. The PFS and OS data were encouraging. Safety was consistent with the adverse events profile previously reported, in the context of a population of patients with advanced malignancy and comorbidities. These data demonstrate the potential of EV as a treatment option without platinum after exposure to anti-PD-1/L1.