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.
Introduction
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.
Conclusion
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.
Reference
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.
