Enfortumab vedotin and pembrolizumab in advanced bladder cancer: initial results

Initial results from the phase 1 EV-103 study, combining enfortumab vedotin with pembrolizumab as a first-line treatment for advanced urothelial cancer, showed that the study met outcome measures for safety and exhibited encouraging clinical activity for this platinum-free combination. Results were presented by Prof. Christopher Hoimes (Case Comprehensive Cancer Center, Cleveland, USA) [1].

EV-103 is an ongoing, multicohort, open-label, multicentre phase 1 trial of investigational drug enfortumab vedotin alone or in combination with a different drug, evaluating safety, tolerability, and efficacy in muscle-invasive, locally advanced, and first- and second-line metastatic urothelial cancer. Enfortumab vedotin is a first-in-class antibody-drug conjugate designed to target nectin-4, a protein present on almost all urothelial tumour cells, coupled to the microtubule disrupting agent monomethyl auristatin E. This initial analysis reported on 45 patients (5 from the dose-escalation cohort and 40 from the dose-expansion cohort A) with locally advanced and/or metastatic urothelial cancer who were ineligible for treatment with cisplatin-based chemotherapy, who had been treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in the first-line setting.

The primary outcome measure of the cohorts was safety. Secondary outcomes included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). DOR and OS were not mature at the time of analysis.

Half of patients (23/45) had an adverse event greater than or equal to grade 3. Among these events, an increase in lipase was the most frequent (13%; 6/45). In total, 4 patients (9%) discontinued treatment due to treatment-related adverse events, most commonly peripheral sensory neuropathy. There was 1 death deemed to be treatment-related by the investigator, attributed to multiple organ dysfunction syndrome. Treatment-related adverse events of clinical interest that were greater than or equal to grade 3 were rash (11%; 5/45), hyperglycaemia (7%; 3/45), and peripheral neuropathy (4%; 2/45); these rates were similar to those observed with enfortumab vedotin monotherapy. One in ten (5/45) of patients had treatment-related immune-mediated adverse events of clinical interest greater than or equal to grade 3 that required the use of systemic steroids (one event each of pneumonitis, dermatitis bullous, hyperglycaemia, tubulointerstitial nephritis, myasthenia gravis). None of the adverse events of clinical interest were grade 5.

The data demonstrated the combination of enfortumab vedotin plus pembrolizumab reduced tumours, resulting in an ORR of 71% (32/45; 95% CI 55.7-83.6). The complete response rate was 13% (6/45), 58% (26/45) of patients had a partial response, and 22% (10/45) had stable disease. Almost all (91%) responses were observed at the first assessment.

1. Hoimes C et al. ESMO Congress 2019. Abstract 901O.

Posted on 26 November 201917 May 2024