Initial results from the phase 1 clinical trial EV-103 were announced. Forty-five patients were evaluated for safety with the combination of the investigational agent Enfortumab Vedotin and the immune therapy Pembrolizumab ( Keytruda ) in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for treatment with Cisplatin-based chemotherapy.
The study met outcome measures for safety and exhibited encouraging clinical activity for this Platinum-free combination in a first-line setting.
The data were presented at the European Society for Medical Oncology ( ESMO ) 2019 Congress in Barcelona, Spain.
Enfortumab Vedotin is a first-in-class antibody drug conjugate ( ADC ) that targets Nectin-4, a protein present on almost all urothelial tumor cells and associated with cancer formation.
Fifty-one percent 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 ). Four patients ( 9% ) discontinued treatment due to treatment-related adverse events, most commonly peripheral sensory neuropathy.
There was one 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 ), hyperglycemia ( 7%; 3/45 ) and peripheral neuropathy ( 4%; 2/45 ); these rates were similar to those observed with Enfortumab Vedotin monotherapy.
Eleven percent ( 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, hyperglycemia, tubulointerstitial nephritis, myasthenia gravis ).
None of the adverse events of clinical interest were grade 5 events.
The data demonstrated the combination of Enfortumab Vedotin plus Pembrolizumab shrank tumors in the majority of patients, resulting in a confirmed objective response rate ( ORR ) of 71% ( 32/45; 95% Confidence Interval [ CI ]: 55.7, 83.6 ).
The complete response ( CR ) rate was 13% ( 6/45 ). Fifty-eight percent ( 26/45 ) of patients had a partial response ( PR ) and 22% ( 10/45 ) had stable disease ( SD ).
Ninety-one percent of responses were observed at the first assessment.
EV-103 is an ongoing, multi-cohort, open-label, multicenter phase 1 trial of Enfortumab Vedotin alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive, locally advanced and first- and second-line metastatic urothelial cancer.
The dose escalation-cohort and expansion cohort A include locally advanced or metastatic urothelial cancer patients who are ineligible for Cisplatin-based chemotherapy.
Patients were dosed in a 21-day cycle, receiving an intravenous ( IV ) infusion of Enfortumab Vedotin on days 1 and 8 and Pembrolizumab on day 1.
At the time of this initial analysis, 45 patients ( 5 from the dose-escalation cohort and 40 from the dose-expansion cohort A ) with locally advanced and/or metastatic urothelial cancer had been treated with Enfortumab Vedotin ( 1.25 mg/kg ) plus Pembrolizumab in the first-line setting.
The primary outcome measure of the cohorts included in this analysis is safety. The analysis of these first cohorts included several of the study's secondary objectives.
Key secondary objectives related to efficacy include 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 and will be included in a future analysis.
Urothelial cancer is the most common type of bladder cancer ( 90% of cases ). In 2018, more than 82,000 people were diagnosed with bladder cancer in the United States. Globally, approximately 549,000 people were diagnosed with bladder cancer last year, and there were approximately 200,000 deaths worldwide.
The recommended first-line treatment for patients with advanced urothelial cancer is a Cisplatin-based chemotherapy.
For patients who are ineligible for Cisplatin, such as people with kidney impairment, a Carboplatin-based regimen is recommended.
However, fewer than half of patients respond to Carboplatin-based regimens and outcomes are typically poorer compared to Cisplatin-based regimens. ( Xagena )
Source: Seattle Genetics & Astellas, 2019