Clinicaltrials.gov identifier:
Sponsor:
Astellas Pharma Inc, in collaboration with Seattle Genetics
Enrollment:
45
Study Design:
This study examined the safety and anticancer activity of EV IV as monotherapy and in combination with other anticancer therapies in UC. The study will be conducted in multiple parts: dose escalation (enfortumab vedotin + pembrolizumab) and dose expansion (cohorts of enfortumab vedotin + pembrolizumab and/or chemotherapy) for locally advanced and metastatic UC and EV alone and in combination with pembrolizumab in patients with earlier stage of the disease (muscle invasive UC).
Rationale:
There is a major unmet medical need for patients with mUC for whom available therapies have failed the patients. Antibody-drug conjugates (ADCs) are monoclonal Abs conjugated to cytotoxic drugs or a radionucleotide. This improves the potency and effectiveness of mAbs, allows for targeted delivery of a toxic payload to tumor cells, thereby minimizing non-specific, systemic toxicity. Enfortumab Vedotin (EV) is an ADC (anti-nectin 4 monoclonal Ab) linked to monomethyl auristatin E (MMAE) with evidence of induction of immunogenic cell death (ICD) in pre-clinical and in vitro data. MMAE disrupts microtubules resulting in ICD. EV showed an ORR of 45% in pts with prior PD-1/L1 inhibitors in a phase 1 study. In a single arm phase II trial (EV-201), single agent EV in pts previously treated with platinum and immune checkpoint inhibitors (NCT03219333) produced a 44% RR (12% CR; 32% PR) in 125 pts. The rationale for combining EV and an immune check point inhibitor such as pembrolizumab (pembro) stems from the fact that ICD releases innate immune activating molecules resulting in APC activation and presentation of tumor antigens to T cells. T cells mount antigen – specific response potentially augmented by PD-1/L1 inhibitors.
Endpoints:
The primary goal of the study is to determine the safety, tolerability, and efficacy of EV alone and in combination with pembro and/or chemotherapy
Comments:
EV alone had a high RR, but this study demonstrated that the combination of EV and immunotherapy with pembro has an even higher RR and is likely to become an important option in the first line setting for cisplatin ineligible pts in the treatment of mUC.
Results:
EV and pembro in cisplatin ineligible 1st line or second line therapy results were reported in 45 pts. The ORR was 71% with 13% CR and 58% PR with rapid responses in 91% at first assessment.
