Enfortumab vedotin (also known as AGS-22ME; Seattle Genetics/Astellas), an antibody-drug conjugate (ADC), will be evaluated in a phase III clinical trial in combination with pembrolizumab (Keytruda®, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.), an anti-PD-1 immune therapy in patients with with previously untreated, advanced or metastatic, urothelial (bladder) cancer.
The clinical collaboration between the three companies was confirmed earlier today.
Urothelial – transitional cell – carcinoma is the most common type of bladder cancer and cancer of the ureter, urethra, and urachus in the United States and Europe (Almost 90% of all diagnosed cases of bladder cancer).
Although the exact causes of bladder cancer remains unknown, age and gender are included among the most common risk factors. Other factors are a history of bladder cancer in the family, an inherited gene mutations or hereditary cancer syndrome and smoking.
In 2019, more than 80,000 people are expected to be diagnosed with bladder cancer in the United States. Globally, approximately 549,000 people were diagnosed with bladder cancer last in 2018, and approximately 200,000 patients with the disease died worldwide.
Current first-line therapy
The current standard of care is a cisplatin-based combination chemotherapy. This approach is the preferred initial therapy for patients with metastatic urothelial cancer. Cisplatin-based combination chemotherapy has resulted in superior survival when compared with single-agent cisplatin. However, cisplatin-related toxicity is a concern and not all patients with this disease are appropriate candidates for cisplatin therapy.
Patients who cannot be treated with cisplatin due to medical frailty or comorbidities may be treated with carboplatin-based regimen such as carboplatin + gemcitabine, or carboplatin, gemcitabine, + paclitaxel). These patients can also be treated with a non-platinum-based combination such as paclitaxel plus gemcitabine.
The available data shows that approximately 50% of patients with advanced urothelial carcinoma who cannot be treated with cisplatin-based chemotherapy because of age or a comorbidity, such as impaired renal function, neuropathy, and heart failure.
Pembrolizumab disrupt the engagement of PD-1 with its ligands and impede inhibitory signals in T cells. In a number of clinical trials, the drug has demonstrated antitumor activity in patients with advanced urothelial cancer.
The multicenter phase II KEYNOTE-052 study included 370 patients with an average age of the of 74 years with advanced urothelial carcinoma who were not eligible for a cisplatin-based chemotherpy. These patients were treated with pembrolizumab (200 mg every three weeks for up to two years).
At the median follow-up of 9.5 months the study results showed an objective response rate (ORR), the primary endpoint of the study, of 29% for the entire cohort, including 7% complete responses (CR) and 22% partial responses (PR). The median duration of response (DOR) had not been reached at the time of analysis. The study’s response rates were consistent across all major subgroups.
Antibody-drug Conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
With five approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
The phase III clinical trial includes a combination of an anti-PD-1 immune therapy with an antibody-drug conjugates.
Rationale for Enfortumab vedotin + pembrolizumab
Enfortumab vedotin is an ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent Monomethyl Auristatin E MMAE. The investigational agent targets Nectin-4, a cell adhesion molecule that is expressed on many solid tumors.
The rational for combining pembrolizumab with enfortumab vedotin is based on the fact that the payload of the investigational drug, monomethyl auristatin E, induces surface expression of calreticulin and HSP70 as well as activation of the transcription factor ATF6 which are classical hallmarks of immunogenic cell death (ICD), an unique class of regulated cell death capable of eliciting complete antigen-specific adaptive immune responses, associated with unfolded protein/ER stress response. 
Immunogenic cell deatheventually results presentation of tumor antigens to T cells, which then mount an antigen-specific response, which PD-1/L1 inhibitors have been shown to augment. 
“Recent data from a phase Ib trial of enfortumab vedotin in combination with pembrolizumab showed evidence of clinical activity leading to the development of [the] phase III trial,” Dansey further noted.
“An unmet medical need exists for previously untreated patients with metastatic urothelial cancer, and we are committed to studying enfortumab vedotin in combination with other agents in different stages of urothelial cancer,” said Andrew Krivoshik, MD., Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas.
Earlier this year, initial results from EV-103, a phase I clinical trial (NCT03288545) of enfortumab vedotin + pembrolizumab as a first-line treatment for advanced urothelial cancer, met outcome measures for safety.
The study also demonstrated encouraging clinical activity for this platinum-free combination in a first-line setting. These findings, presented during an oral session at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain, also confirmed that 71% of participating patients with locally advanced or metastatic urothelial cancer had a confirmed response. 
Following the presentation during the ESMO meeting, Christopher J. Hoimes, DO, Director, Genitourinary Oncology, Case Comprehensive Cancer Center at University Hospitals Seidman Cancer Center, Cleveland, Ohio, noted: “Advanced urothelial cancer is an aggressive disease for which more options are needed, especially for patients who are ineligible for first-line treatment with cisplatin.”
“The initial results of the combination of enfortumab vedotin with …pembrolizumab, support … further development of enfortumab vedotin combinations in … urothelial cancer,” Hoimes added.
Earlier this year, the U.S. Food and Drug Administration (FDA) granted a priority review designation to a biologics license application (BLA) for enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.
Under the Prescription Drug User Fee Act (PDUFA), the FDA will make a decision on the BLA by March 15, 2020.
Phase III registrational trial
Under the terms of the agreement between the three companies, researchers will conduct the registrational phase III clinical trial. Although the trial will be funded by the three partners, the study will be led by Seattle Genetics.
The registration trial will be designed to evaluate the efficacy of the combination of enfortumab vedotin and pembrolizumab in patients with previously untreated locally advanced or metastatic urothelial cancer. The companies are working in consultation with regulatory authorities to finalize the trial design and currently plan to initiate the trial in the first half of 2020.
“We look forward to initiating a randomized phase III trial in patients with previously untreated locally advanced or metastatic urothelial cancer,” said Roger Dansey, MD., Chief Medical Officer at Seattle Genetics.
“We look forward to further evaluating enfortumab vedotin and pembrolizumab in this high unmet need patient population,” Astellas Krivoshik concluded.
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