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EV-202: An open-label, multicenter, phase 2 study of enfortumab vedotin in patients with previously treated locally advanced or metastatic solid tumors, including multiple gastroesophageal cancer cohorts
Background
Gastroesophageal cancers, including esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma and gastric adenocarcinoma, accounted for >1.6 million new cases and >1.2 million deaths worldwide in 2020. Because high Nectin-4 expression in gastric and esophageal cancer is associated with advanced tumor stage and poor prognosis, targeting this transmembrane cell adhesion protein is a rational treatment approach. Enfortumab vedotin (EV) is a Nectin-4 directed antibody-drug conjugate comprised of a fully human anti-Nectin-4 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E, via a protease-cleavable linker. In the phase 3 EV-301 trial of patients with locally advanced or metastatic (la/m) urothelial carcinoma previously treated with platinum-containing chemotherapy and who had disease progression during/after treatment with a PD-1/L1 inhibitor, EV prolonged overall survival versus standard chemotherapy (docetaxel, paclitaxel, or vinflunine). The use of EV for gastroesophageal cancers is being investigated in EV-202.
Trial design
EV-202 (NCT04225117) is a multicohort, open-label phase 2 study evaluating EV antitumor activity and safety in patients with la/m solid tumors progressing on prior anticancer treatment(s). Adult patients with histologically/cytologically confirmed disease and Eastern Cooperative Oncology Group performance status score of ≤1 will enroll into one of the following tumor-specific cohorts including breast, non-small cell lung, head and neck, or gastroesophageal cancers. Each cohort will enroll ∼40 patients. Eligible patients previously enrolled in a single gastroesophageal cancer cohort of gastric, GEJ, or esophageal cancer were reallocated to two histology-specific cohorts (due to differences in tumor biology and standard-of-care treatment for the different histologies) consisting of those with 1) ESCC, or 2) gastric and esophageal adenocarcinoma, including GEJ adenocarcinoma. An interim analysis for futility is planned for each cohort when the first 20 patients enrolled are response evaluable. Patients must have progressed/relapsed/discontinued treatment for toxicity after one platinum-based therapy for la/m disease, but ≤2 cytotoxic therapy lines. Based on tumor PD-1/L1 expression, patients must have previously received PD-1/L1 inhibitor and progressed/relapsed/discontinued treatment for toxicity, unless contraindicated. Patients in gastroesophageal cohorts must have received HER2-directed therapy (if known HER2-positive cancer). Patients with active central nervous system metastases, grade ≥2 sensory/motor neuropathy, grade ≥3 immunotherapy-related hypothyroidism/panhypopituitarism, immunotherapy-related adverse events requiring high-dose steroids, or uncontrolled diabetes mellitus are excluded. Although not required for enrollment, Nectin-4 expression is being tested retrospectively for exploratory outcomes. Patients receive EV 1.25 mg/kg (maximum 125 mg) intravenously on Days 1, 8, and 15 per 28-day cycle; dose reductions/interruptions are permitted. Screening/baseline imaging scan and disease assessment will be performed and repeated every 8 weeks until disease progression is confirmed radiologically, subsequent anticancer treatment is started, death, withdrawal of consent, loss to follow-up, or the study closes. After 1 year of treatment, response assessments will be conducted every 12 weeks. The primary endpoint is confirmed objective response rate (per RECIST v1.1) per investigator assessment. Complete/partial response is confirmed with repeat imaging scan 4 weeks after the first response. Secondary endpoints are duration of response, disease control rate, progression-free and overall survival, and safety/tolerability. Recruitment continues at 51 sites in North America and Japan.
Clinical trial identification
NCT04225117.
Editorial acknowledgement
Medical writing/editorial support was provided by Stephanie Phan, PharmD, Cheryl Casterline, MA, and Elizabeth Hermans, PhD, from Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ.
Legal entity responsible for the study
Astellas Pharma, Inc. and Seagen Inc.
Funding
This study was funded by Astellas Pharma, Inc. and Seagen Inc.
Disclosures
K. Muro: Honoraria (self): Eli Lilly, Chugai, Takeda, Ono, Taiho, Sanofi, Bristol-Myers Squibb, and Bayer; Advisory / Consultancy: Amgen, AstraZeneca, Ono, and Chugai; Research grant / Funding (institution): Astellas, Amgen, Solasia Pharma, Sanofi, Daiichi Sankyo, Parexel International, Taiho, MSD, Merck Biopharma, Pfizer, Eisai, Novartis, and Ono . J. Baranda: Research grant / Funding (institution): Exelixis, Astellas, Nektar, Sanofi, Xencor, Pfizer, Tolero; Shareholder / Stockholder / Stock options: Forty Seven Inc, Moderna, MorphoSys AG, Zymeworks, Hylapharm, Area. M. Campbell: Full / Part-time employment: Seagen Inc. C. Wu: Full / Part-time employment: Astellas Pharma US. S. Gorla: Full / Part-time employment: Astellas. All other authors have declared no conflicts of interest.
