Enfortumab Vedotin in Patients With Advanced Small Bowel Adenocarcinoma Refractory or Intolerant to Platinum-based Combination Therapy
brief summary
Small bowel adenocarcinoma is a rare cancer with a poor prognosis. For patients with locally advanced or metastatic disease, the usual first treatment is chemotherapy with platinum-based combinations such as FOLFOX or CapeOX. However, once the cancer grows after this treatment or the side effects become too severe, there is no widely accepted standard second-line therapy, and outcomes are generally poor. New treatment options are therefore urgently needed. Recent retrospective research from our group has shown that the majority of the small bowel adenocarcinomas strongly express a protein called Nectin-4 on the surface of cancer cells. High Nectin-4 expression was also associated with poorer survival, suggesting that Nectin-4 could be a crucial treatment target in this disease. Enfortumab vedotin is a targeted anticancer drug called an antibody-drug conjugate. It combines an antibody that recognizes Nectin-4 with vedotin, a cytotoxic anticancer agent (payload). After enfortumab vedotin binds to Nectin-4 on the tumor cell surface, it is taken up into the cell and releases the anticancer payload, which damages the cell's internal structure and leads to cell death and apoptosis. Enfortumab vedotin has already shown meaningful antitumor activity and an acceptable safety profile in patients with advanced urothelial carcinoma and is approved over the world. However, its efficacy has never been formally evaluated in patients with small bowel adenocarcinoma. ENVELOPE is a multicenter, single-arm, phase II investigator-initiated trial designed to evaluate the efficacy and safety of enfortumab vedotin in patients with locally advanced or metastatic small bowel adenocarcinoma that has progressed during or after, or is intolerant to, platinum-based combination chemotherapy (FOLFOX or CapeOX). Eligible patients are adults (aged 18 years or older) with histologically or cytologically confirmed small bowel adenocarcinoma, a good performance status, adequate organ function, and at least one measurable lesion on a CT scan. Patients who have genomic alterations that make them candidates for previously approved "tumor-agnostic" targeted drugs (for example, high microsatellite instability or high tumor mutational burden) must already have tried and not benefited from, or not tolerated, those treatments. Testing positive for Nectin-4 is not required to take part in this study. Participants will receive enfortumab vedotin as an intravenous infusion at a dose of 1.25 mg/kg on days 1, 8, and 15 of each 28-day treatment cycle. Treatment will continue as long as the cancer does not grow and side effects remain manageable. Tumor scans with contrast-enhanced CT will be performed every 8 weeks up to week 24 and every 12 weeks thereafter to monitor the response of the enfortumab vedotin. The primary objective is to determine the proportion of patients achieving a tumor response to enfortumab vedotin, as assessed by independent radiologic review. Key secondary objectives include progression-free survival, overall survival, duration of response, and safety profiling. In addition, this study includes a prespecified translational research program. Tumor samples will be examined for Nectin-4 expression using immunohistochemistry, and researchers will investigate the relationship between Nectin-4 levels and the effects of enfortumab vedotin. Blood and tissue samples will also be collected before treatment, during treatment, and at the time of cancer progression, when possible, for detailed "multi-omics" analyses. These translational studies aim to elucidate why some patients respond whereas others do not, and to identify biomarkers that could inform future treatment strategies for small bowel adenocarcinoma. The ENVELOPE trial has been approved by the Institutional Review Board of the National Cancer Center, Japan, as well as by the ethics committees at participating sites. The study is funded by the Japan Agency for Medical Research and Development (AMED), and enfortumab vedotin is supplied by Astellas Pharma. Enrollment began in October 2025 and is planned to continue through October 2027, with patients followed for at least 12 months after the last participant is enrolled.
detailed description
Small bowel adenocarcinoma is a rare gastrointestinal malignancy that accounts for fewer than 3% of all gastrointestinal cancers and is associated with poor prognosis. Most patients are diagnosed at an advanced stage because lesions in the distal duodenum, jejunum, and ileum are difficult to detect endoscopically, and symptoms such as anemia, obstruction, or bleeding often appear only after the disease has progressed. For patients with locally advanced or metastatic small bowel adenocarcinoma, fluoropyrimidine plus oxaliplatin regimens such as FOLFOX and CapeOX are widely used as first-line systemic therapy. Prospective studies have reported objective response rates of approximately 40-50% and median overall survival of about 13-20 months with these platinum-based combinations. However, there is no established standard of care beyond first-line treatment, and outcomes after failure of platinum-based chemotherapy are dismal, with small retrospective series suggesting modest activity of regimens such as irinotecan-based chemotherapy or taxanes and very low response rates in routine practice. In the absence of targetable alterations qualifying for tumor-agnostic approved therapies, best supportive care remains the default recommendation for many patients after failure of first-line therapy.
Enfortumab vedotin is an antibody-drug conjugate composed of a fully human IgG1κ monoclonal antibody directed against the cell adhesion molecule Nectin-4, linked via a protease-cleavable linker to the microtubule inhibitor monomethyl auristatin E. Binding of enfortumab vedotin to Nectin-4 on the tumor cell surface leads to internalization of the antibody-drug conjugate and intracellular release of monomethyl auristatin E, resulting in disruption of tubulin polymerization, cell-cycle arrest at the G2/M phase, and apoptotic cell death. Non-clinical studies have shown high-affinity and selective binding to Nectin-4, Nectin-4-dependent intracellular delivery of monomethyl auristatin E, direct cytotoxicity against Nectin-4-positive tumor cells, and bystander killing of adjacent Nectin-4-negative cells. In clinical trials in patients with urothelial carcinoma, the same schedule used in this trial (1.25 mg/kg intravenously on days 1, 8, and 15 of a 28-day cycle) has demonstrated clinically meaningful antitumor activity and an acceptable safety profile in phase I-III studies, leading to regulatory approval in that indication.
There are no published clinical data for enfortumab vedotin in small bowel adenocarcinoma. To address this gap, the National Cancer Center Hospital conducted immunohistochemical analyses of Nectin-4 in tumor samples from patients with small bowel adenocarcinoma. Among 51 consecutively diagnosed cases, Nectin-4 expression was detected in 42 tumors (82.4%). In patients who received palliative chemotherapy, Nectin-4 positivity was associated with significantly shorter overall survival compared with Nectin-4-negative disease (median 12.6 vs 43.2 months), and higher levels of Nectin-4 expression tended to correlate with worse outcomes. In multivariable analysis, poor performance status and Nectin-4 positivity were both identified as independent adverse prognostic factors. These findings suggest that Nectin-4 is both highly expressed and prognostically unfavorable in small bowel adenocarcinoma, providing a strong biological rationale to investigate Nectin-4-targeted therapy in this setting.
official title
Enfortumab Vedotin in Patients With Locally Advanced or Metastatic Small Bowel Adenocarcinoma Refractory or Intolerant to Platinum-based Combination Therapy: a Multicenter, Phase II Investigator-initiated Trial (ENVELOPE, NCCH2412/MK015)