A phase II open-label study of enfortumab vedotin in patients with previously treated locally advanced, recurrent, or metastatic pancreatic adenocarcinoma (EPIC).

Abstract

730 Background: Nectin-4, a type I transmembrane protein, is critical for adherens junction formation and maintenance. Aberrant overexpression of Nectin-4 has been observed in pancreatic ductal adenocarcinoma (PDAC) and is associated with tumor proliferation and metastasis/ Enfortumab vedotin (EV), an antibody–drug conjugate targeting Nectin-4, delivers the microtubule-disrupting agent monomethyl auristatin E to Nectin-4–expressing cells. EV is approved in urothelial carcinoma, supporting its evaluation in other tumors. Methods: This open-label, single-arm, phase II trial evaluated EV in previously treated locally advanced, recurrent, or metastatic PDAC. Pts received EV 1.25 mg/kg IV on days 1, 8, and 15 of each 28-day cycle until progression or unacceptable toxicity. Imaging was performed every 8 weeks. Mandatory biopsies were obtained pre-treatment and on-treatment (C1, D15–21). Eligible patients had ECOG PS 0–1 and ≥1 prior line of therapy. The primary endpoint was ORR. Secondary endpoints included safety, DOR, DCR, PFS and OS. Exploratory endpoints included correlation of Nectin-4 expression and tumor mutational profile with ORR. A Simon’s two-stage design required ≥3 responses among 28 evaluable patients to reject the null hypothesis. Results: As of January 2025, 43 patients were enrolled (16 female, 27 male; mean age 64.7 y), with 28 evaluable for efficacy. ORR was 10.7% (3/28; 95% CI, 2.3–28.2%), with 1 confirmed PR. Two PRs progressed at confirmatory scans (day 50–55). Prior therapies among PRs included FOLFIRINOX (n=1), FOLFIRINOX→gemcitabine based (n=1), and FOLFIRINOX→gemcitabine/nab-paclitaxel (n=1). DCR for best response was 53.6% (95% CI, 33.9–72.5%); 16-week, 24-week, and 32-week DCRs were 28.6%, 21.4%, and 17.9%. At baseline, 24/28 (85.7%) had elevated CA19-9; 13/24 achieved PR/SD. Mean CA19-9 change from baseline to week 8 was +11,701 (PD group) vs +1,400 (PR/SD group); 6/13 in PR/SD group had ≥50% decrease. Similarly, 24/28 (85.7%) had elevated CEA; 12/24 achieved PR/SD. Mean CEA change was +179 (PD) vs +13 (PR/SD); 4/12 PR/SD patients had ≥30% decrease. Among 38 pts evaluable for safety, TRAE occurred in 79.0% (30/38), and Grade 3/4 TRAE occurred in 47.4% (18/38). The most common TRAE were fatigue (40.0%, 12/30), peripheral neuropathy (26.7%, 8/30), rash maculo-papular (23.3%, 7/30), anorexia (20.0%, 6/30), and neutropenia (20.0%, 6/30). Serious TRAE were reported in 10.5%% (4/38). Only deaths were Grade 5 Pneumonitis possibly related to EV in a pt with diffuse lung mets and death due to disease progression not related to study drug. Conclusions: In this phase II study, EV showed modest antitumor activity with ORR >10% and durable disease control in a heavily pretreated PDAC. Safety was consistent with prior reports. Survival outcomes and nectin 4 biomarker analyses will be reported during the presentation. Clinical trial information: NCT05915351 .