A phase II study of enfortumab vedotin in patients with advanced or metastatic colorectal cancer or hepatocellular carcinoma.

TPS610 Background: Even with the advance of systemic therapy in gastrointestinal (GI) cancers over the past decade, the therapeutic options are still limited for patients (pts) with colorectal cancer (CRC) and hepatocellular carcinoma (HCC) who are refractory to those standard therapies. Nectin-4 is overexpressed in about 70% of CRC and HCC cases and correlates with worse outcomes; and preclinical study suggested that Nectin-4 expression causes 5-fluorouracil (5-FU) resistance in CRC. Based on these findings, the authors suggest Nectin-4 may be a novel therapeutic target for CRC and HCC. Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) designed to specifically target Nectin-4 expressing cancer cells. In a landmark phase III trial, EV demonstrated improved overall survival (OS) compared to investigator’s chosen chemotherapy in patients with refractory metastatic urothelial cancer. In this study, we hypothesize that targeting Nectin-4 with EV may have clinical benefits in advanced or metastatic HCC or CRC refractory to current frontline standard therapies. Methods: This study is a multi-indication, open-label, single-treatment arm, two parallel-cohort phase II study of EV in adult participants with advanced or metastatic CRC or HCC who have been previously treated with one or more lines of systemic therapy. A two-stage design using Bayesian predictive probability is used to evaluate overall response rate (ORR). In each cohort, the first stage will enroll 10 participants for futility analysis. If at least one responder is observed, the trial will enroll 10 additional participants for a total of 20. The trial will be considered promising to warrant future study if there are at least 4 responders out of the 20 participants. Estimated sample size is 20 for each cohort. EV at a dose of 1.25 mg/kg will be administered intravenously (IV) on days 1, 8, and 15 of each 28-day cycle. Key inclusion criteria include measurable disease, ECOG 0-1; CRC pts must have received fluoropyrimidine, oxaliplatin and irinotecan with or without biologic agents; HCC pts must have received first-line immunotherapy combination or a multikinase inhibitor. Uncontrolled brain metastases, grade ≥ 2 neuropathy or impaired organ function that poses risk are key exclusion criteria. Primary endpoint is ORR and secondary endpoints include safety, duration of response, progression-free survival and OS. The trial is in progress and registered on clinicaltrials.gov under NCT06553885. Funding and enfortumab vedotin drug support provided from Astellas Pharma Global Development, Inc./Pfizer, Inc. through the Investigator Sponsored Research program. Clinical trial information: NCT06553885 .