TUC-TOC phase II trial (NCT05955170): Tucatinib in combination with oral etoposide (VP16) and trastuzumab in patients with metastatic HER2-positive breast cancer (HER2+ mBC).

Abstract

TPS1145 Background: Patients with HER2-positive metastatic breast cancer (HER2+ MBC) have limited therapeutic options after progression on tucatinib–trastuzumab–capecitabine. There is a need for later-line regimens combining chemotherapy with dual HER2 targeting. TUC-TOC was designed to evaluate the efficacy and safety of tucatinib combined with oral etoposide (VP16) and trastuzumab in this setting. Oral VP16 was selected because (i) topoisomerase II inhibitors are rarely used in HER2+ MBC, (ii) TOP2A and ERBB2 are frequently co-amplified, and (iii) it enables an almost all-oral regimen. A prior retrospective analysis suggested favorable activity and tolerability of VP16 plus trastuzumab in heavily pretreated HER2+ MBC (PMID: 35565244). Methods: TUC-TOC (NCT05955170) is an open-label, multicenter, academic phase II trial. Eligible patients have histologically-confirmed HER2+ MBC with disease progression on tucatinib-trastuzumab-capecitabine or a contraindication to capecitabine, measurable disease per RECIST v1.1, and adequate cardiac function. Patients with brain metastases are eligible unless urgent local treatment is required. The study includes a safety run-in followed by an expansion phase. In the safety run-in, six patients received oral VP16 50 mg/d on days 1–14 of a 3w cycle, tucatinib 300 mg PO BID, and trastuzumab 600 mg SC q3w. The primary endpoint of this phase was the rate of dose-limiting toxicities (DLTs). The primary endpoint of the expansion phase is the objective response rate (ORR), defined as the best overall response within 24 weeks according to RECIST v1.1. Secondary endpoints include PFS, OS and safety. A total of 55 evaluable patients is planned. As of 01.2026, the safety run-in phase has been completed and enrollment into the expansion phase is ongoing. Clinical trial information: NCT05955170 .