IvoLoC: A phase II trial of ivonescimab (IVO) in endocrine-refractory hormone receptor (HR)–positive or triple-negative (TN) metastatic invasive lobular carcinoma (mILC).

TPS1166 Background: ILC accounts for approximately 10–15% of breast cancers and is predominantly hormone receptor–positive (HR+)/HER2–. Patients with endocrine-refractory mILC have poor outcomes, with median progression-free survival (PFS) of less than three months following standard therapies. ILC is biologically distinct from invasive ductal carcinoma, with unique tumor microenvironmental features. Molecular profiling of primary untreated ILC has demonstrated marked heterogeneity, including immune-enriched (IE) and highly vascularized (HV) molecular functional portraits associated with PD-1/PD-L1 signaling and VEGF pathway activation. IVO is a novel bispecific antibody targeting PD-1 and VEGF, designed to enhance antitumor immunity while inhibiting angiogenesis. We hypothesize that dual immune and vascular targeting will improve clinical outcomes in patients with endocrine-refractory HR+/HER2– or TN mILC. Methods: Trial Design: IvoLoC (NCT07229417) is a single-center, open-label, phase II study conducted at The University of Texas MD Anderson Cancer Center. Eligible patients include those with HR+/HER2– mILC with progression on prior endocrine therapy, including combinations with CDK4/6, PI3K, AKT, and/or mTOR inhibitors, as well as patients with TN mILC. Patients may have received any number of prior endocrine-based regimens but no more than two prior cytotoxic therapies, including antibody–drug conjugates, in the metastatic setting. IVO is administered intravenously at 20 mg/kg every three weeks until disease progression or unacceptable toxicity. Radiographic assessments are performed every 9 weeks and evaluated per RECIST v1.1. Endpoints: The primary endpoint is 6-month PFS. Secondary endpoints include 12-month PFS, median PFS, objective response rate, disease control rate, duration of response, overall survival, and safety. Exploratory objectives include correlation of outcomes with molecular functional portraits, longitudinal circulating tumor DNA analyses, and integrated genomic and transcriptomic biomarker discovery. Enrollment: The study plans to enroll 29 patients. Accrual is ongoing in the United States. Clinical trial information: NCT07229417 .