IvoLoC Trial: A phase II trial evaluating the efficacy of ivonescimab in metastatic endocrine refractory HR-positive HER2-negative or triple negative invasive lobular carcinoma (ILC)

Background: ILC accounts for approximately 10-15% of breast cancers and is predominantly HR+/HER2-. Patients with endocrine-refractory metastatic ILC (mILC) experience poor outcomes, with median progression-free survival (PFS) of less than three months following standard therapies. Unlike invasive ductal carcinoma, ILC exhibits distinct tumor biology and microenvironmental features. Comprehensive molecular profiling of primary untreated ILC has revealed marked heterogeneity, with a substantial proportion demonstrating immune-enriched (IE) and/or highly vascularized (HV) molecular functional portraits characterized by increased PD-1/PD-L1 signaling and VEGF pathway activation. Ivonescimab is a novel bispecific antibody targeting PD-1 and VEGF, designed to simultaneously enhance antitumor immunity while inhibiting angiogenesis. We hypothesize that dual targeting of immune and vascular pathways will improve clinical outcomes in patients with endocrine-refractory HR+/HER2- or Triple negative (TN) mILC. Trial Design: IvoLoC (NCT07229417) is a single-center, open-label, phase II clinical trial conducted at The University of Texas MD Anderson Cancer Center. The study enrolls patients with HR+/HER2- mILC who had disease progression on prior endocrine therapy, including endocrine therapy in combination with targeted agents (such as CDK4/6, PI3K, AKT, and/or mTOR inhibitors) and TN mILC patients. Patients may have received any number of prior endocrine-based regimens but must not have received more than two prior cytotoxic agents including antibody-drug conjugates in the metastatic setting. Participants receive ivonescimab at a dose of 20 mg/kg administered intravenously every three weeks until disease progression or unacceptable toxicity. Baseline tumor tissue is assessed for molecular functional portrait classification, including IE and HV phenotypes, with serial biospecimen collection for correlative studies. Radiographic disease assessments are performed every three cycles (9 weeks) and evaluated per RECIST v1.1 criteria. Endpoints: The primary endpoint is the 6-month PFS rate. The study is powered to detect an improvement in 6-month PFS from 20% to 40%. Secondary endpoints include 12-month PFS, median PFS, objective response rate, disease control rate, duration of response, overall survival, and safety and tolerability. Exploratory objectives include correlating clinical outcomes with molecular functional portraits, evaluating longitudinal circulating tumor DNA dynamics, and performing genomic and transcriptomic analyses to identify biomarkers of response and resistance and to inform development of a predictive responder score. Enrollment: The study plans to enroll 29 patients and is currently open to accrual in the United States at a single site. Enrollment is ongoing and anticipated to be completed within two years.