Abstract P2-12-26: A phase Ib study of novel combination (New) of low dose oral cyclophoSphamide (S) To potentiate axatilimab (A) + retifanlimab (R) in treating metastatic Triple negative breast cancer (NEW START)

Abstract Background: A large proportion of triple negative breast cancer (TNBC) patients (pts) will have residual disease detected post-neoadjuvant systemic therapy (NAST), which is associated with a significant risk of recurrence within 2-3 years following surgery. Moreover, if resistance develops to first-line therapy, the response rate to second or higher lines of therapy is poor (5-10% historically), representing a vast unmet need. Evidence suggests that one mechanism causing resistance is associated with the tumor immune microenvironment (TIME), particularly low T cell infiltrates and high levels of tumor-associated macrophages (TAMs). This led to the hypothesis that eradicating TAMs could re-sensitize NAST-resistant TNBC to tumor growth inhibition. Preclinical models using the preclinical version of axatilimab + low dose cyclophosphamide (CTX) successfully depleted macrophages and treated several primary TNBC models. However, intratumoral heterogeneity within lung metastasis was observed following treatment cessation, along with elevated PD-L1 levels. Suspecting elevated PD-L1 levels as the likely cause of T cell exhaustion, an immune checkpoint blockade drug was added, which showed higher efficacy and prolonged the overall survival of mice bearing established lung metastasis. Given the target relevance in inflammatory breast cancer (IBC), the TNBC and low ER/PR IBC will also be included due to the high infiltration of TAMs and resistance to chemotherapy. After successful pre-clinical models, we propose a phase 1b study to demonstrate safety, response, and to find the optimal biologic dose (OBD) of CTX and axatilimab, along with standard dose retifanlimab to facilitate studies of efficacy. Axatilimab is a monoclonal antibody (mAb) with a high affinity against CSF-1R. Targeting CSF-1R is expected to reduce the circulating levels of pathogenic macrophage precursors and inhibit their activation in tissues. Retifanlimab is a mAb that targets PD-1, currently FDA approved for use in merkel cell carcinoma. It is designed to block checkpoint inhibitory interactions and sustain the function of PD-1–expressing cells. Methods: Up to 24 pts will be enrolled in cohorts of 3 pts. Pts will receive a fixed dose of retifanlimab, one of two dosage levels of CTX, and one of three dosage levels of axatilimab. The utility-based Bayesian optimal interval (U-BOIN) design will be used to determine the OBD weighing both dose limiting toxicities and objective responses. We will study baseline and follow-up biopsy after pharmacodynamics window (4 weeks +/- 7 days) to test exploratory biomarkers such as TAMs, epithelial-mesenchymal transition features, and other TIME cells. Tumor staging will be done at baseline and after every 2 cycles, each cycle defined as 4 weeks. All tumor responses will be evaluated by iRECIST 1.1. The study was sponsored by Incyte and the UT MD Anderson Cancer Center Morgan Welch Inflammatory Breast Cancer Clinic and Research Program. Key inclusion criteria: - Metastatic or locally recurrent unresectable malignancy lacking standard curative treatments - Histologically or cytologically confirmed non-IBC TNBC, defined as ER<1%, PR<1% and HER2 negative per ASCO CAP 2018 guideline, OR - IBC confirmed according to international consensus criteria that is ER<20% and PR<20% - At least 1 week since prior chemotherapy or radiation therapy - Age ≥18 years - Has at least one measurable lesion per RECIST 1.1 - ECOG performance status ≤ 2 - Adequate organ and marrow function. Key exclusion criteria: - Unrecovered >Grade 1 adverse events due to prior anti-cancer therapy, with some exceptions - Evidence of progression in treated brain metastases. The primary endpoints are OBD, dose limiting toxicity, and objective response. The secondary endpoints include clinical benefit, duration of response, progression-free survival, 2-year overall survival, pharmacodynamic markers, and detailed safety and tolerability of the triple combination. Citation Format: Joshua Haney, Diego A. Pedroza, Angela Marx, Angela Alexander, Rebecca Tidwell, Azadeh Nasrazadani, Rachel Layman, Vicente Valero, Huiming Sun, Anthony Lucci, Susie Sun, Carisa Le-Petross, Gary Whitman, Rahul Sheth, Savitri Krishnamurthy, Chelain Goodman, Michael Stauder, Wendy A. Woodward, Jeffrey Rosen, Bora Lim. A phase Ib study of novel combination (New) of low dose oral cyclophoSphamide (S) To potentiate axatilimab (A) + retifanlimab (R) in treating metastatic Triple negative breast cancer (NEW START) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-12-26.