Ivermectin Combined with Pembrolizumab Virtual Integrative Oncology IA IL MO GA FL TX San Antonio Houston Atlanta

Evaluating Ivermectin in Combination with Pembrolizumab for Metastatic Triple-Negative Breast Cancer: Insights from Clinical Trial NCT05318469 Ivermectin Integrative Oncology IA IL MO GA FL TX San Antonio Houston Atlanta

Introduction

Triple-negative breast cancer (TNBC) represents a particularly aggressive subtype of breast cancer, characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This molecular profile limits therapeutic options, as targeted therapies effective in other subtypes are not applicable. Metastatic TNBC (mTNBC) carries a poor prognosis, with median overall survival historically ranging from 12 to 18 months. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors such as pembrolizumab (Keytruda), have shown promise in improving outcomes when combined with chemotherapy for PD-L1-positive mTNBC. However, response rates remain suboptimal, with many patients experiencing limited durable benefits due to immune evasion mechanisms within the tumor microenvironment.nejm.org

Drug repurposing has emerged as a strategy to accelerate therapeutic development by leveraging existing compounds with established safety profiles. Ivermectin, an FDA-approved antiparasitic agent, has garnered attention for its potential anticancer properties, including induction of immunogenic cell death (ICD) and enhancement of T-cell infiltration into tumors. Preclinical studies have demonstrated that ivermectin can convert immunologically "cold" tumors—those with minimal immune cell presence—into "hot" tumors amenable to checkpoint inhibition. This rationale underpins the investigation of ivermectin in combination with immune checkpoint inhibitors for mTNBC.pmc.ncbi.nlm.nih.gov

Clinical trial NCT05318469, a phase I/II study, evaluates the safety and efficacy of ivermectin combined with either balstilimab (an anti-PD-1 antibody) or pembrolizumab in patients with mTNBC. This article provides a comprehensive overview of the trial's design, preclinical foundation, and available outcomes as of November 2025, drawing on published data to assess its implications for TNBC treatment.clinicaltrials.govascopubs.org

Preclinical Rationale

The therapeutic potential of ivermectin in oncology stems from its multifaceted mechanisms. In vitro and in vivo models have shown that ivermectin promotes ICD, a form of cell death that releases damage-associated molecular patterns, thereby stimulating an adaptive immune response. In breast cancer models, ivermectin treatment has been associated with robust T-cell infiltration, effectively sensitizing tumors to immune checkpoint blockade. For instance, studies in mouse models of TNBC revealed that ivermectin synergizes with anti-PD-1 therapy by enhancing tumor immunogenicity and overcoming resistance to monotherapy.sciencedirect.com

Pembrolizumab, a monoclonal antibody targeting PD-1, has been approved for use in combination with chemotherapy for advanced TNBC based on improved progression-free and overall survival in clinical trials. However, resistance mechanisms, such as immunosuppressive tumor microenvironments, limit its efficacy in a subset of patients. The hypothesis for NCT05318469 posits that ivermectin could augment pembrolizumab's effects by promoting immune activation, potentially extending benefits to PD-L1-negative or immunotherapy-refractory cases.merck.comcityofhope.org

Study Design and Methods

NCT05318469 is an open-label, single-arm phase I/II trial sponsored by Gateway for Cancer Research, conducted at multiple sites including City of Hope Comprehensive Cancer Center. The study enrolled patients with histologically confirmed mTNBC who had progressed on at least one prior line of systemic therapy. Key eligibility criteria included measurable disease per RECIST 1.1, Eastern Cooperative Oncology Group performance status of 0-2, and adequate organ function. Exclusion criteria encompassed active autoimmune disease, prior exposure to PD-1/PD-L1 inhibitors in the metastatic setting, and untreated brain metastases.gatewaycr.orgclinicaltrials.gov

The trial incorporates a dose-escalation phase (phase I) to determine the recommended phase II dose (RP2D) of ivermectin, followed by an expansion phase (phase II) to assess efficacy. Ivermectin was administered orally at escalating doses based on body weight (200 mcg/kg, 400 mcg/kg, 600 mcg/kg, or 800 mcg/kg) on days 1-3, 8-10, and 15-17 of each 21-day cycle. This intermittent dosing schedule was selected to balance efficacy with tolerability, based on pharmacokinetic data and preclinical models. Pembrolizumab was given intravenously at 200 mg every 21 days, consistent with standard dosing. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent.clinicaltrials.govbiotechhunter.com

Primary endpoints for phase I included dose-limiting toxicities (DLTs) and determination of the maximum tolerated dose (MTD). For phase II, the primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), safety per CTCAE v5.0, and exploratory biomarkers such as tumor PD-L1 expression and immune cell infiltration. The study aimed to enroll approximately 40-50 patients, with an expansion cohort for PD-L1-negative TNBC.sciencedirect.comascopubs.org

Results

As of November 2025, the trial has completed accrual, and preliminary outcomes have been presented at the American Society of Clinical Oncology (ASCO) annual meeting. In the phase I portion, the combination was reported as generally well-tolerated, with common adverse events including fatigue, nausea, and mild skin rash. Immune-related adverse events were manageable. Detailed safety data and the RP2D have been established, but specific dose-limiting toxicities are not fully detailed in available abstracts.ascopubs.orgclin.larvol.com

Efficacy results from the phase II cohort remain preliminary, with full data awaiting peer-reviewed publication. Available information suggests variable responses, but comprehensive metrics such as ORR, PFS, and OS have not been publicly disclosed in detail. Biomarker studies indicate potential increases in tumor-infiltrating lymphocytes, though correlations with clinical outcomes are under evaluation.ascopubs.orghousecalls.doctor

Discussion

The outcomes of NCT05318469, as currently available, highlight the challenges in translating preclinical findings to clinical efficacy. While ivermectin exhibited promising immunomodulatory effects in animal models, human data remain limited. Potential explanations for any observed limitations could include pharmacokinetic differences, patient heterogeneity, or prior treatment effects.nature.comscience.org

These findings align with broader trends in drug repurposing for cancer, where initial enthusiasm often requires rigorous clinical validation. Nonetheless, the safety profile supports further exploration of ivermectin in other combinations or settings. Future research should incorporate advanced biomarkers to refine patient selection.pmc.ncbi.nlm.nih.gov

Conclusion

Clinical trial NCT05318469 provides valuable insights into the potential of ivermectin as an adjunct to pembrolizumab in mTNBC, demonstrating acceptable safety with ongoing evaluation of efficacy. These findings underscore the importance of bridging preclinical and clinical data through well-designed trials. As the field advances, continued investigation into immunomodulatory agents remains essential to address unmet needs in TNBC management.ascopubs.org

Dr. Kim provides Virtual Integrative Oncology services in IA, IL, MO, FL, GA and Texas

References (APA Style)

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