Abstract

Background. Ivermectin and mebendazole are generic, orally administered anti-infective agents that appear on the WHO Model List of Essential Medicines, carry decades of human safety data from hundreds of millions of administrations, and have each accumulated substantial evidence of antineoplastic activity. Existing reviews address monotherapy, emphasize mechanistic preclinical data, and predate a considerable body of clinical data published between 2021 and 2026. We set out to review the mechanistic, laboratory, and clinical data of ivermectin-mebendazole as adjunctive, combination therapy in patients undergoing conventional cancer care.

Methods. PubMed, Europe PMC and Google Scholar were searched through October 2026 for peer-reviewed in vitro, in vivo, and human studies of ivermectin and mebendazole in malignant disease, supplemented by oncology meeting abstracts, reference-list screening of prior reviews and ClinicalTrials.gov records. Mechanisms were counted at the level of distinct molecular targets or cellular processes rather than at the level of observed phenotypes. Clinical studies reporting efficacy outcomes were classified as positive or neutral; trials designed to determine safety, tolerability, or dose were counted separately, and single-patient case reports were excluded from the outcome classification.

Findings. 29 distinct anticancer mechanisms are documented for ivermectin and 26 for mebendazole. Merging those that act on the same target or pathway yields 37 distinct mechanism classes across the two agents. Ivermectin has demonstrated preclinical activity in 21 malignancies (20 human, 1 canine), and mebendazole in 17 human malignancies, encompassing 25 distinct human malignancies across both agents. The two agents converge mechanistically on hypoxia signaling, DNA damage response, angiogenesis, cancer stem-cell populations and multidrug-resistance transporters, while their transcription-factor targets are almost entirely non-overlapping and their immunological effects fall on separate arms of the immune system, ivermectin acting principally within adaptive immunity and mebendazole within innate immunity. These mechanisms converge on a set of cellular outcomes: mitotic and cell-cycle arrest, caspase-dependent apoptosis through the mitochondrial pathway, autophagy that is lethal in some settings and cytostatic in others, and immunogenic cell death. Six clinical studies reported efficacy outcomes: 3 were positive, 2 were neutral and 1 is an incomplete interim readout that cannot yet be classified. A further 4 trials were designed to determine safety, tolerability or dose, and 1 randomized trial of ivermectin with checkpoint inhibition is registered but not yet reporting. In the only randomized, double-blind, placebo-controlled trial, mebendazole added to bevacizumab and FOLFOX4 in metastatic colorectal cancer produced an overall response rate of 65% (13 of 20) against 10% (2 of 20) with bevacizumab and FOLFOX4 alone, and a median progression-free survival of 9.25 against 3.00 months. The only human study of a combined ivermectin-mebendazole therapeutic, a prospective observational cohort of 197 patients of whom 122 completed six-month follow-up, reported a clinical benefit proportion of 84.4% (103 of 122; 95% CI 77.0-89.8%), with no evidence of disease or regression in 48.4% (59 of 122). No clinical study demonstrated inferior outcomes attributable to either drug, and no completed study has yet evaluated ivermectin as a single agent. A systematic review with individual-patient-data meta-analysis of 36 patients with cancer who received oral ivermectin, several during active chemotherapy, recorded no serious adverse events attributable to the drug, and mebendazole has been co-administered with other anticancer therapy in 5 trials, with safety established at doses up to 200 mg/kg.

Conclusions. Together, ivermectin and mebendazole exhibit 37 distinct anticancer mechanism classes across 25 human malignancies, highlighting their exceptionally broad potential for therapeutic repurposing in oncology. Both are oral, widely available generic drugs that are well-tolerated alongside chemotherapy. No oncology trial of either agent has been stopped for toxicity. Large, prospective, double-blind, parallel-group, randomized trials of combination ivermectin-mebendazole are urgently needed across a broad array of human malignancies.