Efficacy and Safety of Viscum album L. in Patients With Triple-Negative Breast Cancer Receiving Immune Checkpoint Inhibitors: A Protocol for an Open-Label Randomized Clinical Trial.

Although pembrolizumab has shown clinical benefit in triple-negative breast cancer (TNBC), effective long-term responses remain limited. Viscum album (mistletoe extracts, VA) may have immunomodulatory, pro-apoptotic, and immune-stimulating effects in preclinical and clinical studies. This trial was designed to evaluate the immunologic effects and safety of combining pembrolizumab with VA in the adjuvant setting. This open-label, randomized, clinical trial will include 40 adults (≥19 years) with histologically confirmed TNBC who have undergone surgery and started adjuvant pembrolizumab but received adjuvant pembrolizumab no more than three cycles. Participants will be randomized 1:1 to receive pembrolizumab plus Viscum album (VA group, n = 20) or to the wait-list group (n = 20). VA will be administered subcutaneously in escalating doses for 18 weeks. The primary endpoint will be the change in immune-related markers (e.g., interferon gamma, tumor necrosis factor-alpha, interleukin [IL]-2, IL-12, IL-15) assessed at baseline and weeks 4, 7, and 19. Secondary endpoints will include quality of life and safety. This ongoing study will explore whether the addition of VA enhances systemic immune activation, as reflected by cytokine modulation, and improves patient-reported quality of life without increasing adverse events. The integration of VA with pembrolizumab may offer synergistic benefits by augmenting immune responses within the tumor microenvironment. This trial is expected to generate clinical evidence regarding the immunologic implications, safety, and feasibility of this combined regimen, informing future strategies for adjuvant treatment of TNBC. The trial has been registered at https://ClinicalTrials.gov (registration identifier: NCT06920810).