Tolerability and Effectiveness of Combined Immune Checkpoint Blockade and Helixor® Viscum album Therapy in Oncological Patients: Real-World Evidence in Line with Esmo Grow Guidelines

Background: Real-world data (RWD) play a crucial role in clinical research by identifying key subgroups and assessing multimodal therapies in oncology, including integrative and (early) palliative care. Recent advancements in immune checkpoint blockade (ICB) have significantly improved cancer survival, and combining these with complementary therapies such as Viscum album (VA) extracts may further enhance outcomes without introducing additional safety risks. Methods: This RWD study utilized data from the Network Oncology (NO) registry, accredited by the German Cancer Society, following ESMO-GROW guidelines. Between June 2015 and June 2024, patients received PD-1/PD-L1 inhibitors, either alone or with Helixor® Viscum album (HVA) extracts, based on physician discretion. The primary objective was to assess the tolerability of anti-PD-1/PD-L1 therapy, and the secondary objective focused on overall survival in a subgroup of cancer patients. Eligible patients were aged 18+, with data on demographics, diagnosis, and treatment extracted from the NO registry. Statistical analysis included Kaplan-Meier survival curves and Cox proportional hazards models to assess survival, adjusting for key confounders. Results: Among 405 cancer patients receiving ICB, 344 received ICB alone (CTRL) and 61 received ICB with Helixor® Viscum album (COMB). The cohort's median age was 66 years. Lung cancer was the predominant cancer type (78.6%). In total, the combinational PD-1/PD-L1 plus HVA therapy were applied in 17 different tumor entities. Adverse event-related discontinuation was lower in COMB (4.9% vs. 6.4%, p=0.25). The 3-year survival rate in a subgroup of 312 non-small cell lung cancer (NSCLC) patients was 34.3% in the COMB-group, which was twice that of the CTRL group (17.2%), with statistical significance p=0.02. In a subgroup of 137 female patients with NSCLC, multivariate survival analyses revealed that the COMB therapy was significantly associated with reduced death risk by 91.2% (aHR: 0.088; 95% CI: 0.009–0.783), independent of confounding factors. In addition, 5-year survival rate in these patients increased when Helixor® VA was added to ICB (COMB: 50.1% vs. CTRL: 12%). Conclusions: Our RWD registry study highlights the potential benefits of combining immune checkpoint blockade (ICB) with Helixor® VA (COMB) to improve outcomes in oncological patients, particularly NSCLC patients. The 3-year survival rate was doubled significantly when HVA was added to ICB in these patients. In addition, the COMB therapy showed a 91.2% reduction in the adjusted risk of death compared to ICB alone in female NSCLC patients, supporting further investigations into its safety, efficacy, and broader applicability in cancer care. In addition, combinatorial immune checkpoint blockade with Helixor® VA has been shown favorable tolerability across more than fifteen tumor entities. By leveraging RWD, we were able to assess the potential role of HVA as an adjunct to ICB in improving survival and tolerability, particularly in subgroups such as female NSCLC patients, where significant effects were observed. The study was registered (DRKS00013335).