This article is a preprint and has not been peer-reviewed. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Background: Recent advancements in cancer treatment have shown the potential of PD-1/PD-L1 inhibitor (ICB) plus Viscum album L. (VA) therapy in improving survival rates for patients with advanced or metastasized non-small cell lung cancer (NSCLC). The objective of this study was to investigate factors associated with improved survival in NSCLC patients treated with a combination of ICB and VA. Methods: Patients with advanced or metastasized NSCLC from the accredited national Network Oncology registry were included in the real-world data study adhering to ESMO-GROW criteria. The study was conducted with ethics approval. Survival and the impact on hazard were compared between patients receiving PD-1/PD-L1 inhibitor therapy alone versus combinational PD-1/PD-L1 inhibitors and abnobaViscum therapy. Adjusted multivariate Cox proportional hazard analysis was utilized to examine factors linked to survival. Results: Enrolled patients (n = 300) had stage III or stage IV NSCLC, had a 1.19 male/female ratio and were 68 years old (median). Two hundred and twenty-two patients (74%) were in the control (CTRL, PD-1/PD-L1 inhibitor therapy) and seventy-eight patients (26%) in the combinational (COMB, PD-1/PD-L1 inhibitor plus abnobaViscum therapy) group. The three-year survival was significantly prolonged by 7 months when abnobaViscum therapy was added to the anti-PD-1/PD-L1 therapy (Comb: 13.8 months vs. Control: 6.8 months, p = 0.005). The three-year survival rate was 16.5% in the COMB group and two times higher than the three-year survival rate in the CTRL group (8.0%). Adjusted multivariable Cox regression analysis was performed for patients with PD-L1 positive (</=1%) NSCLC treated with a first-line PD-1 inhibitor and revealed that the addi-tion of abnobaViscum therapy to anti-PD-1 significantly lowered the hazard of death by 75% in (aHR: 0.25; 95%CI: 0.11-0.60, p=0.002). Conclusions: Our results indicate that addition of ab-nobaViscum therapy is significantly linked to enhanced survival in patients with advanced or metastasized NSCLC who are undergoing treatment with standard PD-1/PD-L1 inhibitor therapy irrespective of their age, tumor stage, ECOG status, surgery or radiation. The mechanisms could involve a synergistic modulation of the immune response, reduced primary PD-1/PD-L1 inhibitor resistance via immunogenic cell death and/or modification of the tumor microenvironment by combinational PD-1/PD-L1 inhibitor and abnobaViscum therapy. Our findings should be com-plemented with analyses of RCT or R-RCT. Trial registration: The study was registered retrospectively (DRKS00013335).