DOI: 10.25934/00006062
title: Neutrophils, NLR and Neutropenia as Predictors of Treatment Efficacy of Atezolizumab Monotherapy and Atezolizumab-Chemotherapy-Combinations

description: Immune-checkpoint inhibitors (ICIs) are drugs that prevent cancer cells evading the destruction by the immune system. ICIs have transformed the treatment of non-small cell lung cancer (NSCLC) and significantly improved the prognosis of this disease. Therefore, international guidelines have defined this novel treatment approach as the new standard of care. Nevertheless, not all patients are responding to this novel form of immunotherapy.

Atezolizumab is on of the approved ICIs and amongst the most widely used. Despite lung cancer it is used in many other cancer types like kidney, blader or breast cancer.

Neutrophils are the most common type of white blood cells. They are one form of myeloid derived suppressor cells (MDSCs), which are derived from the bone marrow. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expands during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses, the latter being an important part of the immune system. We hypothezise that neutrophils have a causal relationship with inferior outcomes in patients treated with ICIs and ICI combinations. Neutrophils are attracted to the tumor lesions by cytokines (signaling molecules regulating the immune system) and can make up to 50% of the tumor volume. They inhibit a sufficient immune response and fuel tumor progression by increasing the proliferation of tumor cells, inducing pro-survival signals as well as promoting metastatis (spread of cancer cells to other parts on the body).

Therefore we would like to establish the role of a high neutrophil count and a high neutrophil-to-lymphocyte ratio in this context (Lymphocytes are another type of white blood cells important for tumor immunity). In Contrast, we believe that neutropenia (low neutrophil count induced by chemotherapy) can overcome the negative impact of neutrophils and ultimately lead to better treatment results. For a long time neutropenia was only seen as a treatment-emergent adverse event until we and others were able to show an association with improved survival outcomes. Since 75% of the NSCLC patients do not develop neutropenia, these patients have the potential to benefit from treatment modifications and dose adaptations.

We believe that our research would be an important contribution to the understanding of immune-checkpoint inhibitor efficacy in NSCLC. Additionally, the results would offer a starting point for future interventions, since neutropenia is a dynamic and dose-dependent biomarker compared to many other biomarkers, which are currently investigated in this disease. In many countries in the world lung cancer is the malignancy with the highest mortality (approx. 20% in Switzerland). Therefore, this project would be an valueable contribution to public health as it adresses one of the most prevalent malignancies. We have carefully evaluated the addition of a one- or two-step meta-analysis. We came to the conclusion that the heterogeneity of the trials (histology, treatment regimen, line of treatment and study design) do not justify such an approach to the current time point. Therefore, the studies will be analyzed separately.