Lead Investigator: Alex Meisel, University Hospital of Zurich
Title of Proposal Research: Neutrophils, Neutrophil-to-Lymphocyte Ratio (NLR) and Neutropenia as Predictors of Treatment Efficacy of Atezolizumab Monotherapy and Atezolizumab-Chemotherapy-Combinations
Vivli Data Request: 6062
Funding Source: None
Potential Conflicts of Interest: Real conflicts of interest: none.
Potential conflicts of interest: A.M. has provided a consulting/advisory role for Astellas, Boehringer Ingelheim, MSD, Roche, Celgene, Novartis, Vifor, Sanofi, Takeda, Amgen, and Merck, has received research funding from Bayer (Pers), Amgen (Pers) and MERCK (Inst), has intellectual property interests relating to Merck (not related to this presentation), has been paid to provide expert testimony for Sanofi, and has reported travel/accommodation/other expenses paid for by Amgen, Astellas, Janssen, Servier, Sanofi, Roche, and Boehringer Ingelheim.
These potential conflicts of interest have no impact on the planned research. ROCHE as the sponsor of the requested trials had no influence on analysis plan. The transfer of the trial data on the Vivli platform was initiated upon our request. We have provided you all details to guarantee maximum transparency. This has meanwhile become an important and common standard for the publication of research results.
Summary of the Proposed Research:
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, bladder 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 hypothesize 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 metastasis (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 valuable contribution to public health as it addresses 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.
Statistical Analysis Plan:
Overall survival (OS) and progression-free survival (PFS) will be estimated by the Kaplan-Meier method and comparisons will be made by the log rank test.
We are planning to analyse, whether the stratification factors (mentioned in the chapters before) have influence on the outcome parameters using Cox proportional-hazards survival models.
The Wilcoxon signed rank sum test will be employed to test, whether the stratification factors are associated with the overall response rate (ORR).
If applicable, the responses will also be displayed as waterfall plots.
A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared With Docetaxel in Patients With Non-Small Cell Lung Cancer After Failure With Platinum Containing Chemotherapy
Study ID: NCT02008227
Sponsor ID: GO28915
A Phase III, Open-Label, Randomized Study of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Paclitaxel With or Without Bevacizumab Compared With Carboplatin + Paclitaxel + Bevacizumab in Chemotherapy-Naïve Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer
Study ID: NCT02366143
Sponsor ID: GO29436
A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer
Study ID: NCT02367781
Sponsor ID: GO29537
Meisel, A., Mark, M., Haider, A., Holer, L., Hayoz, S., Gebhard, C., Bengs, S., Hochmair, M., Cappuzzo, F., Reck, M., von Moos, R., & Stenner-Liewen, F. (2021). 1279P The prognostic value of chemotherapy-induced neutropenia (CIN) in patients with advanced non-small cell lung cancer (NSCLC) in the era of chemoimmunotherapy (CIT). Annals of Oncology, 32, S996. doi: 10.1016/j.annonc.2021.08.1881