DOI: 10.25934/pr00010112
title: TP53 missense and truncating mutations may be linked to differential response to checkpoint blockade in patients with advanced non-small cell lung cancer: a post hoc analysis of the OAK and POPLAR trials.

description: Lung cancer is the leading cause of cancer death among both men and women, accounting for almost 25% of all cancer deaths. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, making up about 84% of all lung cancer cases. The likelihood that a man will develop lung cancer in his lifetime is about 1 in 15, while for a woman, the risk is about 1 in 17.
In recent years, the treatment of advanced NSCLC has seen significant advancements with the introduction of immune checkpoint inhibitors (ICIs). These are a type of immunotherapy—drugs designed to enhance the immune system's ability to recognize and fight cancer cells. However, only some patients experience long-term benefits from these therapies. Notably, those who benefit often do not have what is known as "oncogene-addicted disease," where specific genetic mutations are the main drivers of cancer growth.
A mutation is a change in the normal DNA sequence of a gene. One of the genes commonly mutated in NSCLC is TP53. TP53 stands for tumor protein p53, a gene that plays a crucial role in regulating cell growth by providing instructions for making a protein that controls cell division. This protein acts like a "stop sign" for cell growth, helping to prevent cells from growing and dividing too quickly or in an uncontrolled manner, which can lead to cancer.
Mutations in the TP53 gene are common in NSCLC and can influence how patients respond to ICIs. There are different types of TP53 mutations that affect its function:
Missense Mutations: These mutations involve a small change in the gene, where just one part (or amino acid) of the TP53 protein is altered. This is like making a minor tweak to a recipe—most of the protein's tumor-suppressing functions may still work, but not perfectly.
Truncating Mutations: These mutations result in the TP53 protein being cut short or incomplete, similar to a recipe with half the instructions missing. This can cause the protein to lose its ability to control cell growth, potentially leading to increased cancer development and a poor response to treatment.
Some studies suggest that tumors with TP53 mutations might be more responsive to ICIs, but the specific effects of different types of TP53 mutations are still not fully understood. Research has shown that TP53 mutations can lead to increased expression of proteins associated with the body's anti-tumor immune response, potentially making these tumors more likely to respond to treatments. However, while missense mutations might allow some function to remain, truncating mutations often lead to a complete loss of TP53 function, which has been associated with immune suppression and decreased response to ICI treatments.
To explore this further, we will investigate the different impacts of TP53 missense mutations and TP53 truncating mutations compared to no TP53 mutations in patients with NSCLC treated with ICI-based regimens.
We plan to analyze data from two major clinical trials: POPLAR and OAK. The POPLAR trial is a multicenter, randomized, open-label phase 2 study that enrolled patients with advanced NSCLC who had already received treatment. These patients were randomly assigned to receive either atezolizumab (an immunotherapy drug that blocks PD-L1, a protein that helps cancer cells evade the immune system) or docetaxel (a chemotherapy drug). The trial confirmed that immunotherapy with atezolizumab provides a survival benefit over chemotherapy with docetaxel. Similarly, the OAK trial is a larger, international phase 3 study that also compared atezolizumab to docetaxel in patients with advanced NSCLC, further confirming the survival benefit of immunotherapy.
Our aim is to merge the datasets from the POPLAR and OAK studies to analyze the clinical outcomes of patients treated with atezolizumab and docetaxel, specifically looking at how these outcomes vary depending on the TP53 mutation status. By doing this, we can evaluate whether TP53 missense and truncating mutations have different effects on patient survival and treatment response compared to no TP53 mutations.
The findings of this study could significantly impact how NSCLC is treated. If we find that certain TP53 mutations predict better outcomes with immunotherapy, doctors could use genetic testing to identify which patients are more likely to benefit from this type of treatment. This personalized approach could lead to better survival rates and fewer side effects, as treatments would be more precisely targeted to the genetic profile of each patient's cancer. Ultimately, this research aims to improve the quality of care and outcomes for patients with advanced NSCLC by providing more tailored and effective treatment options.