Survival analysis of advanced lung adenocarcinoma harboring epidermal growth factor receptor gene mutation receiving the combination treatment of atezolizumab, Bevacizumab,carboplatin and Paclitaxel

Lead Investigator: Xiaoling Shang, Shandong University
Title of Proposal Research: Survival analysis of advanced lung adenocarcinoma harboring epidermal growth factor receptor gene mutation receiving the combination treatment of atezolizumab, Bevacizumab,carboplatin and Paclitaxel.
Vivli Data Request: 7395
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Lung cancer is the leading cause of cancer mortality worldwide. Non-small cell lung cancer accounts for more than 80% of primary lung tumors. Lung adenocarcinoma is a pathological type of non-small cell lung cancer, accounting for about 40% of primary lung tumors. It is more likely to occur in women and non-smokers. The epidermal growth factor receptor mutation is the most common gene mutation in patients with lung adenocarcinoma, and the mutation incidence is as high as 50% in Asians with lung adenocarcinoma. The epidermal growth factor receptor tyrosine kinase inhibitors are the preferred treatment for these patients, and the effective rate is more than 60%-70%. And the median progression free survival, which is defined as the time between the beginning of treatment and the observation of disease progression or death from any cause, for patients using the first/second generation tyrosine kinase inhibitors is 9-13 months, and the median progression free survival of the third generation tyrosine kinase inhibitors is 18.9 months. However, epidermal growth factor receptor tyrosine kinase inhibitors resistance is inevitable in the later stage, and there is no effective treatment scheme for drug-resistant patients, which is an important clinical problem to be solved urgently.

Patients with epidermal growth factor receptor mutations reveals poor response to immunotherapy. Immunotherapy is a treatment method to artificially enhance and inhibit the immune function of the body in order to achieve the purpose of treating diseases. The purpose of tumor immunotherapy is to activate the human immune system and kill cancer cells and tumor tissues by relying on autoimmune function. Immunotherapy has a variety of classification methods, for example, targeting programmed death-1 or programmed death ligand-1. Programmed death-1 (PD-1) is a regulatory protein of T lymphocytes, but it inhibits the immune killing effect of lymphocytes and reduces the killing effect of T lymphocytes on tumors, resulting in the occurrence of tumors. Programmed death ligand-1 (PD-L1) is a ligand protein produced by tumor cells, which can be combined with PD-1 of T lymphocytes. The immune recognition function of T lymphocytes is inhibited, so that T lymphocytes will not kill tumor cells with PD-L1 and the tumor can grow smoothly. Based on the above principles, the drugs of targeting PD-1/PD-L1 can specifically combine with PD-1/PD-L1, so as to relieve the immunosuppressive regulation of T lymphocytes, so that T lymphocytes can kill tumor cells.

The subgroup analysis of IMPower 150 revealed a preliminary effect on patients with epidermal growth factor receptor mutations who received programmed death ligand-1 and anti-angiogenesis plus chemotherapy with better prognosis. Anti-angiogenesis is a method that can inhibit the growth of blood vessels and without a stable blood supply, the tumor stops growing and many cancer cells in the tumor eventually die. This clinical dataset brings hope to patients with epidermal growth factor receptor mutations who are not responsive to immune checkpoint inhibitors monotherapy, suggesting a dramatically improvement of science and health.

Statistical Analysis Plan:

Patients with unknown epidermal growth factor receptor mutation status will be excluded. Patients’ baseline characteristic including age, gender, race, Eastern Cooperative Oncology Group performance status score, histological subtype, presence of liver metastases, programmed death ligand-1 expression, epidermal growth factor receptor mutation status, V-Ki-ras2 Kirsten ratsarcoma viral oncogene homolog (KRAS) mutation status, Echinoderm Microtubule like 4-Anaplastic Lymphoma kinase (EML4-ALK) rearrangement status and effector T cell gene signature will be shown in table (the classification of clinical variables will be reflected in the article table, such as how many male and female are in gender). Next, Cox proportional hazards regression will be used to assess the prognostic significance of epidermal growth factor receptor mutation with survival outcomes. Complete case analyses adjusted for age, sex, Eastern Cooperative Oncology Group performance status score, race, smoking status, histology, presence of liver metastases, effector T cell gene signature score, programmed death ligand-1 and epidermal growth factor receptor mutation status will be conducted. Survival probabilities will be estimated via Kaplan-Meier analysis.

Requested Studies:

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
Data Contributor: Roche
Study ID: NCT02366143
Sponsor ID: GO29436

Summary of Results:

Due to various reasons, we did not complete the data analysis within one year. Although we have made some meaningful results, these are not relevant to our research topic. We originally wanted to obtain the gene expression of immune cell population of patients with EGFR mutation from the data, but we haven’t found it. Therefore, we will not publish the content. A brief summary is as follows:

Abstract
Objective: A Nomogram model based on clinical variables was conducted to predict survival for NSCLC patients receiving atezolizumab combined with chemotherapy.
Methods: Atoatl of 383 patients with NSCLC receiving atezolizumab combined with chemotherapy from IMPower150 study were randomly divided into the training cohort and the test cohort. Univariate and multivariate Cox analysis were performed to analyze the influence of different variables on overall survival (OS). Next, a Nomogram model-based on clinical variables in the training cohort was established to predict the survival of patients receiving atezolizumab combined with chemotherapy. The concordance index, area under curve (AUC) and calibration plots were used to assess the performance of the Nomogram model. Using Kaplan-Meier and log-rank test, we compared the survival difference between high- and low-risk group, respectively and validated by the test cohort.
Results: We successfully constructed a Nomogram model based on age, race, ECOG performance and stage to predict survival in patients with NSCLC receiving atezolizumab combined with chemotherapy using the training cohort (n=192). The C-index of the model was 0.676. The ROC curve showed that the AUC in the training cohort to predict 1-year, 2-year survival was 0.672, 0.675, respectively. According to risk score, patients receiving atezolizumab combined with chemotherapy were divided into high- and low-risk group. Importantly, compared with the low-risk group, patients had worse OS in high-risk group

(P = 0.0028). As our expected, the high-risk patients in the test cohort (n=191) also showed a worse OS (P = 0.0069).
Conclusions: The clinical variable based-Nomogram model could predict survival benefit for NSCLC patients receiving atezolizumab combined with chemotherapy.