An Observational Phase II Study to Evaluate the Efficacy and Safety of Aspirin in Combination With Trametinib and Dabrafenib in Advanced Non-small Cell Lung Cancer Patients With BRAF V600E Mutation

lung cancer is the leading cause of morbidity and mortality in China, and non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. The incidence of V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in NSCLC is 1.5% to 3.5%, and BRAF V600 accounts for about 30-50% of all BRAF mutations, among them, V600E mutation is the most common . NSCLC patients with BRAF V600 mutation have poor prognosis and shorter overall survival (OS). In terms of drug therapy for these patients didn't get a better clinical benefits of chemotherapy and immunotherapy, and the progression free survival (PFS) of chemotherapy is only 1.5~4.2 months . The PFS of patients with BRAF-mutated NSCLC treated with immune checkpoint inhibitors was only 3.1 to 5.3 months . In recent years, the application of targeted therapy has brought new hope for patients with lung cancer BRAF mutation. In three cohorts of the Phase II clinical trial BRF113928, the BRAF inhibitor darafenib, was demonstrated has a significant efficacy as a single agent in treated patients with BRAF V600E mutation (cohort A), combined with mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor trametinib in treated patients (cohort B), and combined with trametinib in treated patients (cohort C), respectively. Objective response rates (ORR) were 33.0%, 63.2%, and 64.0%, and PFS were 5.5, 9.7, and 14.6 months, respectively. BRF113928 research shows that Dabrafenib combined with Trametinib had good efficacy in the treatment of BRAFV600 mutant NSCLC patients, regardless of whether it was used as first-line therapy or back-line therapy, and was superior to BRAF single-agent targeted therapy. In terms of safety, the most common adverse event (AE) of Dabrafenib combined with Trametinib was fever. In cohort B and cohort C, the incidence of fever of all grades was 46% and 64%, respectively, but most of them were grade , while the incidence of grade 3-4 AE was relatively low, 2% and 11%. In general, it is safe and controllable . The main management methods for fever AE caused by Dabrafenib combined with Trametinib as follows: after the first occurrence of fever syndrome, the patient should stop taking both drugs and immediately start oral antipyretic therapy. After the fever, it is still recommended to continue the drug for 3 days before stopping the fever treatment. The selection and usage of related antipyretic drugs should be comprehensively evaluated by doctors, and the options include non-steroidal anti-inflammatory drugs, acetaminophen, and anethene. At present, the latest NCCN and CSCO both regard Dabrafenib combined with Trametinib as the preferred first-line treatment for BRAF V600E mutated advanced NSCLC patients . In March 2023, Dabrafenib combined with Trametinib entered the national medical insurance directory, reducing the economic burden of patients. However, drug resistance to targeted drugs is inevitable. Studies have shown that the resistance mechanism of BRAF/MEK inhibitors is mainly mediated by the PI3K-Akt-mtor and RAS-RAF-MEK pathways, such as cell cycle related gene changes, PI3K-AKT pathway activation, NRAS/KRAS mutations, etc. Drug resistance mechanism of Dabrafenib combined with Trametinib is complicated, there are few opportunities to use targeted drugs, also lack of clear recommendation for follow-up treatment guidelines, usually systemic treatment such as immunotherapy and chemotherapy are adopted. How to overcome the resistance mechanism, delay drug resistance, and further prolong the PFS and OS of patients of Dabrafenib combined with Trametinib still need more exploration.

Previous epidemiological studies have suggested that aspirin may reduce the incidence of certain cancers, including lung cancer. A study from the United States included 365 patients with advanced non-small cell lung cancer treated with Osimertinib, 77 of whom were taking aspirin while taking Osimertinib. The results showed that the median PFS of patients treated with aspirin was 21.3 months, which was significantly longer than the median PFS of 11.6 months of patients treated with Osimertinib alone. However, the median OS of patients treated with aspirin was lower than that of patients treated with Osimertinib alone, which was 32.3 months. Combined with aspirin could significantly reduce the risk of death of patients by 44%, suggesting that EGFR-TKI combined with aspirin could improve the patients' PFS and reduce the risk of death and bleeding events. And the same as the targeted drugs, Dabrafenib who joint Trametinib whether can combine with aspirin? How safe is it? Can the combination of aspirin with Dabrafenib and Trametinib improve the PFS and OS of patients? Aspirin has antipyretic and analgesic effects, while one of the most common adverse reactions of Dabrafenib combined with Trametinib is fever. Can the combination of Dabrafenib combined with Trametinib reduce the occurrence of adverse events of fever? At present, in the field of lung cancer, there is no literature report on aspirin combined with Dabrafenib and Trametinib in the treatment of BRAF V600E mutated advanced NSCLC. In order to solve the above problem, further improve the BRAF V600E mutations in NSCLC patients with long-term survival, we proposed the observational phase II study to evaluate the efficacy and safety of aspirin combined with Dabrafenib and Trametinib in advanced NSCLC with BRAF V600E mutation.

Primary Objectives: To determine the progression-free survival time (PFS) of aspirin combined with Dabrafenib and Trametinib;

Secondary Objectives:

A, To determine the 3 year Overall Survival (OS) in the aspirin combined with Dabrafenib and Trametinib; B, To observe the Objective Response Rate (ORR) of aspirin combined with Dabrafenib and Trametinib; C, To observe the Disease Control Rate (DCR) in aspirin combined with Dabrafenib and Trametinib; D, To observe the fever-reducing rate of aspirin combined with Dabrafenib and DabrafenibTrametinib E, To observe the risk of coronary events in patients with aspirin combined with Dabrafenib and Trametinib.