Osimertinib Combined With Aspirin Neoadjuvant Therapy for Resectable EGFR Mutated NSCLC Patients.

Lung cancer is currently the leading cause of cancer-related deaths in humans, with its incidence and mortality rates continuously rising. Among them, non-small cell lung cancer (NSCLC) accounts for the vast majority of lung cancer cases (approximately 80%). About one-third of NSCLC cases are early-stage and potentially resectable. Curative surgical resection is the primary treatment approach for these patients. However, even with curative surgery, the 5-year survival rate of patients still needs improvement. It has been reported that approximately 30-55% of early-stage NSCLC patients experience recurrence within 5 years after surgery, indicating the presence of occult micro-metastases in early NSCLC. Neoadjuvant therapy before surgery can eliminate micro-metastases, downsize tumors, and reduce the risk of recurrence, thereby improving patient prognosis and extending survival. Previous studies have shown that neoadjuvant chemotherapy only achieves a 5% improvement in overall survival (OS) for patients, and the toxic side effects of chemotherapy limit its broad clinical application. Therefore, there is an urgent need for better neoadjuvant treatment strategies to enhance patient survival.

Research has shown that the epidermal growth factor receptor (EGFR) plays a significant role in the occurrence and progression of non-small cell lung cancer (NSCLC). For resectable stage IIA to IIIB NSCLC patients without EGFR mutations, the emergence of neoadjuvant immunotherapy combined with chemotherapy has been found to significantly prolong the patient's progression-free survival, improve the pathological complete response rate (pCR), and not increase the incidence of adverse events, thus providing survival benefits to patients. In the case of resectable stage IIA to IIIB NSCLC patients with EGFR mutations, several targeted neoadjuvant treatment attempts using third-generation EGFR-TKIs like osimertinib have been made, with promising data demonstrating favorable outcomes.

The 2019 World Conference on Lung Cancer (WCLC) reported a phase II clinical study using osimertinib as neoadjuvant therapy for patients with EGFR mutant NSCLC. Twenty-seven patients with stage I-IIIA EGFR mutant NSCLC received 1-2 months of osimertinib as neoadjuvant treatment prior to surgery. The major pathological response rate (MPR) for 6 assessable patients was 16%, and the objective response rate (ORR) was 66%. Thirty-three percent of patients achieved pathological downstaging. In an updated efficacy evaluation of 27 patients presented at the 2023 American Society of Clinical Oncology (ASCO) meeting, the MPR was 15%, ORR was 48%, R0 resection rate was 89%, median disease-free survival (mDFS) was 32.4 months, and median overall survival (mOS) was not reached. Another real-world retrospective study presented at the 2021 WCLC also explored the efficacy and safety of osimertinib in neoadjuvant therapy for stage I-IIIB patients. Seventeen patients who received osimertinib as neoadjuvant treatment had an MPR of 23.5%, pathological complete response (pCR) rate of 5.9%, and ORR of 88.2%. Overall, the treatment was well-tolerated. The mid-term results of the NEOS study presented at the 2021 ASCO Annual Meeting further confirmed the benefits of osimertinib as neoadjuvant therapy, although the data is still immature. From October 17, 2018, to June 8, 2021, a total of 88 patients were screened, and 40 patients were ultimately enrolled. Among the 38 patients who completed 6 weeks of osimertinib neoadjuvant therapy, the ORR was 71.1% , and the disease control rate reached 100%. This indicates that no disease progression occurred during the neoadjuvant treatment, and 71.1% of patients had significant tumor shrinkage, creating an opportunity to reduce the extent of surgical resection, decrease the difficulty of surgery, and improve surgical outcomes. However, among the 28 patients with assessable pathology, only 11% achieved MPR, and only 1 patient (4%) achieved pCR. It is well known that pathological response rates are closely related to postoperative recurrence and survival time. It would be clinically significant to further enhance the pathological response rate of osimertinib neoadjuvant patients through combination therapy strategies, which could reduce postoperative recurrence rates and improve overall survival.

Aspirin, a classic drug known for its antiplatelet effects, exhibits safety, affordability, and easy accessibility. Its potential role in cancer treatment has been widely explored. Recent studies have demonstrated the following:1. Women who take aspirin at least three times a week have a 16% reduced risk of developing breast cancer.2. Aspirin enhances the efficacy of the anti-tumor drug sorafenib in mouse models of lung cancer and melanoma with RAS gene mutations.3. By binding to the key amino acid Glu225, aspirin inhibits enzymatic activity of acetylheparinase, thereby suppressing tumor angiogenesis and metastasis.4. Aspirin boosts the effectiveness of T-cell therapy and enhances the body's immune response against cancer.5. Aspirin has received FDA approval for its preventive use in colorectal cancer.Numerous clinical and basic trials have validated the role of aspirin in cancer prevention and treatment. Moreover, our earlier research indicated that aspirin improves the immunosuppressive microenvironment associated with osimertinib, activates cytotoxic T-cell function, and enhances the killing ability of T cells against tumor cells, ultimately promoting tumor cell apoptosis. Lung cancer patients inherently experience a hypercoagulable state and are prone to critical cardiovascular events. Regular low-dose aspirin usage reduces the incidence of coronary events in lung cancer patients. Therefore, if further evidence confirms aspirin's ability to overcome osimertinib resistance beyond its antiplatelet effects, combining osimertinib with aspirin in neoadjuvant therapy for NSCLC patients could potentially enhance pathological response, reduce postoperative recurrence, and further improve the overall prognosis of patients eligible for surgical intervention.