Does the Combined Use of Aspirin and Immunotherapy Result in Better Outcomes in Non-Small Cell Lung Cancer Than Immunotherapy Alone?

Introduction: Immunotherapy works by stimulating the immune system against cancer cells. Resistance to immunotherapy represents a significant challenge in the field of medical oncology. The mechanisms by which cancer cells evade immunotherapy are not well understood. Prior research suggested overexpression of prostaglandin E-2 (PGE- 2) by cancer cells, which bind to EP-2 and EP-4 receptors on the tumor-specific cytotoxic T- lymphocytes (CTLs) and suppress their anticancer role. This immunosuppressive effect is involved in evading the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade of immunotherapy, which fuels cancer cell growth and recurrence. Studies found that combining PGE-2 blockade and a PD-1 signaling inhibitor helped promote the anticancer immunity cells. If confirmed in a clinical setting, the above in vitro findings could be of great clinical significance. Methods: Given that aspirin (ASA) blocks PGE-2 production, this work aimed to evaluate whether ASA use with immunotherapy results in better outcomes than immunotherapy alone. We performed a retrospective chart review of 500 non-small cell lung cancer (NSCLC) patients aged 21 years or older treated with PD-1 and/or PD-L1 directed immunotherapy at St. Luke's University Health Network between July 2015 and July 2021. Relevant patient, disease, and treatment-related variables were collected, including ASA use (>= 81 mg daily) and the type of immunotherapy. Bivariate analyses were conducted to determine which variables to include in a multivariable model. The four primary outcomes included survival at 18-months, both after diagnosis and starting immunotherapy, achieving complete remission (CR), and having a progressive disease (PD), as defined by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Secondary outcomes included therapyrelated toxicities and complications in the different treatment groups. Results: After bivariate analysis, no statistical significance was found for a difference in 18-month survival between ASA and non-ASA groups (50.3% vs 49.7%, p-value = 0.79). ASA with PD-L1 inhibitor showed a trend towards a higher likelihood of achieving CR [adjusted odds ratio (AOR) 1.85] with a p-value close to statistical significance (0.06). However, ASA with PD-L1 showed high statistical significance as an independent variable associated with a decreased likelihood of having PD (AOR 0.44, p < 0.001). These findings suggest that NSCLC patients receiving PD-L1 inhibitors could benefit more from daily ASA than patients treated with PD-1 inhibitors. Our study emphasizes using the Eastern Cooperative Oncology Group (ECOG) scoring of the performance status (PS) in NSCLC patients. Poorer PSwas associated with lower survival, decreased likelihood of CR, and more PD. Other variables associated with worse outcomes were advanced cancer stage at diagnosis and male gender. Low-PD-L1 expression in NSCLC was associated with an increased likelihood of survival; this could be of clinical significance, especially with previous studies suggesting better outcomes of using ASA in PD-L1 low tumors. Conclusion: These findings suggest that daily ASA use with PD-L1inhibitors is associated with more favorable outcomes in NSCLC. More studies are needed to investigate further the potential benefits vs. risks of using ASA with different immunotherapies and the other possible variables affecting treatment outcomes.