Statins and immunotherapy: Togetherness makes strength The potential effect of statins on immunotherapy for NSCLC

Abstract Background Recent researches suggested that statins, beside their role in inhibiting endogenous cholesterol synthesis and in cardiovascular prevention, could influence several processes in cancer biology. In fact, a recent meta‐analysis demonstrated that statins could positively influence OS in lung cancer patients. Aim There is a lack of large cohort studies that could support a potential antineoplastic role of statins in clinical practice. We collected data from 162 patients treated with immunotherapy for Nonsmall Cell Lung Cancer (NSCLC) in first‐ and second‐line setting to investigate the impact of these drugs on survival parameters. Methods and Results In our observational study, we enrolled 162 patients who received immunotherapy for lung cancer between October 2015 and April 2020. We used descriptive statistics to analyze patients' baseline features. Tumor response was evaluated using RECIST version 1.1 guidelines. Uni and multivariate analysis were conducted to investigate the relationship between statin use and response to immunotherapy, using the χ2‐test. We used Kaplan‐Meier curves to estimate OS and PFS in statin and nonstatin users. We included 122 patients in the final analysis. Median PFS was 17.57 months in the statin group and 9.57 months in the nonstatin group, with a P = <.001. Moreover, median OS was superior in the statin‐users group, with a statistically significant difference (19.94 vs 10.94 months, P = <.001). Conclusion Although in our study, statin use positively correlates with PFS and OS in lung cancer patient treated with immunotherapy, these results require a further validation with randomized clinical trials.


| INTRODUCTION
Statins are commonly used agents in the primary and secondary prevention of cardiovascular disease. 1 Recent studies suggested that they could display pleiotropic effects on several cancer-related cellular processes, such as proliferation, apoptosis, angiogenesis, and metastasis. 2 Even though the promising molecular features, results of randomized clinical trials investigating the combinations between statins and anticancer treatments have been controversial so far, 3,4 especially on lung cancer, the most common and deadly neoplasm worldwide. 5 Despite the impressive advances in the management of this disease, the 5-year survival rate is still at 18%. 5,6 In metastatic nonsmall cell lung cancer (NSCLC) immunotherapy, along with targeted therapy, increased progression-free (PFS) and overall survival (OS). [6][7][8][9][10][11][12] A recent meta-analysis suggested that statins could positively affect the risk of all-cause mortality and improve OS in lung cancer patients 13 ; conversely, no influence on PFS and overall response rate (ORR) was observed. Statins exhibit an immunomodulatory effect by preventing protein prenylation, 14 and this leads to increased antigen presentation, T-cell activation, and cytolytic response. Prenylation creates a hydrophobic region that determines protein attachment to the membrane and enables their optimal functioning. Proteins of key signaling pathways that are overactivated in many types of cancer, such as those from Ras, Rho, and Rab superfamily, are prenylated; therefore, preventing the prenylation branch could be a potential strategy in cancer treatment. 15,16 This suggested that these drugs could synergize with immunotherapy in the treatment of lung cancer. 17 The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC. Almost all patients are treated in the first-or second-line setting with immunotherapeutic agents, alone or in combination with other cytotoxic drugs. Not all patients respond in the same way to immunotherapy, and peculiar response patterns could be observed in some cases, such as pseudo or hyperprogression. 18 Alongside hyperprogression, a rare phenomenon that consists in primary resistance to treatment with a paradoxical and abnormal increase in tumor growth, secondary resistance to therapy after an initial excellent response, is more frequently observed.  The study was conducted following the Declaration of Helsinki.
Due to the retrospective nature of the study, Institutional Review Board approval was obtained before the divulgation of scientific data.

| Statistical analysis
Descriptive statistics were used to analyze patients' baseline features.  Table 1. According to the iRECIST criteria, we There were no significant differences between CR and SD rates over the two groups (P = .317 and P = .78, respectively). Median OS was superior in the statin-users group, with a statistically significant differ- Details about reported toxicities are listed in Table 2.   be taken into account. Taken together, these results suggest that second-line, rather than first-line, ICI treatment combined with statins could positively affect survival outcomes in patients affected by metastatic NSCLC. Our study certainly presents some limitations. First, due to its observational nature, it is more prone to selection biases, and results should be interpreted with caution. Second, statin-based therapy was investigated before diagnosis, and we did not assess the impact of an eventual post-diagnosis use on survival outcomes. Third, although the well-known differences in pharmacokinetic profiles among statins, we did not discriminate between hydrophobic and hydrophilic compounds.

| CONCLUSION
Immunotherapy, alone or in combination with standard chemotherapy regimens, has dramatically changed the landscape of lung cancer treatment over the last years. 9,23,24 Despite promising results, we need to better understand the complex interaction between the immune system and cancer microenvironment to achieve better outcomes and durable responses. 25 In our study, we demonstrated a significant relationship between improved PFS and OS and pre-existing statin use. Although interesting, this result needs to be validated with randomized clinical trials and larger cohorts (to select which type of patients could benefit the most with this pharmacological association).
To date, many efforts have been made to ameliorate lung cancer patients prognosis and quality of life, even with the use of nonconventional anticancer drugs beside available therapies 26,27 ; our study provides a useful hint in this intricate scenario and paves the way for a new use of an already worldwide available treatment.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

ETHICAL STATEMENT
Institutional Ethical Review Board approval was obtained before the divulgation of scientific data, with ID 5585_2019. Ethical Body

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.