The Relationship of Diabetes Mellitus to Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer

Abstract

<b><i>Introduction:</i></b> Immune checkpoint inhibitors (ICI) are the new standard therapy in patients with metastatic NSCLC (mNSCLC). Metformin, previously associated with improved chemotherapy efficacy in diabetic and nondiabetic cancer patients, was recently associated with increased ICI efficacy. In this study, we aimed to explore the correlations between diabetes mellitus (DM), metformin use, and benefit from ICI in mNSCLC patients. <b><i>Methods:</i></b> All mNSCLC patients treated with ICI in our center between February 2015 and April 2018 were identified. Demographic and clinical data were extracted retrospectively. Cox proportional hazards regression, <i>t</i> tests, and χ<sup>2</sup> tests were employed to evaluate associations of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR), with DM status, metformin use, and HbA1c levels, as appropriate. <b><i>Results:</i></b> Of 249 mNSCLC patients treated with ICI, 57 (22.8%) had DM. Thirty-seven (64.9% of all diabetic patients) patients were treated with metformin. A significant negative correlation of DM with PFS and OS was demonstrated (HR 1.5 [1.01–2.06], <i>p</i> = 0.011, and HR 1.5 [1.08–2.08], <i>p</i> = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61–1.93], <i>p</i> = 0.79, and HR 1.29 [0.69–2.39], <i>p</i> = 0.42, respectively). There were no differences between groups with respect to ORR and DCR. <b><i>Conclusion:</i></b> Our data show a potential negative relationship between DM and ICI efficacy in mNSCLC patients. In contrast to reports with chemotherapy, we found no positive relationship between metformin use and ICI therapy in diabetic patients with mNSCLC. Further studies are needed to evaluate the effect of metformin in nondiabetic mNSCLC patients.

Advances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review)

“…There is growing evidence that metformin exerts its anticancer effects by inhibiting tumor metabolism and that metformin may be a potential candidate for combination therapy in NSCLC. A number of preclinical studies have reported good results of metformin acting concurrently with radiotherapy, tyrosine kinase inhibitors (TKIs) and ICIs in NSCLC ( 104 – 107 ), which has encouraged the use of combination therapies. In a meta-analysis of 14 clinical studies comprising 3,856 patients, the combination of metformin with standard antineoplastic drugs significantly improved OS in patients with lung cancer ( 108 ).…”

“…Promising results have also been reported by two recent studies of metformin in combination with TKIs and ICIs, respectively, which suggested that metformin was able to significantly improve PFS and OS in patients with NSCLC by overcoming acquired resistance to TKIs and enhancing PD-1 blockade by anti-PD-1 antibodies, respectively ( 101 , 102 ). Other studies ( 111 – 114 ) suggested that metformin may increase tumor response to ICI through a variety of mechanisms, including upregulation of CD8 + tumor-infiltrating lymphocytes and their function, downregulation of myeloid suppressor cells with immunosuppressive effects, reduction of tumor hypoxia, anti-angiogenic effects and shifting the composition of the patient's gut flora to bacterial strains that may respond better to immunotherapy ( 107 ). Although it has been suggested that metformin treatment may exert a synergistic antitumor effect with ICIs, the study by Jacobi et al ( 107 ) did not obtain any positive association between metformin and ICIs in the treatment of patients with diabetes combined with NSCLC.…”

“…Other studies ( 111 – 114 ) suggested that metformin may increase tumor response to ICI through a variety of mechanisms, including upregulation of CD8 + tumor-infiltrating lymphocytes and their function, downregulation of myeloid suppressor cells with immunosuppressive effects, reduction of tumor hypoxia, anti-angiogenic effects and shifting the composition of the patient's gut flora to bacterial strains that may respond better to immunotherapy ( 107 ). Although it has been suggested that metformin treatment may exert a synergistic antitumor effect with ICIs, the study by Jacobi et al ( 107 ) did not obtain any positive association between metformin and ICIs in the treatment of patients with diabetes combined with NSCLC. More prospective studies are required to further evaluate the effect of metformin in combination with radiotherapy, TKIs and ICIs on the outcome of patients with NSCLC.…”

Cancer Resistance to Immunotherapy: Molecular Mechanisms and Tackling Strategies

“…The benefits of immunotherapy to cancer patients with obesity are ambiguous [ 108 ]. Diabetes has negative effects on ICB in metastatic NSCLC [ 109 ]. Mechanistic studies are needed to shed light on the linkage between metabolic pathologies and immunotherapy efficacy.…”

A retrospective study for prognostic significance of type II diabetes mellitus and hemoglobin A1c levels in non-small cell lung cancer patients treated with pembrolizumab

“…However, since immunotherapy has been implemented widely in clinical practice, the effect of DM among patients treated with ICIs should be clarified. Additionally, the peripheral blood glycated hemoglobin A1c (HbA1c) was a regular indicator for DM diagnosis and treatment evaluation, previous studies have reported the negative prognostic role of higher HbA1c levels in patients who underwent surgical resection, while the reported results are too scarce for a robust conclusion to be drawn in these patients received ICIs at present, although pembrolizumab therapy has achieved obvious clinical benefits (17)(18)(19)(20).…”