Prognostic impact of immune-related adverse events on patients with and without cardiovascular disease: a retrospective review

Abstract Background The emergence of immune checkpoint inhibitors (ICIs) has brought about a paradigm shift in cancer treatment as the use of these drugs has become more frequent and for a longer duration. As a result of T-cell-mediated inflammation at the programmed cell death-1, programmed death-ligand-1, and cytotoxic T-lymphocyte antigen-4 pathways, immune-related adverse events (irAEs) occur in various organs and can cause a rare but potentially induced cardiotoxicity. Although irAEs are associated with the efficacy of ICI therapy and better prognosis, there is limited information about the correlation between irAEs and cardiotoxicity and whether the benefits of irAEs apply to patients with underlying cardiovascular disease. This study aimed to investigate the association of irAEs and treatment efficacy in patients undergoing ICI therapy with and without a cardiovascular history. Methods We performed a retrospective review of the medical records of 409 consecutive patients who received ICI therapy from September 2014 to October 2019. Results Median patient age was 69 years (29.6% were female). The median follow-up period was 278 days. In total, 69 (16.9%) patients had a history of any cardiovascular disease and 14 (3.4%) patients experienced cardiovascular irAEs after ICI administration. The rate of cardiovascular irAEs was higher in patients with prior non-cardiovascular irAEs than without. The prognosis of patients with irAEs ( +) was significantly better than that of the patients without irAEs (P < 0.001); additionally, this tendency did not depend on the presence or absence of a cardiovascular history. Furthermore, the Cox proportional hazards analysis revealed that irAEs were an independent predictor of mortality. Conclusions Although cardiovascular irAEs may be related to prior non-cardiovascular irAEs under ICI therapy, the occurrence of irAEs had a better prognostic impact and this tendency was not affected by cardiovascular history.

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Prognostic Impact of Immune-Related Adverse Events on Patients with and Without Cardiovascular Disease: A Retrospective Review

10.21203/rs.3.rs-282517/v1 ◽

2021 ◽

Author(s):

Shingo Kazama ◽

Ryota Morimoto ◽

Yuki Kimura ◽

Naoki Shibata ◽

Reina Ozaki ◽

...

Keyword(s):

Cardiovascular Disease ◽

Adverse Events ◽

Retrospective Review ◽

Proportional Hazards ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Prognostic Impact ◽

Limited Information ◽

History Of

Abstract Background: The emergence of immune checkpoint inhibitors (ICIs) has brought about a paradigm shift in cancer treatment as the use of these drugs has become more frequent and for a longer duration. As a result of T-cell-mediated inflammation at the programmed cell death-1, programmed death-ligand-1, and cytotoxic T-lymphocyte antigen-4 pathways, immune-related adverse events (irAEs) occur in various organs and can cause a rare but potentially induced cardiotoxicity. Although irAEs are associated with the efficacy of ICI therapy and better prognosis, there is limited information about the correlation between irAEs and cardiotoxicity and whether the benefits of irAEs apply to patients with underlying cardiovascular disease. This study aimed to investigate the association of irAEs and treatment efficacy in patients undergoing ICI therapy with and without a cardiovascular history.Methods: We performed a retrospective review of the medical records of 409 consecutive patients who received ICI therapy from September 2014 to October 2019.Results: Median patient age was 69 years (29.6% were female). The median follow-up period was 278 days. In total, 69 (16.9%) patients had a history of any cardiovascular disease and 14 (3.4%) patients experienced cardiovascular irAEs after ICI administration. The rate of cardiovascular irAEs was higher in patients with prior non-cardiovascular irAEs than without. The prognosis of patients with irAEs (+) was significantly better than that of the patients without irAEs (P < 0.001); additionally, this tendency did not depend on the presence or absence of a cardiovascular history. Furthermore, the Cox proportional hazards analysis revealed that irAEs were an independent predictor of mortality.Conclusions: Occurrence of irAEs had a prognostic impact regardless of cardiovascular history. Although non-cardiovascular irAEs may be related to cardiovascular irAEs under ICI therapy, occurrence of this cardiotoxicity had little impact on prognosis.

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A case report of psoriasis flare following immunotherapy: Report of an important entity and literature review

SAGE Open Medical Case Reports ◽

10.1177/2050313x19897707 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X1989770 ◽

Cited By ~ 2

Author(s):

Anastasia Politi ◽

Dimas Angelos ◽

Davide Mauri ◽

George Zarkavelis ◽

George Pentheroudakis

Keyword(s):

Adverse Events ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Skin Lesions ◽

Inflammatory Disorder ◽

Immune Mediated ◽

Programmed Death ◽

History Of ◽

Programmed Death 1 ◽

Cessation Of Treatment

Immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed death-1, are a type of cancer immunotherapy approved for late-stage malignancy treatment. However, such therapies often induce immune-related adverse events. During anti-programmed death-1 blockade therapy, the most commonly reported adverse effects are skin toxicities, such as psoriasis—a chronic immune-mediated inflammatory disorder affecting the skin. We present the clinical characteristics of flared psoriasis in one patient under anti-programmed death-1 therapy who was diagnosed with T2N2M0/IIIB squamous lung carcinoma with a history of psoriasis for the past 5 years, exacerbated after the first cycle of nivolumab. After the third cycle, the extensive skin plaques necessitated treatment cessation. Following the discontinuation of anti-programmed death-1 treatment, skin lesions were treated locally. Possibly, anti-programmed death-1 immunotherapy can trigger immune-mediated diseases, such as psoriasis. Physicians should be alert to immune-related adverse events. Continuation or permanent cessation of treatment depends on the severity and reversibility of immune-related adverse events.

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Prognostic impact of tumor MET expression among patients with stage IV gastric cancer: A Danish cohort study.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.43 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 43-43 ◽

Cited By ~ 3

Author(s):

Rune Erichsen ◽

Kelly S. Oliner ◽

Michael A. Kelsh ◽

Karsten B. Nielsen ◽

Trine Frøslev ◽

...

Keyword(s):

Gastric Cancer ◽

Mortality Rate ◽

Protein Expression ◽

Proportional Hazards ◽

Stage Iv ◽

Clinical Trial Data ◽

Cox Proportional Hazards ◽

Prognostic Impact ◽

Limited Information ◽

Stage Iv Gastric Cancer

43 Background: Recent clinical trial data indicate poor prognosis for patients with late-stage gastric cancer and positive tumor mesenchymal epithelial transition factor (MET) protein expression. However, there is limited information about the real-world prevalence of MET-positive (-pos) cancers and the associated prognosis. Methods: Using medical registries, we identified a cohort of patients with stage IV gastric cancer in a single institution in Northern Denmark from 2003-2010. From these patients, we collected archived (paraffin-embedded) cancer specimens and analyzed MET protein expression by immunohistochemistry (MET-pos if ≥25% of tumor cells showed membrane staining). We calculated the prevalence of patients with MET-pos tumors. We estimated survival using the Kaplan-Meier method and computed mortality rate ratios comparing MET-pos to MET-negative (-neg) patients using Cox proportional hazards models adjusted for age, gender, and Charlson’s Comorbidity Index (score of 0, 1-2, and 3+). Results: 101 patients with stage IV gastric cancer were included in the study of which 55% had MET-pos tumors. The group of patients with MET-pos tumors were younger at diagnosis than patients with MET-neg tumors (median age 65 vs 68 years), included more men, showed higher comorbidity levels, included more poorly differentiated cancers, and were less likely to undergo surgery or chemotherapy. In patients with MET-pos tumors, one-year survival was 18% compared to 39% in patients with MET-neg tumors (mortality rate ratio=2.3, 95% CI: 1.4-3.9). Conclusions: A large proportion of patients with stage IV gastric cancer had tumors demonstrating MET protein expression, and these patients had poor survival compared with patients without tumor MET expression. [Table: see text]

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Multiple immune-related adverse events and anti-tumor efficacy: real-world data on various solid tumors

10.21203/rs.2.21095/v1 ◽

2020 ◽

Author(s):

Keitaro Shimozaki ◽

Yasutaka Sukawa ◽

Noriko Beppu ◽

Isao Kurihara ◽

Shigeaki Suzuki ◽

...

Keyword(s):

Retrospective Study ◽

Adverse Events ◽

Real World ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

University Hospital ◽

Real World Data

Abstract Background Immune checkpoint inhibitors have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in the real-world practice. Methods We conducted a retrospective study on patients with recurrent or metastatic non-small cell lung cancer, melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model. Results Among 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. OS in patients with multiple irAEs was significantly longer than that in patients with single irAE (42.3 months vs. 18.8 months; hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25–0.93; P = 0.03). Moreover, OS from the development of a second irAE in those with multiple irAEs was longer than that from the development of the first irAE in patients with single irAEs (median OS, 26.9 months vs. 17.7 months, respectively; HR, 0.59; 95% CI, 0.30–1.14; P = 0.11). Conclusions Our single-center retrospective study revealed a remarkable tendency associating the development of multiple irAEs with favorable prognoses.

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Association of dairy intake with all-cause, cancer, and cardiovascular disease mortality in Japanese adults: a 25-year population-based cohort

European Journal of Nutrition ◽

10.1007/s00394-021-02734-6 ◽

2021 ◽

Author(s):

Yukai Lu ◽

Yumi Sugawara ◽

Sanae Matsuyama ◽

Akira Fukao ◽

Ichiro Tsuji

Keyword(s):

Cardiovascular Disease ◽

Proportional Hazards ◽

Population Based ◽

Cox Proportional Hazards ◽

Dairy Intake ◽

Japanese Adults ◽

All Cause Mortality ◽

History Of ◽

Using Data ◽

Cvd Mortality

Abstract Purpose The association between dairy intake and mortality remains uncertain, and evidence for the Japanese population is scarce. We aimed to investigate the association between dairy intake and all-cause, cancer, and cardiovascular disease (CVD) mortality in Japanese adults. Methods A total of 34,161 participants (16,565 men and 17,596 women) aged 40–64 years without a history of cancer, myocardial infarction, or stroke at baseline were included in the analysis, using data from the Miyagi Cohort Study initiated in 1990. Milk, yogurt, and cheese intake were obtained using a validated food frequency questionnaire. Total dairy intake was calculated as the sum of milk, yogurt, and cheese intake and then categorized by quartile. The outcomes were all-cause, cancer, and CVD mortality. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality risks. Results During 750,016 person-years of follow-up, the total number of deaths was 6498, including 2552 deaths due to cancer and 1693 deaths due to CVD. There was no association between total dairy intake and all-cause, cancer, and CVD mortality for both men and women. We also examined the associations between subgroup dairy products and mortality. For milk and yogurt intake, our results suggest null associations. However, cheese intake was modestly associated with lower all-cause mortality in women; compared with non-consumers, the multivariable HRs (95%CIs) were 0.89 (0.81–0.98) for 1–2 times/month, 0.88 (0.78–1.00) for 1–2 times/week, and 0.89 (0.74–1.07) for 3 times/week or almost daily (p trend = 0.016). Conclusion Dairy intake was not associated with mortality in Japanese adults, except for limited evidence showing a modest association between cheese intake and a lower all-cause mortality risk in women.

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Risk of non-infectious uveitis or myasthenia gravis in patients on checkpoint inhibitors in a large healthcare claims database

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2020-317060 ◽

2020 ◽

pp. bjophthalmol-2020-317060 ◽

Cited By ~ 1

Author(s):

Tian Xia ◽

Alexander J Brucker ◽

Brendan McGeehan ◽

Brian L VanderBeek

Keyword(s):

Multivariate Analysis ◽

Myasthenia Gravis ◽

Index Date ◽

Proportional Hazards ◽

Checkpoint Inhibitors ◽

Cox Proportional Hazards ◽

Proportional Hazards Regression ◽

Increased Risk ◽

History Of ◽

Infectious Uveitis

AimTo determine if checkpoint inhibitors (CPIs) confer an increased risk of non-infectious uveitis or myasthenia gravis (MG) compared to patients on non-checkpoint inhibitor (N-CPI) chemotherapy.MethodsA retrospective cohort study was performed comparing patients in a large commercial and Medicare advantage database exposed to CPI compared to N-CPI. All patients who initiated a CPI (ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, cemiplimab and durvalumab) were eligible. Date of earliest CPI in the exposure group and N-CPI chemotherapy in the comparator group was considered the index date. Exclusion occurred in both cohorts for any history of uveitis or MG diagnosis and having <1 year in the insurance plan prior to the index date, and <6 months in plan following the index date. Every exposed patient was matched up to 1:10 based on demographics and index year to patients on N-CPI chemotherapy. Multivariate Cox proportional hazards regression modelling was performed.ResultsFor evaluation of incidence of non-infectious uveitis, 26 (0.3%) of 8678 patients on CPI and 123 (0.2%) of 76 153 N-CPI comparators were found to have non-infectious uveitis. After multivariate analysis, CPIs showed an increased hazard for uveitis compared to N-CPI (HR=2.09; 95% CI 1.36 to 3.22, p=0.001). For the MG analysis, 11 (0.1%) of 9210 patients developed MG in the CPI group and 36 (0.04%) of 80 620 comparators. The CPI cohort had a higher hazard of developing MG (HR=2.60; 95% CI 1.34 to 5.07, p=0.005) compared to controls in multivariate analysis.ConclusionsExposure to CPI confers a higher risk for non-infectious uveitis and MG compared to N-CPI chemotherapy.

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Association between incarceration and incident cardiovascular disease events: results from the CARDIA cohort study

BMC Public Health ◽

10.1186/s12889-021-10237-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jordan Coleman ◽

Donald M. Lloyd-Jones ◽

Hongyan Ning ◽

Norrina B. Allen ◽

Catarina I. Kiefe ◽

...

Keyword(s):

Cardiovascular Disease ◽

Proportional Hazards ◽

White Men ◽

Incidence Rates ◽

Cox Proportional Hazards ◽

Study Objective ◽

Black And White ◽

All Cause Mortality ◽

History Of ◽

Incident Cardiovascular Disease

Abstract Background Incarceration has been associated with higher cardiovascular risk, yet data evaluating its association with cardiovascular disease events are limited. The study objective was to evaluate the association between incarceration and incident fatal and non-fatal cardiovascular disease (CVD) events. Methods Black and white adults from the community-based Coronary Artery Risk Development in Young Adult (CARDIA) study (baseline 1985–86, n = 5105) were followed through August 2017. Self-reported incarceration was measured at baseline (1985–1986) and Year 2 (1987–1988), and fatal and non-fatal cardiovascular disease events, including coronary heart disease, stroke, and heart failure, and all-cause mortality, were captured through 2017. Analyses were completed in September 2019. Cumulative CVD incidence rates and Cox proportional hazards were compared overall by incarceration status. An interaction between incarceration and race was identified, so results were also analyzed by sex-race groups. Results 351 (6.9%) CARDIA participants reported a history of incarceration. Over 29.0 years mean follow-up, CVD incidence rate was 3.52 per 1000 person-years in participants with a history of incarceration versus 2.12 per 1000 person-years in participants without a history of incarceration (adjusted HR = 1.33 [95% CI, 0.90–1.95]). Among white men, incarceration was associated with higher risk of incident cardiovascular disease (adjusted HR = 3.35 [95% CI, 1.54–7.29) and all-cause mortality (adjusted HR = 2.52 [95% CI, 1.32–4.83]), but these associations were not statistically significant among other sex-race groups after adjustment. Conclusions Incarceration was associated with incident cardiovascular disease rates, but associations were only significant in one sex-race group after multivariable adjustment.

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Intracranial Stenting of Subacute Symptomatic Atherosclerotic Occlusion Versus Stenosis

Stroke ◽

10.1161/strokeaha.111.622282 ◽

2011 ◽

Vol 42 (12) ◽

pp. 3470-3476 ◽

Cited By ~ 16

Author(s):

Peng-Hua Lü ◽

Jee Won Park ◽

Soonchan Park ◽

Jong Lim Kim ◽

Deok Hee Lee ◽

...

Keyword(s):

Adverse Events ◽

Proportional Hazards ◽

Artery Occlusion ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Intracranial Artery ◽

Significant Difference ◽

History Of ◽

Procedural Success ◽

Antegrade Flow

Background and Purpose— Limited data are available concerning the outcome of angioplasty/stenting for subacute atherosclerotic intracranial artery occlusion, which is often associated with progressive symptom development in the salvageable brain under ischemic threat due to poor collateral blood supply. Methods— Among 177 patients who underwent angioplasty and/or stenting for severe symptomatic intracranial steno-occlusion, 26 had subacute atherosclerotic intracranial artery occlusion. Outcome after stenting (N=22) was assessed according to procedural success (return of antegrade flow and residual stenosis <50%), adverse event (any stroke or death) rate, and restenosis (>50%) using weighted Cox proportional hazards regression in the overall cohort and in separate subgroups. Results— Successful recanalization was achieved in 95%. Three adverse events (13.6%) occurred among patients undergoing stenting for occlusion, including 2 major strokes and 1 nonprocedure-related death. Good outcome (modified Rankin Scale ≤2) was achieved in 73%. In the overall cohort, no significant difference was observed between the occlusion and stenosis groups in terms of the risk of adverse events (hazard ratio for the occlusion group, 1.055; 95% CI, 0.29–3.90) or the risk of restenosis (hazard ratio for the occlusion group, 1.2; 95% CI, 0.19–7.72). A trend toward a higher rate of adverse events was observed in older age (>65 years), progressive worsening, balloon-expandable stent, and no history of a preprocedural P2Y12 assay. Conclusions— In a cohort of patients undergoing angioplasty/stenting for subacute atherosclerotic intracranial artery occlusion, no significant difference in the rates of adverse events was observed. However, several factors, including age, tended to be associated with a higher event rate.

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CTLA-4 Synergizes With PD1/PD-L1 in the Inhibitory Tumor Microenvironment of Intrahepatic Cholangiocarcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.705378 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiao-Jun Guo ◽

Jia-Cheng Lu ◽

Hai-Ying Zeng ◽

Rong Zhou ◽

Qi-Man Sun ◽

...

Keyword(s):

Risk Factors ◽

Recurrence Rate ◽

Intrahepatic Cholangiocarcinoma ◽

Proportional Hazards ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Combined Therapy ◽

Tumor Resection ◽

Cox Proportional Hazards ◽

Independent Risk Factors

Intrahepatic cholangiocarcinoma (ICC) is highly invasive and carries high mortality due to limited therapeutic strategies. In other solid tumors, immune checkpoint inhibitors (ICIs) target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD1), and the PD1 ligand PD-L1 has revolutionized treatment and improved outcomes. However, the relationship and clinical significance of CTLA-4 and PD-L1 expression in ICC remains to be addressed. Deciphering CTLA-4 and PD-L1 interactions in ICC enable targeted therapy for this disease. In this study, immunohistochemistry (IHC) was used to detect and quantify CTLA-4, forkhead box protein P3 (FOXP3), and PD-L1 in samples from 290 patients with ICC. The prognostic capabilities of CTLA-4, FOXP3, and PD-L1 expression in ICC were investigated with the Kaplan–Meier method. Independent risk factors related to ICC survival and recurrence were assessed by the Cox proportional hazards models. Here, we identified that CTLA-4+ lymphocyte density was elevated in ICC tumors compared with peritumoral hepatic tissues (P <.001), and patients with a high density of CTLA-4+ tumor-infiltrating lymphocytes (TILsCTLA-4 High) showed a reduced overall survival (OS) rate and increased cumulative recurrence rate compared with patients with TILsCTLA-4 Low (P <.001 and P = .024, respectively). Similarly, patients with high FOXP3+ TILs (TILsFOXP3 High) had poorer prognoses than patients with low FOXP3+ TILs (P = .021, P = .034, respectively), and the density of CTLA-4+ TILs was positively correlated with FOXP3+ TILs (Pearson r = .31, P <.001). Furthermore, patients with high PD-L1 expression in tumors (TumorPD-L1 High) and/or TILsCTLA-4 High presented worse OS and a higher recurrence rate than patients with TILsCTLA-4 LowTumorPD-L1 Low. Moreover, multiple tumors, lymph node metastasis, and high TumorPD-L1/TILsCTLA-4 were independent risk factors of cumulative recurrence and OS for patients after ICC tumor resection. Furthermore, among ICC patients, those with hepatolithiasis had a higher expression of CTLA-4 and worse OS compared with patients with HBV infection or undefined risk factors (P = .018). In conclusion, CTLA-4 is increased in TILs in ICC and has an expression profile distinct from PD1/PD-L1. TumorPD-L1/TILsCTLA-4 is a predictive factor of OS and ICC recurrence, suggesting that combined therapy targeting PD1/PD-L1 and CTLA-4 may be useful in treating patients with ICC.

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

Oncology ◽

10.1159/000516671 ◽

2021 ◽

pp. 1-7

Author(s):

Oded Jacobi ◽

Yosef Landman ◽

Daniel Reinhorn ◽

Oded Icht ◽

Michal Sternschuss ◽

...

Keyword(s):

Diabetes Mellitus ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Proportional Hazards ◽

Checkpoint Inhibitors ◽

Negative Relationship ◽

Progression Free Survival ◽

Significant Negative Correlation ◽

Cox Proportional Hazards ◽

Diabetic Patients

Introduction: 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. Methods: 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, t tests, and χ2 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. Results: 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], p = 0.011, and HR 1.5 [1.08–2.08], p = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61–1.93], p = 0.79, and HR 1.29 [0.69–2.39], p = 0.42, respectively). There were no differences between groups with respect to ORR and DCR. Conclusion: 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.

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