Immune-Related Adverse Events Are Associated With Clinical Benefit in Patients With Non-Small-Cell Lung Cancer Treated With Immunotherapy Plus Chemotherapy: A Retrospective Study

Morimoto, Kenji; Yamada, Tadaaki; Takumi, Chieko; Ogura, Yuri; Takeda, Takayuki; Onoi, Keisuke; Chihara, Yusuke; Taniguchi, Ryusuke; Yamada, Takahiro; Hiranuma, Osamu; Morimoto, Yoshie; Iwasaku, Masahiro; Kaneko, Yoshiko; Uchino, Junichi; Takayama, K.

doi:10.3389/fonc.2021.630136

Cited by 22 publications

(14 citation statements)

References 29 publications

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“…We also found that individuals who developed IMC had improved survival outcomes when compared to those who did not develop IMC, including in a landmark sensitivity analysis, which is concordant with previously published literature [43][44][45][46][47][48] . However, PRS UC and PRS CD were not associated with PFS or OS, suggesting that the genetic basis of autoimmune disease susceptibility is distinct from genetic factors influencing survival outcomes.…”

Section: Discussionsupporting

confidence: 90%

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis

Middha

Thummalapalli

Betti

et al. 2023

Preprint

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Immune checkpoint inhibitors (ICIs) are a remarkable advancement in cancer therapeutics; however, a substantial proportion of patients develop severe immune-related adverse events (irAEs). Understanding and predicting irAEs is the key to advancing precision immuno-oncology. Immune-mediated colitis (IMC) is a significant complication from ICI and can have life-threatening consequences. Genetic susceptibility to Crohns disease (CD) and ulcerative colitis (UC) may predispose to IMC, but the link is poorly understood. We developed and validated polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and assessed the role of each of these PRSs on IMC in a cohort of 1,316 patients with non-small cell lung cancer (NSCLC) who received ICIs. Prevalence of all-grade IMC in our cohort is 4% (55 cases), and for severe IMC, 2.5% (32 cases). The PRSUCpredicted the development of all-grade IMC (HR=1.34 per standard deviation [SD], 95% CI=1.02-1.76, P=0.04) and severe IMC (HR=1.62 per SD, 95% CI=1.12-2.35, P=0.01). PRSCDwas not associated with IMC or severe IMC. This is a first study to demonstrate the potential clinical utility of a PRS for ulcerative colitis in identifying NSCLC patients receiving ICI at high risk of developing IMC, where risk reduction and close monitoring strategies could help improve overall patient outcomes.

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Section: Discussionsupporting

confidence: 90%

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis

Middha

Thummalapalli

Betti

et al. 2023

Preprint

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“…To our knowledge, the present study is the first to demonstrate this by combining rigorous ITB control using landmark ( Tables 3 , 4 ) and time-dependent analyses ( Supplementary Table 5 ), with multivariable testing that includes all currently established survival predictors, both laboratory (PD-L1 TPS, NLR) and clinical (treatment type, treatment line, ECOG PS, Table 4 and Supplementary Table 5 ). Furthermore, particularly relevant for the contemporary practice is the inclusion of a large chemoimmunotherapy subcohort (n > 250, Table 1 ) in this analysis, which is the predominant therapeutic strategy for most NSCLC patients currently ( 3 , 4 ), in contrast to previous studies who have analyzed IO-monotherapy ( 41 , 50 ) or small chemoimmunotherapy series with less than 100 patients ( 51 ). Our results show that the relationship between occurrence of irAEs and ICI efficacy is very strong (HR = 0.4, Table 4 ), stronger than that of PD-L1 TPS or NLR, and that it persists regardless of concurrent or previous chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic and Prognostic Implications of Immune-Related Adverse Events in Advanced Non-Small-Cell Lung Cancer

et al. 2021

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IntroductionPD-(L)1 inhibitors have improved prognosis of non-small-cell lung cancer (NSCLC), but can also cause immune-related adverse events (irAEs) that complicate management.MethodsWe analyzed NSCLC patients receiving PD-(L)1 inhibitors from 2012 to 2020 in a German academic center.ResultsIrAE showed comparable frequencies in stage IV (198/894 or 22%) vs. III (14/45 or 31%, p = 0.15), after anti-PD-(L)1 monotherapy vs. chemoimmunotherapy (139/483 vs. 58/213, p = 0.75), and across treatment lines. In stage IV, irAE occurred after 3.1 months in median, affected multiple organs (median 2) in 27/894 patients and were associated with PD-L1 positivity (25 vs. 14%, p = 0.003), lower neutrophil-to-lymphocyte ratios (29 vs. 17%, p < 0.001 for NLR dichotomized at 5), better ECOG status (26 vs. 18% for 0 vs. 1, p = 0.004), but not related to age, sex, smoking and palliative radiotherapy. Two hundred thirty two irAEs occurred mostly in endocrine glands (4.9%), lungs (4.4%), the musculoskeletal system (4.2%), colon (4.1%), liver (3.7%), and skin (2.6%), while pneumonitis was most frequent with durvalumab following definitive chemoradiation (16% or 7/45, p < 0.01). IrAE severity was grade 1 in 11%, 2 in 41%, 3 in 36%, and 4 in 11% events, while two were lethal (<1%, myocarditis and pneumonitis). Therapy was suspended in 72%, while steroids were initiated in 66% and complemented by other immunosuppressants in 6%, with longest treatment duration for rheumatic events (mean >3 months), and average cumulative prednisone doses >700 mg for all organs, except for skin. Patients developing irAE had longer progression-free (PFS) and overall survival (OS) in multivariable 12/14-week landmark analyses including ECOG status, treatment line, treatment type, PD-L1 TPS, and NLR (median PFS 17 vs. 10 months, HR = 0.68, p = 0.009; median OS 37 vs. 15 months, HR = 0.40, p < 0.001), regardless of grade. OS was longest with skin (95% at 2 years) and shortest with pneumonitis, hepatitis, neurologic, and cardiologic irAE (38, 37, 28, and 0% at 2 years, p < 0.001).ConclusionsApproximately one-fourth of immunotherapy-treated NSCLC patients develop irAEs, most of which necessitate treatment suspension and steroids. Despite more frequent occurrence with PD-L1 positive tumors, lower NLR, and better ECOG PS, irAEs are independently associated with longer survival, especially when affecting the skin. Lethality is below 1%.

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“…The literatures that could be evaluated after screening were all duplicated with those previously screened. Finally, a total of 11 studies (Figure 2) were included in the systematic review (11)(12)(13)15,(41)(42)(43)(44)(45)(46)(47). The study was conducted by 3 people to extract data, statistical survival data, and perform statistical analysis.…”

Section: Resultsmentioning

confidence: 99%

Immune-related thyroid dysfunction is associated with improved long-term prognosis in patients with non-small cell lung cancer treated with immunotherapy: a systematic review and meta-analysis

Li¹,

Xia²,

Xia³

et al. 2023

J Thorac Dis

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Background: Immunotherapy has changed the treatment landscape of lung cancer (LC), but its prognosis is still poor. Whether immunorelated thyroid dysfunction associated with the prognosis of LC patients remains controversial. We aimed to summarize the scientific evidence on whether thyroid dysfunction associated with immunotherapy for LC has a beneficial outcome on the survival of LC patients. Methods:We searched the databases of MEDLINE and Embase for articles published until 31 December 2021 that quantified the impact on non-small cell lung cancer (NSCLC) patients' survival of immunerelated thyroid dysfunction. Study-specific data were pooled into hazard ratio (HR) and corresponding 95% confidence intervals (CIs) using random effect models of meta-analysis. Meta-analysis was used to evaluate the relationship between immune-associated thyroid dysfunction and prognosis.Results: A total of 11 articles published between 2015 and 2021 were included, which encompassed a total of over 1,962 NSCLC patients. The studies differed in terms of design, patient characteristics, treatment received, rate/time to immunotherapy-related thyroid dysfunction, and duration of follow-up. But after immunotherapy, we extract survival data. Patients with immunotherapy-associated thyroid dysfunction had better progression-free survival (PFS) (HR 0.54, 95% CI: 0.44-0.64) and overall survival (OS) rate (HR 0.34, 95% CI: 0.25-0.44).Conclusions: Thyroid dysfunction associated with immunotherapy is common and associated with a good prognosis. It can be used as a biological indicator of good prognosis of immunotherapy.

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Immune-Related Adverse Events Are Associated With Clinical Benefit in Patients With Non-Small-Cell Lung Cancer Treated With Immunotherapy Plus Chemotherapy: A Retrospective Study

Cited by 22 publications

References 29 publications

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis

Therapeutic and Prognostic Implications of Immune-Related Adverse Events in Advanced Non-Small-Cell Lung Cancer

Immune-related thyroid dysfunction is associated with improved long-term prognosis in patients with non-small cell lung cancer treated with immunotherapy: a systematic review and meta-analysis

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