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Abstract
Background Immune checkpoint inhibitors (ICIs) are now approved for several cancer types due to superior outcomes compared to chemotherapy. PD-1/PD-L1 and CTLA-4 inhibitors reactivate T-cell mediated anti-tumor immunity but may also lead to immune-related adverse events (irAEs). Growing evidence suggests the onset of irAEs could be correlated with the efficacy of ICIs.1. 2 In this study, we investigated patterns and incidence of irAEs and their relationship to overall survival (OS) and progression-free survival (PFS) in multiple cancer types.
Methods The electronic medical record was queried at the University of Cincinnati Medical Center for the administration of ICIs for the identification of irAEs. Data on new irAEs diagnosed after administration of at least one dose of ICI was collected along with relevant demographic and clinicopathologic variables including treatment type, cancer type, staging information, and the administration of immune suppression following the identification of an IRAE either inpatient or outpatient. Univariant and multivariant analysis were conducted and survival analysis was determined according to log-rank testing.
Results Of our 210 initial patients, the median age was 64 (range 22–93), 37% were female, 72% had ECOG 0-1, and 79% were white. Cancer types included melanoma 24%, non-small cell lung cancer (NSCLC) 34%, small cell lung cancer 2%, renal cancer 12%, urothelial cancer 11%, head and neck cancers 12%, and 16% other primaries while 19% remained on ICI at the time of data entry. The most common ICIs were pembrolizumab, nivolumab, followed by ipilimumab-nivolumab, ipilimumab, and durvalumab. The overall incidence of irAEs was 22.6%. Overall survival and progression-free survival was improved for those who suffered an IRAE (median OS 8.3 vs. 3.5 years, HR 0.56, p=0.0092; median PFS 5.0 vs 2.5 years, HR 0.57, p=0.0052) (figure 1 and 2 respectively). ICI treatment in NSCLC was associated with decreased overall IRAE events by univariant analysis (Odds Ratio 0.39, 95% CI 0.17 - 0.86). Our multivariate analysis showed ICI treatment in hepatocellular carcinoma to be significantly associated with irAEs, however, this was likely due to low enrollment (n=4) and was not significant by univariant analysis. The most common IRAE overall was diarrhea/colitis (figure 3).
irAEs are associated with enhanced overall survivaloverall survival of patients who suffered at least one irAE demonstrated increased median survival of 8.3 years compared to 3.5 years from diagnosis for a mix of malignancies. The hazard ratio for this finding was 0.56, with a p-value of 0.0092 by Mantel-Cox log-rank test
irAEs are associated with enhanced progression-freeSimilarly, progression-free survival of patients who suffered at least one irAE demonstrated increased median survival of 1.6 years compared to 0.51 years from initiation of treatment with a checkpoint inhibitor for a mix of malignancies. The hazard ratio for this finding was 0.51, with a p-value of 0.0018 by Mantel-Cox log-rank test
irAE Types Observed by IncidenceIn our cohort, 47 patients suffered a total incidence of 71 irAEs the most common individual event of which was colitis of all grades (12/71). Rash and transaminitis occurred the second most frequently (9/71 respectively), and pneumonitis/thyroiditis was the third most frequent (8/71 respectively) which together represented 65% of all irAEs in this cohort
Conclusions In our data set, irAEs were associated with increased OS and PFS regardless of disease site. ICI treatment of NSCLC was associated with significantly fewer irAEs compared to other malignancies. Further research is needed to determine irAE type-specific incidence, the incidence of multiple irAEs in a single patient, and response to corticosteroid therapy.
Acknowledgements We would like to thank the Department of Hematology/Oncology of the University of Cincinnati, the University of Cincinnati Cancer Center, and the Department of Internal Medicine of the University of Cincinnati for their support.
Ethics Approval Considered and Approved by the University IRB Approval #2019-0610.
References
Weber JS, Hodi FS, Wolchok JD, et al. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol 2017;35(7):785–792.
Yamauchi I, Yasoda A, Matsumoto S, et al. Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab. PLoS ONE. 2019;14(5):e0216954.
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