Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: a multicentre study

Abstract

<jats:p>Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICI) are lacking. We performed a retrospective multicenter study to characterized irAEs occurring after a 12- months minimum treatment period with PD-(L)1 ICIs in advanced cancer patients. IrAEs were categorized into early (≤12 months) and late (&gt;12 months). From September 2013 to October 2019, 436 consecutive patients were evaluated. 223 experienced any grade early-irAEs (51.1%), while 132 experienced any grade late-irAEs (30.3%) (p &lt; 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, while 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced G3/G4 irAEs (4.8%). Median time to onset of earlyirAEs was 3.4 months (95%CI: 2.8-4.2), while the median time to onset of late-irAEs was 16.6 months (95%CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (HR = 0.63 [95%CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95%CI: 0.37-1.56], p = 0.452). Also the time-adjusted cumulative risk of death according to both early-irAEs (HR = 0.79 [95%CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95%CI: 0.49-1.74], p = 0.811) did not show statistically significant differences. Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs, and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.</jats:p>

Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes

“…Moreover, the spectrum of irAEs is in line with what has been described in both clinical trials and real life studies with PD-1/PD-L1 inhibitors across different malignancies. 6,[22][23][24] Therefore, we confirm the feasibility and safety of first-line, single-agent pembrolizumab in a large real-world cohort of patients with NSCLC with PD-L1 expression ! 50%, including frail patients with poor performance status, who are usually not enrolled in clinical trials.…”

“…As previously described, 6,24 single-site irAEs were more frequent than multiple-site irAEs. IrAEs result from an aberrant immune selfresponse, and it is reasonable to assume that, as in autoimmune disorders, 25 the pathologic mechanisms of irAEs are based on tissuespecific T-cell and B-cell mediated cross-reactions.…”

CD4/CD8 Ratio of Pleural Effusion Is A Prognostic Predictor for Non-Small Cell Lung Cancer Patients Under Immune Checkpoint Inhibitor Treatments

“…The time from treatment to rst thoracentesis was as long as 25 months (case no.8). It is not surprising that the occurrence of irAEs was delayed, since Nigro et al reported earlier that late-irAEs (after 12 months) are common (incidence 30.3%) in long responders to ICIs 15 . The cytology of pleural effusion was never documented positive before or after ICI use so this type was not categorized as pseudoprogression.…”

How to optimize the incorporation of immunotherapy in trials for oligometastatic non-small cell lung cancer: a narrative review

“…Last, focus should also be on minimizing long-term toxicity of systemic therapies and LRT, as aim is to improve long-term survival in these patients. Importantly, approximately 30% of patients with metastatic NSCLC treated with PD-(L)1 inhibition experience late (>12 months after start of ICI) immune related toxicity (46). Furthermore, attention should be paid to the organ receiving LRT, as for example patients with brain metastases treated with ICI and SRT could develop symptomatic radiation necrosis as a late toxicity (47).…”