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

Abstract

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%.

Peripheral absolute eosinophil count identifies the risk of serious immune-related adverse events in non-small cell lung cancer

“…However, we make reference to the fact that Reschke et al used flow cytometry to examine peripheral blood samples from melanoma patients receiving ICIs and discovered that PD-1 downregulation had the greatest impact on CD3+, CD4 +, and CD8+ T cells at all time points after treatment initiation Prognostic studies on patients with irAEs have consistently presented conflicting results. Multiple retrospective investigations demonstrate that immunotherapy is more effective for individuals who experience irAEs (7,18,50,51). In our study, overall prognosis did not differ significantly between patients with and without irAEs.…”

Distinct immune-effector and metabolic profile of CD8+T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors

“…De novo arthralgia, inflammatory arthritis, tendinitis/tenosynovitis, enthesitis and (poly-)myalgia have been reported in about 20% of ICI patients in clinical trials, with a large variation in prevalence due to differing criteria and awareness of these side effects 4 5. Intriguingly, the development of ICI-induced irAE has been associated with a better survival and clinical outcome,6–8 including patients with rheumatic irAEs 9–11. However, severe irAEs may force clinicians to terminate ICI therapy due to ICI-irAE-associated mortality for 0.5%–1.5% of patients 12.…”

Anti-PD-1 sintilimab-induced bilateral optic neuropathy in non-small cell lung cancer: A case report and literature review

“…A real-world analysis and a retrospective analysis demonstrated that irAE occurrence was significantly associated with response to anti-PD-1 therapy and improved survival in PD-1-treated melanoma ( 34 , 35 ). Patients developing irAEs had longer survival, especially when affecting the skin in advanced NSCLC patients receiving PD-(L)1 inhibitors ( 36 ). A multicenter retrospective study showed that multisystem irAEs were associated with related with improved survival in stage III/IV NSCLC patients treated with anti-PD-(L)1 ICIs alone or in combination with another anticancer agent ( 37 ).…”