5P - Blood immune-inflammatory dynamic unveils distinctive irAE features in ICI treated NSCLC

Background

We tested whether the longitudinal monitoring of peripheral blood (PB) immune-inflammatory benchmarks might intercept immune-related adverse events (irAEs) onset and their impact on clinical outcome in ICI-treated NSCLC.

Methods

On PB collected at baseline (T0) and first disease assessment (T1) from 105 advanced NSCLC undergoing ICIs, comprehensive immune cell phenotyping (flow-cytometry), LDH, derived Neutrophil-to-Lymphocyte ratio (dNLR), LIPI and serum multiplex cytokine array were prospectively evaluated, including their delta (Δ) variation [(T1-T0)/T0*100]. irAEs type and grading (G) were defined according to CTCAE (Common Terminology Criteria in Adverse Events) v5.0. Correlations of irAEs with clinicopathological/PB parameters and survival outcome were statistically analyzed.

Results

irAEs occurred in 51 (48.6%) patients with 14.3% G3-4 incidence and involving the skin (36%), diarrhea/colitis (24%), liver (12%), thyroid (4%) and multiple sites (33.3%); median time-to-onset: 48-278 days; and leading to temporary or permanent ICI discontinuation in 11.4% of cases. irAEs were more frequent in females (58.3%) and absent in performance status (PS) 2 patients. Baseline PB parameters didn’t substantially differ according to irAE occurrence, except for higher IFNγ (P=0.014) and lower IL1β and IL6 (P=0.02) levels in irAEs cases. At T1, lower NLR, dNLR and LIPI characterized irAE patients, together with increased CD8+ cytotoxic (Perforin+, P=0.09) and proliferating (Ki67+, P=0.05) activity, higher IFNγ and TNFα and lower TGFβ1 levels compared to no-irAEs cases. Intriguingly, PB immune cells dynamic more closely reflected irAE severity as G3-4 cases displayed a sharp rise (Δpos) in cytotoxic NKs and CD8+GnzB+ lymphocytes (P=0.04) and a drop (Δneg) in CD4+CD25+FOX3^high Tregs (P=0.07). Importantly, irAEs patients exhibited greater disease control rate (84% vs 65.1%, P=0.05) and significantly longer PFS (Median PFS=10.4 vs 5.4 mos, P=0.002, HR=0.47) and OS (Median OS=NR vs 11.3 mos, P<0.001, HR=0.34) vs no-irAEs NSCLC.

Conclusions

irAEs involve a distinctive cellular and humoral immune dynamic and might positively condition ICI efficacy.

Legal entity responsible for the study

University Hospital of Parma.

Funding

Associazione Italiana per la Ricerca sul Cancro-AIRC.

Disclosure

All authors have declared no conflicts of interest.