2315P - Clinical and blood immune-inflammatory profiling to decode different patterns of acquired resistance in immunotherapy treated NSCLC patients

Background

To uncover the underpinnings of acquired resistance (AR) to Immune Checkpoint Inhibitors (ICIs), we determined whether distinctive clinicopathological and peripheral blood (PB) immune-inflammatory features reflect oligo and systemic (sys) AR in advanced NSCLC patients undergoing ICIs.

Methods

On PB collected at baseline (T0) and first disease assessment (T1) from 105 ICI-treated NSCLC, we prospectively assessed LDH, derived Neutrophil-to-Lymphocyte ratio (dNLR), LIPI score, relevant immunophenotypes (flow-cytometry) and their respective delta (Δ) % variation [(T1-T0)/T0]. AR, defined as progression after initial response (CR/PR/SD ≥ 6 mos.), was subdivided according to the number of new and/or progressive lesions in oligoAR (≤ 3) and sysAR (> 3). Initial PD or SD < 6 mos. embodied non responders (NR), while absence of progression or PFS ≥ 12 mos. enclosed long-term/not progressors (LT/NP). Clinicopathological, PB parameters and survival outcome were statistically evaluated according to AR pattern.

Results

OligoAR involved 24% of cases, while sysAR 12.4%. Compared to NR, oligoAR pattern was associated with significantly lower T0 and Δ LDH, dNLR and LIPI, whereas no differences were observed vs sysAR and LT/NP. While baseline PB immune profiles were comparable, a Δ positive cytotoxic (NK, NKT, CD8+Ki67+, CD8+Gnz+) and Δ negative immunosuppressive (CD14+ monocytes, CD4+CD25+FOXP3+ Tregs) dynamics was distinctive of oligoAR vs sysAR (P < 0.05). Conversely, compared to LT/NP, oligoAR cases showed a lower cytotoxic/proliferating CD8 response coupled with higher CD14+/Tregs feedback (P < 0.05). Within oligoAR, patients with 1 progressive lesion, compared to those with ≥ 2, exhibited baseline lower LDH and higher NK/CD8+Gnz+ cytotoxic cells (P < 0.05) which in turn appeared to condition longer OS (HR: 4.90; P=0.04). Importantly, despite similar clinical profile, prolonged post-progression survival characterized oligoAR vs sysAR (median OS not reached vs 11.3 mos.; HR: 0.21, 95% CI: 0.08-0.59; P = 0.001).

Conclusions

The longitudinal analysis of blood immune hallmarks intersected with clinicopathological features may decipher the distinct patterns of AR in ICI-treated NSCLC patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

University Hospital of Parma.

Funding

AIRC - Italian Association for Cancer Research.

Disclosure

All authors have declared no conflicts of interest.