Abstract 1298P
Background
Myeloid-mediated immunosuppression is a potential mechanism of resistance to PD-1 immune checkpoint inhibitors (ICI) in metastatic (m)NSCLC. Our group has previously demonstrated that expansion of myeloid derived suppressor cells (MDSC), of which the neutrophil-to-lymphocyte ratio (NLR) acts as a surrogate, is associated with poor survival to ICI treatment. We hypothesized that patients with high NLR may preferentially benefit from combination ICI with chemotherapy as a myeloid debulking therapy. As proof of concept, we investigated patients receiving standard chemo/ICI compared to ICI-alone.
Methods
We reviewed patients with metastatic mNSCLC treated with ICI between 2016-2020. A threshold NLR of ≥5 was used to define the high (H) and low (L) groups, based on published literature. The effect of chemo/ICI on ORR, PFS and OS was compared to ICI alone within NLR and PD-L1 subgroups.
Results
We identified a total of 312 patients: median age 66, 52% male, 68% smoker, 80% adeno, 80% EGFR/ALK wt, median NLR 5.0 (1.1-55.8). In multivariate regression, NLR and PD-L1 were independent predictors of ORR and survival (Table). Combination chemo/ICI was found to offset the poor outcomes associated with NLR even after adjusting for line of treatment and PD-L1. The median PFS of NLR-H patients treated with chemo/ICI was similar to NLR-L, PD-L1<50% patients treated with ICI-alone (HR 1.1, p=0.53). Furthermore, improved median PFS was seen in NLR-H patients treated with chemo/ICI compared to ICI-alone (HR 0.5, p=0.05). Table: 1298P
| Group (N) | ORR | mPFS (months, HR, p-value) | OS (months, HR, p-value) |
| ICI alone, PDL1-H, NLR-L (66) | 50% | 12.5 (0.6, p=0.03) | 30.6 (0.4, p=0.005) |
| ICI alone, PDL1-H, NLR-H (77) | 34% | 4.4 (0.9, p=0.53) | 12.5 (0.9, p=0.65) |
| ICI alone, PDL1-L, NLR-L (55) | 11% | 2.6 (0.9, p=0.53) | 11.4 (0.9, p=0.64) |
| ICI alone, PDL1-L, NLR-H (40) | 13% | 2.0 (2.0, p=0.05) | 5.0 (1.8, p=0.05) |
| ICI/Chemo, NLR-L (21) | 48% | 8.7 (0.8, p=0.41) | 16.4 (0.7, p=0.03) |
| ICI/Chemo, NLR-H (28) | 39% | 5.4 (ref) | 14.9 (ref) |
Conclusions
Combination chemo/ICI therapy appears to overcome the poor survival driven by myeloid-mediated immunosuppression as manifested by NLR-H status. It provides a potential mechanism for the synergistic effect of chemo/ICI seen in clinical trials and supports the investigation of combination strategies that modulate the tumor-myeloid axis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.