1498P - HGF/MET pathway is associated with poor efficacy of Immune checkpoint inhibitors (ICIs) in advanced-stage NSCLC

Background

A pilot study has revealed a significant correlation between high levels of circulating HGF and poor response to ICIs therapy in late-stage NSCLC patients treated with ICIs. This study aimed to evaluate the prognostic value and role of the HGF/MET pathway in first-line immunotherapy treatment in advanced NSCLC patients.

Methods

We included 82 consecutive patients, 49 treated with immunotherapy and 33 treated with chemotherapy alone as a group control. We analysed the plasma levels of HGF by ELISA. Immunohistochemistry was used to assess the expression levels of PD-L1, MET, and CD8+ T-Cell infiltration. The contribution of HGF/MET to NSCLC response to ICIs was further investigated by culturing peripheral blood mononuclear cells (PBMC)stimulated with 10 μg/mL phytohemagglutinin (PHA) and/or pembrolizumab (20 nM). The cells were cultured with recombinant HGF or co-cultured with NSCLC patients-derived explants.in the presence of cMET inhibitors Crizotinib or SGX. The immune response was quantified through CD8+ activation and INFγ production.

Results

Correlation tests demonstrated that lower HGF levels were associated with a good response to ICIs (RR=2.143; p=0.004) and low progression (RR=0; p=0.01). Patients with low HGF levels (< Q1) at treatment initiation had longer progression-free survival (PFS) (841 vs 136.5 days; HR = 0.26 95% CI 0.1292-0.5411; p=0.0003) and longer overall survival (OS) (median not reached vs. 489 days; HR 0.36; 95% CI 0.1505-0.8408; p=0.02). Furthermore, when activated PBMCs were cultured in the presence of recombinant HGF or on NSCLC monolayer, the activation/proliferation of CD3+CD8+ lymphocytes, was inhibited, even in the presence of pembrolizumab. The addition of HGF/MET inhibitors (Crizotinib and SGX) suppressed the immunosuppressive properties of recombinant HGF or NSCLC, stimulating INFγ production.

Conclusions

Our study found that high levels of HGF in the peripheral blood are associated with poor response to ICIs, disease progression, and shorter survival in patients with advanced NSCLC. Furthermore, we showed through in vitro experiments that inhibiting the HGF/MET signaling pathway could be a promising therapeutic approach to enhance the efficacy of ICIs in this patient population.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

University of Paris Saclay, UVSQ.

Funding

Legs Poix Subvention (2018).

Disclosure

E. Giroux-Leprieur: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Advisory Board: AstraZeneca, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, Takeda. All other authors have declared no conflicts of interest.