1333P - Prognostic value of circulating nucleosomes during treatment with or without immunotherapy in non-small lung cancer (NSCLC): Results from the NUCLEO-lung study

Background

Nucleosomes (DNA wound around histone complex) may be relevant cancer biomarkers. ONCOPRO (NCT03787056) is a prospective case-control study that collected plasma at diagnosis and during disease management of 421 patients with 16 newfound cancers. The promising diagnostic and prognostic value of H3K27Me3 baseline titers in metastatic NSCLC regarding overall survival (OS) was previously presented (Couraud et al. ELCC 2024). Here, the prognostic value of nucleosomes concentrations at different times during the first-line treatment with/without immune checkpoint inhibitor (ICI) was explored.

Methods

The NUCLEO-Lung study measured plasmatic titers of methylated H3K27 (ng/mL) with Nu.Q® immunoassays (Volition SRL) in 45 patients with NSCLC of the ONCOPRO cohort, at diagnosis and after 1 or 2 cycles of first-line therapy. ICI was employed in 1st-line settings for 47% of patients, and at any line for 80%. The prognostic values of H3K27Me3 titers (< or ≥ median) were explored for median PFS/OS (mPFS/mOS) and hazard-ratio (HR) [95% CI].

Results

The prognostic value of higher H3K27Me3 titers (≥ vs < median) regarding OS was significant at baseline (mOS, NR vs 7.98 mo, HR = 0.17 [0.05-0.59]) and after 2 cycles of treatment (mOS, NR vs 7.16 mo, HR = 0.27 [0.08-0.87]), regardless of ICI treatment. A trend for a prognostic value of baseline H3K27Me3 titers regarding PFS was more marked in patients treated without 1st-line ICI (mPFS, NR vs 3.02 mo, HR = 0.34 [0.10-1.16]), than in those treated with 1st-line ICI (mPFS, NR vs 10.32 mo, HR = 0.66 [0.18-2.45]). This prognostic differential was higher after 2 treatment cycles (without 1st line ICI, mPFS, HR = 0.26 [0.03-2.50]; with 1st-line ICI, HR = 0.87 [0.20-0.95]). No relationships between H3K27Me3 titers and tumor or circulating DNA mutational status were observed.

Conclusions

The titers of H3K27Me3 are strong prognostic markers for OS in metastatic NSCLC. Interestingly, the prognostic value in 1st-line settings was stronger in patients treated without ICI, and hypothetically increased during therapy upon the treatment-induced selection pressure. Further analyses of nucleosome prognostic/predictive values for ICI/non-ICI treatment are warranted.

Clinical trial identification

Ancillary study: ONCOPRO (NCT03787056), CSE N23-5168 16/06/2023.

Editorial acknowledgement

Legal entity responsible for the study

Benoît You.

Funding

Volition.

Disclosure

L.F. Payen: Financial Interests, Institutional, Sponsor/Funding: Volition; Financial Interests, Institutional, Funding: AstraZeneca. B. You: Financial Interests, Institutional, Funding: Gilead. All other authors have declared no conflicts of interest.