Abstract 6497: Early assessment of liquid biomarkers to predict pneumonitis after chemoradiation in patients with locally advanced non-small cell lung cancer (LA-NSCLC)
Authors: Zeng Jing , Rengan Ramesh , Santana-Davila Rafael , Hippe Daniel S. , Houghton Ashley M. , Kinahan Paul E. , Vesselle Hubert J. , Lampe Paul , Bowen Stephen R. 
Published: September 2020

Abstract
PURPOSE: Patients undergoing chemoradiation (CRT) for LA-NSCLC are at significant risk of developing radiation pneumonitis. As consolidation checkpoint inhibitor immunotherapy (IO) becomes standard of care after chemoradiation, pneumonitis (either radiation or immune-mediated) is also the most common rationale for cessation of IO and management with steroids. Our goal is to develop an early predictive biomarker for pneumonitis post-CRT, to risk stratify patients for treatment toxicity. We analyzed relationships between plasma cytokine levels, single cell functional assays, and pneumonitis prevalence within a prospective phase II clinical trial of chemoradiation for LA-NSCLC.
METHODS: 35 Patients with AJCC v7 stage IIB-IIIB NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238) from 2016-2019. All patients underwent chemoradiation; 18 patients also received consolidation IO (durvalumab) after it became standard of care in late 2017. 24 patients consented to peripheral blood collection at baseline and 21 patients during week 3 of CRT. Plasma concentrations of 43 common inflammatory cytokines were measured at both time points. Pneumonitis was defined as CTCAE v4 grade 2 or higher, irrespective of radiation-induced or immune-mediated causality. Bootstrapping over 100 iterations of LASSO feature selection was performed to reduce dimensionality and guard against false discoveries. Univariate Cox regression of selected cytokine concentrations were evaluated for associations to time-dependent pneumonitis incidence.
RESULTS: Grade 2+ pneumonitis occurred in 13/35 patients, 7 of whom received durvalumab. Four plasma cytokines were most consistently associated with pneumonitis: GMCSF, E selectin, sIL6R (soluble Interleukin-6 Receptor), and SCF (stem cell factor). Higher baseline GMCSF and sIL6R (HR 2.1-4.2, p=0.01-0.03) were correlated with pneumonitis. Higher mid-CRT GMCSF, sIL6R and E selectin (HR 1.6-3.2, p=0.02-0.05), along with decline in mid-CRT SCF (HR 0.2, p=0.02), were associated with pneumonitis. The 4-cytokine signature at mid-CRT predicted for subsequent pneumonitis incidence (cross-validated AUC=0.84). Since GMCSF and SCF are linked to monocyte development, and sIL6R and E selectin are both associated with monocyte function, we performed single cell functional assay (Isocode chips) of mid-CRT peripheral monocytes from two patients with different pneumonitis status. A patient who subsequently developed grade 3 pneumonitis showed higher peripheral monocyte function (5.7% producing MIP1b) relative to a patient who did not develop pneumonitis (0% producing MIP1b).
CONCLUSIONS: Our results show it may be possible to predict development of pneumonitis after chemoradiation in patients with LA-NSCLC, with mid-treatment assessment of 4 plasma cytokines: GMCSF, E selectin, sIL6R, and SCF. Changes in these cytokines may be related to monocyte function. These biomarkers need to be validated in other independent patient populations.
Citation Format: Jing Zeng, Ramesh Rengan, Rafael Santana-Davila, Daniel S. Hippe, Ashley M. Houghton, Paul E. Kinahan, Hubert J. Vesselle, Paul Lampe, Stephen R. Bowen. Early assessment of liquid biomarkers to predict pneumonitis after chemoradiation in patients with locally advanced non-small cell lung cancer (LA-NSCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6497.