Abstract 1247: Comprehensive molecular profiling to predict first-line immunochemotherapy outcomes in inoperable esophageal adenocarcinoma
Authors: Carroll Thomas M. , Chadwick Joseph A. , Owen Richard P. , White Michael J. , Kaplinsky Joseph , Peneva Iliana , Frangou Anna , Chang Jaeho , Xie Phil F. , Roth Andrew , Amess Bob , Lou Hantao , McCann Katy J. , Berridge Georgina , Fischer Roman , Phetsouphanh Chansavath , Omiyale Ayo O. , Jacobs Brittany-Amber , Ahern David , Lord Simon R. , Norris-Bulpitt Stewart , Dobbie Sam T. , Griffiths Lucinda , Ramirez Kristen Aufiero , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Venhaus Ralph R. , Van den Eynde Benoit J. , Karydis Ioannis , Kessler Benedikt M. , Schuster-Böckler Benjamin , Middleton Mark R. , Lu Xin 
Published: June 2022

Abstract
For patients with inoperable esophageal adenocarcinoma (EAC), prognosis on conventional chemotherapy (CTX) remains poor. In 2021, the FDA approved two αPD-1 immune checkpoint inhibitors (ICI) for addition to fluoropyrimidine/platinum-containing CTX in this first-line setting. As ICI+CTX enters the clinic, understanding ICI responses and predicting which patients will benefit from ICI addition are key challenges. To address these challenges, we assessed clinical and molecular profiles from the experimental LUD2015-005 trial (NCT02735239, EudraCT 2015-005298-19). Treatment consisted of an initial four-week ICI-only window with durvalumab (αPD-L1) with or without a single dose of tremelimumab (αCTLA-4), followed by 6 cycles of ICI+CTX (CapOx). 38 inoperable patients received treatment (35 EAC; 3 ESCC); median overall survival (OS) and progression-free survival (PFS) were 13.4 and 9.3 months, respectively. All patients reported at least one treatment emergent adverse event (TEAE), with 29 (76.3%) reporting grade 3 or higher TEAEs. EAC patients with available samples (n = 33) were taken forward for biomarker analysis, using tumor and adjacent normal biopsies collected at pre-treatment (PreTx), after four weeks of ICI-only (ICI-4W), and at the end of ICI+CTX (PostTx).
Transcriptomic comparison of paired PreTx and ICI-4W EAC biopsies (n = 28) revealed ICI-induced upregulation of a novel T-cell inflammation signature (termed INCITE). Stronger INCITE upregulation correlated with greater tumor shrinkage during the ICI-only window, and tumors with minimal INCITE upregulation showed markers of ICI resistance, including Innate PD-1 Resistance (IPRES). Despite correlation with ICI-only responses, INCITE changes were not associated with overall ICI+CTX outcomes.
To find predictive biomarkers of ICI+CTX outcomes, we conducted comprehensive genomic and transcriptomic profiling of PreTx EAC biopsies (n = 33). First, we generated a novel 65,000 cell scRNA-seq dataset and designed a deconvolution workflow to resolve tumor cell composition. Unexpectedly, monocyte composition was strongly linked with greater overall survival (OS) (HR: 0.40 [0.23-0.69]; p = 0.001; FDR = 0.047). Coding tumor mutational burden (TMB) was also associated with improved OS (HR: 0.50 [0.28-0.89]; p = 0.019). Multivariate modelling suggested monocyte composition and TMB were independent and complementary predictors of outcomes. Neither factor was associated with outcomes in a TCGA cohort of EAC patients not treated with ICI, suggesting these biomarkers may be specific to ICI or ICI+CTX.
Our findings suggest monocyte composition and TMB may identify EAC patients likely to benefit from ICI+CTX. INCITE upregulation may also serve as a useful monitor of ICI efficacy. These timely findings further our understanding of ICI response and resistance and may help inform patient selection for ICI+CTX.
Citation Format: Thomas M. Carroll, Joseph A. Chadwick, Richard P. Owen, Michael J. White, Joseph Kaplinsky, Iliana Peneva, Anna Frangou, Jaeho Chang, Phil F. Xie, Andrew Roth, Bob Amess, Hantao Lou, Katy J. McCann, Georgina Berridge, Roman Fischer, Chansavath Phetsouphanh, Ayo O. Omiyale, Brittany-Amber Jacobs, David Ahern, Simon R. Lord, Stewart Norris-Bulpitt, Sam T. Dobbie, Lucinda Griffiths, Kristen Aufiero Ramirez, Toni Ricciardi, Mary J. Macri, Aileen Ryan, Ralph R. Venhaus, Benoit J. Van den Eynde, Ioannis Karydis, Benedikt M. Kessler, Benjamin Schuster-Böckler, Mark R. Middleton, Xin Lu. Comprehensive molecular profiling to predict first-line immunochemotherapy outcomes in inoperable esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1247.