Abstract CT039: Immunomodulatory effects of ceralasertib in combination with durvalumab in patients with NSCLC and progression on anti-PD-(L)1 treatment (HUDSON, NCT03334617)
Authors: Iyer Sonia , Conway James , Russell Deanna , Reddy Avinash , Cosaert Jan , Barry Simon , Dressman Marlene , Mensi Ilhem , Aronson Boaz , Peters Jane , Ambrose Helen , Park Keunchil , Forde Patrick , Besse Benjamin , Heymach John V. , Barrett J. Carl 
Published: April 2023

Abstract
Background: Promising clinical activity has been described with the combination of ceralasertib (oral ATR inhibitor) and durvalumab (anti-PD-L1 mAb) in patients with NSCLC who have progressed on prior anti-PD-(L)1 immunotherapy (HUDSON, NCT03334617) (Besse et al., OA15.05, IASLC 2022 WCLC). Similarly promising clinical benefit has been seen with this combination in patients with immunotherapy-resistant melanoma, prompting ongoing Phase2/Phase3 trials in both melanoma (NCT05061134) and NSCLC (NCT05450692). Preliminary preclinical data showed that ceralasertib can modulate innate and adaptive immunity; here we extend these findings in the peripheral blood of HUDSON patients.
Methods: Longitudinal blood samples were collected at baseline, on-therapy samples after 7 days of ceralasertib alone and after durvalumab treatment to evaluate gene expression analyzed using a linear mixed effects model, and T-cell receptor (TCR) repertoire sequencing were analyzed using paired Wilcoxon analyses.
Results: Matched pre- and on-treatment blood samples were available for analysis from 48 patients for gene expression analysis and 62 patients for TCR repertoire sequencing. Gene expression analysis revealed dynamic, reversible changes upon ceralasertib treatment for 7 days (prior to durvalumab). Consistent with pre-clinical data, changes in innate and adaptive immunity-relevant signatures such as monocyte lineage (adjusted p-value [p.adj]=1.1e-23), cytotoxic (p.adj=7.4e-04), exhausted T-cell signatures (p.adj=1.5e-05) and increases in the IFNγ response (p.adj=2.0e-03), IFNα response (p.adj=3.7e-05), and TNFα signaling (p.adj=2.3e-13) signatures were seen, which reverted to baseline levels after ceralasertib followed by durvalumab treatment. Longitudinal TCR sequencing demonstrated similar cyclical changes, most notably reductions in clonality after ceralasertib treatment for 7 days (p=1.1e-06), with a return to baseline after ceralasertib followed by durvalumab treatment. An increase in peripheral TCR clonality was observed in most patients (n=48/58) after the addition of durvalumab, followed by an increase in expanded (p=3.29e-13) and newly detected expanded TCR clones (p=1e-15). The net result of TCR changes after ceralasertib followed by durvalumab treatment was an overall increase in clonality in most patients, without a significant difference in the composition of the most abundant T-cell clones, as measured by the Morisita index.
Conclusions: We found that ceralasertib, combined with durvalumab treatment in relapsed/refractory NSCLC patients, decreased signatures associated with exhausted T-cells and, conversely, increased interferon pathway activation. Furthermore, we observed an expansion and maintenance of abundant T-cell clones indicative of an anti-tumor response.
Citation Format: Sonia Iyer, James Conway, Deanna Russell, Avinash Reddy, Jan Cosaert, Simon Barry, Marlene Dressman, Ilhem Mensi, Boaz Aronson, Jane Peters, Helen Ambrose, Keunchil Park, Patrick Forde, Benjamin Besse, John V. Heymach, J. Carl Barrett. Immunomodulatory effects of ceralasertib in combination with durvalumab in patients with NSCLC and progression on anti-PD-(L)1 treatment (HUDSON, NCT03334617) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT039.