Predictive biomarkers of response to the IRAK4/FLT3 inhibitor emavusertib in hematological malignancies.
Authors: Klaus H Metzeler, Uwe Platzbecker, Eric S. Winer, Amit Verma, Daniel J. DeAngelo, Mariano Severgnini, Gaurav S Choudhary, Wanying Zhao, Maureen E Lane, Cole Gallagher, Dora Ferrari, Alyssa Masciarelli, Reinhard W. Von Roemeling, Samantha Carlisle, David Nickle, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2024)

6550 Background: Myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) display a dynamic and diverse mutational landscape. Various mutations can induce the overexpression of a highly active long isoform of interleukin-1 receptor-associated kinase 4 (IRAK4), leading to downstream activation of transcription factors such as NFκB. This activation triggers inflammation, oncogenesis, and the survival of cancer cells. Emavusertib, a potent oral inhibitor of IRAK4 and FLT3, has demonstrated efficacy in pre-clinical leukemia models and in patients. In this abstract, we present data suggesting potential biomarkers of response to emavusertib based on clinical samples from the ongoing TakeAim Leukemia trial. Methods: In Phase I/IIa of the TakeAim Leukemia trial (NCT04278768), patients with relapsed/refractory (R/R) AML or high-risk MDS (hrMDS) received treatment with emavusertib monotherapy. Baseline and on treatment patient samples underwent RNA sequencing and proteomic analyses. RNA-seq was conducted on mononuclear cells from bone marrow or peripheral blood (n=42). Plasma proteins were quantified by the Luminex platform (n=51). Results: hrMDS patients responding to emavusertib monotherapy exhibited decreased gene expression levels of the NFκB target gene IL1β (P≤0.05) compared to non-responders. Protein analyses revealed that hrMDS responders had lower baseline levels of proliferation and migration-related factors, like Vascular Endothelial Growth Factor (VEGF-A) and CXCL12, in plasma compared to non-responders (P≤0.05). In AML samples, baseline VEGF-A levels were significantly higher in responders. The concentration of soluble PD1 (sPD1) increased in on-treatment samples in hrMDS patients (P≤0.05), but not in AML patient samples. Additionally, hrMDS samples presented lower IL2 and higher sCD47 levels compared to AML (P≤0.05). Conclusions: In this work, several baseline biomarkers indicative of a response to emavusertib were identified in patients with hematological malignancies. Responders in hrMDS showed lower baseline expression of the NFκB-associated pro-inflammatory gene, IL1β, and lower protein levels in plasma of the angiogenic factor VEGF-A and the chemokine CXCL12. In AML samples, responders have higher baseline levels of VEGF-A, indicating distinct predictive biomarkers for both pathologies. Other molecules of clinical interest, such as sPD1, showed increased concentrations in on-treatment plasma samples of hrMDS patients regardless of their response to emavusertib. Our findings highlight distinct baseline biomarkers for AML and hrMDS related to the pathophysiology of hematological malignancies. These results suggest that inflammatory and migration mediators, along with angiogenesis factors, hold potential as predictive biomarkers for assessing responses to emavusertib monotherapy treatment in hematological malignancies. Clinical trial information: NCT04278768 .