COMBINATION OF IRAK4 (CA‐4948) AND BTK (VECABRUTINIB) INHIBITORS SHOW SUPERIOR EFFICACY IN PRECLINICAL MODELS OF ABC DLBCL TUMORS CONTAINING MYD88‐L265P MUTATIONS (2019)

Introduction: NF-κB signaling is required for proliferation and survival of activated B cell-like diffuse large B cell lymphoma cells (ABC DLBCL). Alterations in the upstream toll-like receptor (TLR) and B-cell receptor (BCR) signaling pathways contribute to constitutive NF-κB activity. In particular, activating mutations in MYD88 in the TLR pathway and CD79A/B, TNFAIP3 and CARD11 in the BCR pathways are prevalent, and alterations in both TLR and BCR pathways co-occur frequently in ABC DLBCL tumors (Ngo et al 2011, Schmitz et al 2018, Chapuy et al 2018). Thus, a combination strategy whereby inhibiting key enzymes in both pathways may be required for effective drug treatment. Potential targets include the MYD88 proximal IRAK4 kinase in the TLR pathway and the well validated BTK kinase in the BCR pathway. We are developing an IRAK4 kinase inhibitor, CA-4948, as a therapeutic agent for cancers with dysregulated MYD88/IRAK4 signaling. We previously demonstrated that CA-4948 exhibits PD and antitumor activity in in vitro and in vivo models with MYD88 alterations. Vecabrutinib is a selective, reversible, noncovalent BTK inhibitor that has shown potent activity in vitro against both wild type and C481S-mutated BTK, the most common mutation associated with resistance to ibrutinib. In the present study, the efficacy of CA-4948 in combination with vecabrutinib was studied in in vivo preclinical ABC DLBCL tumor models. Methods: Two human ABC DLBCL subcutaneous tumor xenograft models in immunodeficient mice were evaluated. OCI-Ly10 (ap-1) is an ABC DLBCL, MYD88-L265P, CD79A mutant cell line. LY0257 is an ABC DLBCL, MYD88-L265P, BCL6 translocation patient-derived xenograft (PDX) tumor (CrownBio). CA-4948 was dosed orally at 75 mg/kg BID and vecabrutinib was dosed orally at 50 mg/kg BID, either as single agent or in combination. The control group was dosed BID with the two respective drug vehicles. Efficacy was determined by measurement of tumor volumes and calculated as percent tumor growth inhibition (%TGI) relative to the vehicle control group. Results: In both tumor models, significant superior efficacy was observed with CA-4948 plus vecabrutinib combination treatment compared to single agent alone treatment (p≤0.001). In the OCI-Ly10 (ap-1) model, CA-4948, vecabrutinib, and combination treatments showed 28%, 42%, and 97% TGI, respectively, after 21 days of treatment. The combination group had a 2% mean body weight loss. In the LY0275 model, CA-4948, vecabrutinib, and combination treatments showed 25%, 56%, and 85% TGI, respectively, with no body weight loss, after 19 days of treatment. Conclusion: These results demonstrate that targeting both TLR/MYD88 and BCR signaling pathways may be an effective therapeutic strategy in ABC DLBCL. The combination of the IRAK4 inhibitor CA-4948 and vecabrutinib, a noncovalent BTK inhibitor, merits further investigation clinically in R/R NHL subtypes. Keywords: BTK inhibitors; diffuse large B-cell lymphoma (DLBCL); MYD88. Disclosures: Booher, R: Employment Leadership Position: Curis, Inc.; Stock Ownership: Curis, Inc. Borek, M: Employment Leadership Position: Curis, Inc.; Stock Ownership: Curis, Inc. DellaRocca, S: Employment Leadership Position: Curis, Inc.; Stock Ownership: Curis, Inc. Samson, M: Employment Leadership Position: Curis, Inc.; Stock Ownership: Curis, Inc. Fox, J: Employment Leadership Position: Sunesis Pharmaceuticals; Stock Ownership: Sunesis Pharmaceuticals. Taverna, P: Employment Leadership Position: Sunesis Pharmaceuticals; Stock Ownership: Sunesis Pharmaceuticals.