Abstract 2199: BOS172738: A novel highly potent and selective RET kinase inhibitor in Phase 1 clinical development

Background: RET gene alterations including point mutations and gene fusions have been detected in multiple cancers, including colorectal cancer, NSCLC and various thyroid cancers. RET fusion events involve the kinesin family member 5B (KIF5B-RET), as well as a number of other fusion partners such as CCDC6, TRIM33, and NCOA, and are considered to be the driver mutations in NSCLC and other tumors harboring RET fusions. Selective inhibitors of RET kinase recently has been associated with durable objective responses in patients with RET gene-altered NSCLC and papillary thyroid carcinoma. BOS172738 (formerly DS-5010) is an orally available small-molecule RET kinase inhibitor that has previously been shown to have potent in vitro RET inhibitor activity and in vivo potency against transfected allograft and xenograft models. In this study, we discuss additional in vitro characterization and in vivo efficacy in patient derived xenograft (PDX) models driven by RET fusions and emergent resistant mutations. Results: An expanded kinase profile was conducted with BOS172738 against over 450 kinases, and demonstrated exquisite potency for RET and RET mutations with Kd values ≤ 1 nM for RETwt, RET(M918T), RET(V804L) and RET(V804M). BOS172738 also demonstrated high selectivity over KDR (>300 fold). To confirm this selectivity in vitro, BOS172738 was compared to ponatinib, a multikinase inhibitor with potent activity against both KDR and RET. While BOS172738 demonstrated similar potency to ponatinib (IC50 0.5 µM vs. 0.3 µM) in inhibiting the in vitro proliferation of a NCO4-RET human CRC cell line (CR1520), it resulted in significantly less anti-proliferative activity in HUVEC normal endothelial cells (IC50 2.9 µM vs 0.2 µM). BOS172738 was also evaluated in a number of PDX models of RET fusion cancers, including three CRC PDX models (CR2518:CCDC6-RET, CR1520: NCOA4-RET and CR2545: CCDC6-RET with a V804M mutation) and one NSCLC PDX model (CTG-0838:KIF5B-RET). In all cases tested, BOS172738 demonstrated potent and durable tumor regression at doses of 30 mg/kg, with tumor growth inhibition at lower doses. BOS172738 also demonstrated potent tumor regression on larger, established tumors (>1000 mm3). Conclusion: These results support that BOS172738 is a potent and selective RET kinase inhibitor, with strong antitumor activity against a range of RET fusion proteins, as well as resistant RET active site mutations. BOS172738 is currently being evaluated in a Phase 1 clinical study.