Abstract 787: FLX925 (AMG 925) is a rationally designed FLT3, CDK4/6 inhibitor that retains potency against clinically relevant secondary resistance mutations in FLT3

Acquired secondary resistance mutations to clinically active kinase inhibitors remains a key obstacle between valid therapeutic hypotheses and meaningful patient benefit. In AML, evidence suggests that inhibition of FLT3 (particularly in FLT3-ITD mutated cancers) can be efficacious; however, relapse from complete remission is common and often rapid. As with other cancers driven by key oncogenic kinase mutations (e.g. BCR-ABL in CML), a primary mechanism of resistance is the acquisition of secondary resistance mutations in the oncogenic kinase themselves. Multiple strategies have been pursued to address such resistance, including the development of kinase inhibitors that either bind their respective targets differently or by targeting multiple important pathways simultaneously. Herein we describe a rationally conceived next generation FLT3 inhibitor, FLX925 (previously AMG 925), that was prospectively designed to address or avoid common resistance mechanism to earlier FLT3 inhibitors with its unique binding mode and potent activity against CDK4/CDK6. FLX925 is a potent and selective type 1 inhibitor of FLT3 that retains its cellular potency against clinically relevant secondary resistance mutations in FLT3 occurring with quizartinib or sorafenib treatment (FLX925 IC50: MOLM13ITD, 15 nM; MOLM13ITD/D835, 28 nM; MV4-11ITD, 16 nM; MV4-11ITD/D835, 19 nM; MV4-11ITD/N841, 16 nM; MV4-11ITD/F691, 73 nM). Indeed, while compounds currently in the clinic became more than 200-fold less potent against a number of mutants, FLX925 remained relatively equipotent (+/- 5-fold the parental cell line IC50) in these same resistant clones. This is in stark contrast to the striking cross-resistance observed with quizartinib in sorafenib resistant cells. Moreover, the few clones that grew out of a screen for resistance to FLX925 displayed a ‘persistence’ phenotype with modestly reduced sensitivity to FLX925 (∼5-fold IC50 shift) that was rapidly reversible. This persistence was associated with higher FLT3 protein levels and no detectable secondary mutations in FLT3. In addition to its suppression of FLT3 signaling, FLX925 potently inhibits CDK4/CDK6, central components of the cell cycle machinery. This unique profile may reduce the likelihood of emergent resistant clones and extends the therapeutic potential of FLX925 to other malignancies dependent on these pathways (e.g. MCL). Indeed, the addition of PD0332991 (a selective CDK4/6 inhibitor) to a relatively selective FLT3 inhibitor reduced the frequency of acquired resistance in a cell based screen, relative to a FLT3 inhibitor alone. These data suggest the unique profile of FLX925 makes it an ideal inhibitor for the treatment of cancers driven by FLT3 signaling, such as AML. A phase I clinical trial evaluating the safety, tolerability pharmacokinetics and pharmacodynamics effects of FLX925 in patients with AML is ongoing. Citation Format: Cong Li, Lingming Liang, Liqin Liu, Zhen Xia, Zhihong Li, Xianghong Wang, Lawrence McGee, Angus Sinclair, Sasha Kamb, Dineli Wickramasinghe, Sachie Marubayashi, Juan C. Jaen, Jordan S. Fridman, Kang Dai. FLX925 (AMG 925) is a rationally designed FLT3, CDK4/6 inhibitor that retains potency against clinically relevant secondary resistance mutations in FLT3. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 787. doi:10.1158/1538-7445.AM2015-787