31IN - AKT inhibitors and other new kids on the block

Abstract

AKT mutations are uncommon in cancers with the AACR GENIE Project cohort of 27,290 patients demonstrating AKT1 alterations in 1.9%, AKT2 alterations in 1.6%, and AKT3 alterations in 1.3% of cases (Courtesy AACR GENIE). The development of first generation AKT inhibitors has been limited by poor therapeutic index and the unselected patient populations being treated with these compounds. AKT1 E17K is the predominant functionally activating mutation most frequently found in breast cancer, gynecological cancer, bladder, prostate and lung cancer. A recently published basket study of the pan-AKT kinase inhibitor AZD5363, demonstrated objective responses in tumors harboring this oncogenic mutation (Hyman et al. J Clin Oncol 2106). The first-in-human phase I study of ipatasertib (GDC-0068) was also reported in solid tumor patients with or without AKT pathway aberrations, and demonstrated stabilization in about 30% of patients whose disease were progressing on prior therapies (Saura et al. Cancer Dis 2017). Paired tumor biopsies demonstrated inhibition of multiple on-target effectors but upregulation of pERK and pHER3 were observed suggesting compensatory feedback following ipatasertib administration. The path forward for AKT inhibitors will involve selection of patients with molecular vulnerabilities for this target and also combination studies with inhibitors of other signaling pathways such as the RAS/MEK pathway. Catalytic mTOR inhibitors such as MLN0128 and AZD2014 are also undergoing clinical evaluation in multiple tumor types. Challenges associated with the development of these classes of compounds will be discussed. Legal entity responsible for the study: N/A Funding: Has not received any funding Disclosure: L. Siu: Consultant for: Merck (compensated), AstraZeneca/Medimmune (compensated), Symphogen (compensated), Morphosys (compensated) Speaker’s Bureau for: None Grant/Research support from (Clinical Trials): Merck, Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche, Karyopharm, AstraZeneca/Medimmune, Celgene, Genentech/Roche, Symphogen, Astellas. Stockholder in: None.