AKT inhibitors

GSK2141795 and MK2206 are inhibitors targeting AKT, acting upstream of mTOR.^200,201 A phase II trial tested dual inhibition of PI3K and Ras signaling by combining the AKT inhibitor (GSK2141795, 50 mg orally daily) and the MEK inhibitor (trametinib, 1.5 mg orally daily) in recurrent CC, with AEs including gastrointestinal events, fatigue, and rash. One patient had an unconfirmed partial response, with an ORR of 7.1%. Eight patients (57.1%) had stable disease.²⁰² However, the combination of trametinib and GSK2141795 was shown to have high levels of toxicity in EC at this dose. And the preliminary efficacy is disappointing in another phase II trial ({"type":"clinical-trial","attrs":{"text":"NCT01935973","term_id":"NCT01935973"}}NCT01935973).^203,204 Moreover, a two-arm, PIK3CA mutation stratified phase II trial ({"type":"clinical-trial","attrs":{"text":"NCT01307631","term_id":"NCT01307631"}}NCT01307631) in recurrent EC demonstrated limited single-agent activity of MK2206 (200 mg orally weekly) in both PIK3CA mutant and wild-type populations.²⁰⁵ Afuresertib, another AKT inhibitor, combined with chemotherapy showed an acceptable safety profile in patients with platinum-resistance OC in a phase I study.²⁰⁶ A phase II trial of afuresertib plus weekly paclitaxel in platinum-resistance OC ({"type":"clinical-trial","attrs":{"text":"NCT04374630","term_id":"NCT04374630"}}NCT04374630, PROFECTA-II) is under way.