AZD5363, a catalytic pan-Akt inhibitor, in Akt1 E17K mutation positive advanced solid tumors

Background: The Akt1 E17K mutation results in pathological localization of Akt1 to the plasma membrane, stimulating constitutive downstream signaling via oncogenic Akt effector pathways. This mutation is observed in various solid tumors, eg breast (4%), bladder (2%), colorectal (1.5%), cervical (1%), ovarian (1%), prostate (1%) and lung adenocarcinoma (0.5%). Whether Akt1 E17K represents an oncogenic driver and rational drug target in these tumor types is unknown. Here we present preliminary data from patients (pts) with Akt1 E17K mutant advanced solid tumors treated with an oral selective Akt kinase inhibitor, AZD5363, in two Phase 1 studies (NCT01226316, NCT01353781).Methods: Eligible pts had advanced solid tumors refractory to standard treatments and measurable disease by RECIST v1.1. For NCT01226316, Akt1 E17K mutation status was prospectively confirmed on archival or fresh tumor samples prior to enrollment; pts with known RAS mutations were excluded. In NCT01353781, Akt1 E17K mutation status was retrospectively assessed in a subset of enrolled pts. For all pts except one, AZD5363 was administered orally at a starting dose of 480mg bid on a ‘4 days on/3 days off’ schedule. Investigator-assessed RECIST responses were determined every 6 wks for 6 mths, then every 12 wks. Serial plasma samples were collected for detection and tracking of Akt1 E17K mutation (expressed as the mutant allele fraction [MAF]) in circulating tumor DNA (ctDNA) by droplet digital PCR.Results: 33 pts with known Akt1 E17K mutant tumors have been treated to date: estrogen receptor positive (ER+) breast (n=15), triple-negative breast (TNBC; n=4), gynecological (4 endometrial, 2 cervical, 2 ovarian, 1 fallopian; n=9) and other (n=5). 29 pts were evaluable for response. Overall, 20/29 pts (69%) demonstrated target lesion regression. RECIST partial responses (PRs) have been observed in 6 pts (5 confirmed, 1 unconfirmed); ER+ breast cancer (n=2), lung adenocarcinoma (n=1), cervical squamous cancer (n=1), endometrioid ovarian cancer (n=1) and TNBC (n=1, unconfirmed). Median duration on study for the PR pts was 8.3 mths (range 2.4-38.1), with 4/5 maintaining PR. Overall, 15/29 (52%) pts had an on-study duration of ≥4 mths and 14/33 (42%) continue on study. Serial ctDNA assessments were available in 15/33 pts. The Akt1 E17K mutation was detectable in ctDNA in 14/15 (93%) pts at baseline. Akt1 ctDNA declined in 13/14 (93%) pts and became entirely undetectable in 6/13 (46%) pts, 3 of whom attained a PR. Declines in Akt1 ctDNA were transient in non-responders, while persistent declines (≥21 days) correlated with durable tumor regression and RECIST response (P=0.0061). Rise in Akt1 ctDNA preceded clinicoradiological progression by a median of 37 days (range 17-104) in 7/7 (100%) assessable pts. Safety profile of AZD5363 was consistent with previous reports; the most common AEs were diarrhea, rash and hyperglycemia.Conclusions: The Akt1 E17K mutation is an actionable genomic alteration in several solid tumor types. AZD5363 monotherapy shows promising clinical activity in various heavily pre-treated Akt1 E17K mutant solid tumors, including ER+ breast, cervical and ovarian cancer, and lung adenocarcinoma. ctDNA may enable prediction of clinicoradiological response and eventual progression. NCT01226316 continues to accrue pts with Akt1 E17K mutant solid tumors and updated results will be presented.