Abstract P5-21-32: AZD5363 in combination with fulvestrant in AKT1-mutant ER-positive metastatic breast cancer
Authors: Smyth LM , Oliveira M , Ciruelos E , Tamura K , El-Khoueiry A , Mita A , You B , Renouf DJ , Sablin M-P , Lluch A , Mayer IA , Bando H , Yamashita H , Ambrose H , de Bruin E , Carr TH , Corcoran C , Foxley A , Lindemann JPO , Maudsley R , Pass M , Rutkowski A , Schiavon G , Banerji U , Scaltriti M , Taylor BS , Chandarlapaty S , Baselga J , Hyman DM 
Published: February 2018

Abstract
Background: E17K is the most common activating AKT1 mutation and was shown to be a therapeutic target in this multipart Phase 1 study of AZD5363 (NCT01226316), an oral and selective pan-AKT kinase inhibitor, in patients (pts) with AKT1-mutant (AKT1m) advanced solid tumors. In heavily pretreated AKT1m (E17K) ER+ metastatic breast cancer (MBC) pts, monotherapy achieved an objective response rate (ORR) of 20% and a median progression-free survival of 5.5 months (95% CI, 2.9−6.9). Suppression of PI3K-AKT signaling results in induction of ER-dependent transcription, potentially limiting the response to single-agent PI3K/AKT inhibitors. We explored the hypothesis that simultaneous inhibition of AKT and ER signaling would enhance antitumor efficacy in AKT1m ER+ MBC.
Methods: In an expansion of this study, we administered oral AZD5363 400 mg twice daily, 4 days on 3 days off, and fulvestrant 500 mg, to AKT1m (detected in tumor tissue by local screening and/or plasma BEAMing) ER+ HER2– MBC pts, enrolled into a fulvestrant-naïve (FN) or fulvestrant-resistant (FR) cohort (max 24 pts/cohort). Key objectives included safety and efficacy by RECIST v1.1. We report results of a planned interim analysis conducted when 12 pts/cohort reached maturity for assessment of 24-week clinical benefit rate (CBR), defined as the percentage of responders plus those with stable disease (SD) ≥24 weeks.Data cut-off occurred in June 2017.
Results: At the time of analysis, 24 AKT1m pts (23 E17K, 1 E40K) had received treatment. FN had more visceral disease (83.3% vs 66.7%) and ER+/PR– status (25% vs 8.3%) than FR. Median number of prior anticancer regimens was 4.5 (range 1–9) and 6 (2–11) in FN and FR, respectively, with more chemotherapy (CT) and less hormone therapy (HT) exposure in FN vs FR [3 (0–5) vs 2 (0–6) and 2 (0–4) vs 4 (2–6) prior CT and HT, respectively]. Prior palbociclib was received by 1 (8.3%) and 4 (33.3%) pts in FN and FR, respectively. Clinical efficacy is detailed below; CBR was 33% and 42% in FN and FR, respectively (Table 1). There was 1 unconfirmed partial response in patients treated with prior palbociclib and 3 SD. At data cut-off, 18 pts had discontinued treatment: progressive disease, n=12; adverse events (AEs), n=2; other reasons, n=4. AEs were observed in all 24 pts, most commonly diarrhea (71%), nausea (63%), vomiting and decreased appetite (29%). Grade ≥3 AEs occurred in 13 (54%) pts, most frequently maculopapular rash (n=3), nausea, hyperglycemia and back pain (all n=2). Dose reduction due to AEs occurred in 3 pts.
Table 1. Clinical efficacy FNFREligible for interim data cut-off, n1212ORR, n (%)2 (17)4 (33)CBR, n (%)4 (33)5 (42)Confirmed response (complete/partial response), n (%)2 (17)4 (33)SD ≥24 weeks, n (%)2 (17)1 (8)
Conclusions: AZD5363 plus fulvestrant is clinically active in AKT1m ER+ MBC pts, including in pts with demonstrated prior resistance to fulvestrant. Comparatively lower efficacy was observed in the FN cohort; factors that may have potentially contributed (eg disease characteristics) will be explored. cfDNA and genomic data will also be presented.
Citation Format: Smyth LM, Oliveira M, Ciruelos E, Tamura K, El-Khoueiry A, Mita A, You B, Renouf DJ, Sablin M-P, Lluch A, Mayer IA, Bando H, Yamashita H, Ambrose H, de Bruin E, Carr TH, Corcoran C, Foxley A, Lindemann JPO, Maudsley R, Pass M, Rutkowski A, Schiavon G, Banerji U, Scaltriti M, Taylor BS, Chandarlapaty S, Baselga J, Hyman DM. AZD5363 in combination with fulvestrant in AKT1-mutant ER-positive metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-32.