Abstract PS17-08: A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies
Authors: Xu Binghe , Zhang Pin , Sun Tao , Wang Ying , Tong Zhongsheng , Phadke Sneha , Feinstein Trevor , Guo Pengfei , Qu Jing , Wang Xiaoyu 
Published: May 2024

Abstract
Background
The combination of an aromatase inhibitor with a CDK4/6 inhibitor is the mainstay of first-line endocrine therapy (ET) for locally advanced or metastatic HR+/HER2− breast cancer (LA/mBC). Management of recurrent disease in the post-CDK4/6 inhibitor setting includes additional lines of ET single agent or in combination with a targeted agent. For patients with HR+/HER2− LA/mBC tumors, fulvestrant monotherapy as the second- or third-line therapy has limited activity with a median PFS of 1.9-3.6 months. Effective targeted treatments for these patients are needed to maintain quality of life, improve survival, and delay the initiation of cytotoxic chemotherapy.
Methods
This ongoing single arm, open-label global study (NCT04851613) is to evaluate the efficacy and safety of the combination therapy of afuresertib (a pan-AKT inhibitor) plus fulvestrant in patients with HR+/HER2− LA/mBC. Eligible patients must have received 1-2 prior lines of ET. Patients may have prior treatment of CDK4/6 inhibitors (up to 1 therapy), and/or up to 1 line of chemotherapy. Patients received afuresertib (125 mg PO, QD) in combination with fulvestrant (500 mg IM; Day 1 and 15 in Cycle 1, and Day 1 in subsequent 28-day cycles). The safety of the initial treatment doses of the combination therapy was evaluated in the first 6 patients during the Cycle 1 safety run-in period. Radiographic assessment per RECIST 1.1 was performed every 8 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included safety and tolerability of the combination therapy and pharmacokinetic characterization.
Results
Twenty patients (1 male and 19 females, 3 in the US and 17 in China) were enrolled between May 2022 and April 2023. As of the data cut-off date of May 26th, 2023, 10 patients had discontinued the study treatment (9 due to disease progression, 1 due to patient’s withdrawal of consent) and 10 patients were still in treatment. Of the 19 patients who had at least one post-baseline tumor assessment, 4 patients observed confirmed Partial Response (cPR), 12 had best overall response of Stable Disease, and 3 had Progressive Disease (PD). The Disease Control Rate is 84%. Of the 15 patients who had at least 2 tumor assessments or who discontinued treatment early due to PD, the confirmed ORR is 26.7% (4 cPR). No dose modification was required during the safety run-in. The most common treatment-emergent adverse events (TEAEs, &gt; 20% of patients) of all grades were hyperglycemia (50%), diarrhea (45%), ALT/AST increase (40%), nausea (35%), rash (35%), hypercholesterolemia (35%), and anemia (30%), the majority of which were Grade 1. Grade 3 AEs were reported in 4 patients, including diarrhea (1 patient), WBC increase (1 patient), creatine phosphokinase increase (1 patient), and ALT/AST increase and rash (1 patient). No SAE or TEAE &gt;= Grade 4 were reported. No patient discontinued treatment due to TEAE.
Conclusions
The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2− LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study.
Citation Format: Binghe Xu, Pin Zhang, Tao Sun, Ying Wang, Zhongsheng Tong, Sneha Phadke, Trevor Feinstein, Pengfei Guo, Jing Qu, Xiaoyu Wang. A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-08.