On February 6, 2026, Nature Communications published online a study led by Academician Xu Binghe from the National Cancer Center / Cancer Hospital, Chinese Academy of Medical Sciences. The single-arm Phase Ib trial evaluated the efficacy and safety of the novel oral pan-AKT inhibitor afuresertib combined with fulvestrant in previously treated patients with HR-positive/HER2-negative advanced breast cancer.The study demonstrated encouraging antitumor activity with a manageable safety profile, offering a promising new strategy for overcoming endocrine resistance. Professor Zhang Pin from the Cancer Hospital, Chinese Academy of Medical Sciences, served as first author, while Academician Xu Binghe was the corresponding author.
Targeting the PI3K/AKT Pathway to Overcome Endocrine Resistance
Endocrine therapy remains the cornerstone of treatment for HR-positive/HER2-negative advanced breast cancer. However, both primary and acquired resistance continue to limit long-term efficacy. Among the key mechanisms driving endocrine resistance is aberrant activation of the PI3K-AKT-PTEN signaling pathway.
More than 50% of patients with HR-positive/HER2-negative breast cancer harbor PIK3CA or AKT1 mutations or experience PTEN loss. These alterations can activate the estrogen receptor independently of ligand binding, allowing tumor cells to escape the suppressive effects of endocrine therapy.
Although CDK4/6 inhibitors combined with endocrine therapy have significantly improved patient outcomes, resistance remains common. Once disease progression occurs, subsequent treatment options are limited, and the effectiveness of conventional chemotherapy gradually declines. As a result, targeting the PI3K/AKT pathway — particularly the central signaling node AKT — has become a major research focus for reversing endocrine resistance and overcoming CDK4/6 inhibitor resistance.
AKT inhibitors such as capivasertib have already received approval in the United States. However, because AKT plays a crucial role in glucose homeostasis, these agents are frequently associated with hyperglycemia and related adverse effects.
Afuresertib is a novel oral, highly selective ATP-competitive pan-AKT inhibitor. Preclinical studies demonstrated exceptionally potent inhibitory activity against the AKT1 subtype, with an IC50 value of only 0.08 nM, while showing relatively weak activity against other kinases. This high selectivity theoretically reduces off-target effects and may provide a more favorable glucose safety profile, potentially improving patient tolerability.
LAE205INT3101 Study: First-in-Human Trial Demonstrates Efficacy and Safety
This Phase Ib study was part of the broader LAE205INT3101 clinical program and aimed to evaluate the efficacy, safety, and tolerability of afuresertib combined with fulvestrant in previously treated HR-positive/HER2-negative advanced breast cancer, while also identifying the recommended dose for subsequent Phase III development.
A total of 31 patients with a median age of 54 years were enrolled. All patients had previously received endocrine therapy, 64.5% had prior exposure to CDK4/6 inhibitors, and 83.9% had visceral metastases.
Patients received afuresertib at 125 mg orally once daily combined with standard-dose fulvestrant at 500 mg intramuscularly.
According to investigator assessment, the objective response rate (ORR) reached 25.8% (8/31 patients; 90% CI 13.5–41.8), successfully meeting the predefined primary endpoint. All eight responders achieved partial response.
The clinical benefit rate (CBR), defined as complete response, partial response, or stable disease lasting at least 24 weeks, reached 71.0%. Median duration of response was 9.1 months, while median progression-free survival (mPFS) was 8.2 months. The six-month and twelve-month progression-free survival rates were 60.8% and 35.8%, respectively.
Exploratory biomarker analyses revealed particularly encouraging outcomes in patients harboring PI3K/AKT/PTEN pathway alterations. Among 18 patients with these genomic alterations, the ORR reached 33.3%, compared with only 9.1% among patients without pathway mutations.
Notably, among seven patients carrying both ESR1 mutations and PI3K/AKT pathway alterations, therapeutic benefit was even more pronounced, with an ORR of 42.9% and a CBR of 85.7%. These findings suggest that afuresertib may have especially strong therapeutic potential in biomarker-selected populations.
Favorable Safety Profile with Particularly Encouraging Glycemic Safety
Afuresertib also demonstrated an impressive safety profile. Grade 3 or higher adverse events occurred in 29% of patients, yet no patient discontinued treatment because of treatment-related toxicity.
Importantly, although 51.6% of patients experienced hyperglycemia of any grade, no Grade 3 or higher hyperglycemia events were observed.
Academician Xu Binghe, corresponding author of the study, commented:
“Although endocrine therapy combined with CDK4/6 inhibitors has become the standard treatment for HR-positive advanced breast cancer, post-resistance treatment strategies remain a major clinical challenge. This study is the first to confirm the activity of afuresertib combined with fulvestrant in this patient population. Even among patients with a high prior CDK4/6 inhibitor exposure rate of 64.5%, the combination achieved an ORR of 25.8% and a progression-free survival of 8.2 months, without any Grade 3 or higher hyperglycemia. These results are highly competitive within the AKT inhibitor class.”
Overall, this study represents the first clinical trial demonstrating antitumor activity of the China-developed AKT inhibitor afuresertib combined with endocrine therapy in HR-positive/HER2-negative advanced breast cancer.
Its promising efficacy and favorable safety profile — particularly its manageable impact on blood glucose — provide a strong foundation for future clinical development.
