Efficacy and safety of AKT inhibitor NTQ1062 combined with fulvestrant in patients with HR-positive/HER2-negative metastatic breast cancer：a proof-of-concept, multicenter, open-label, nonrandomized, phase Ib/II study.

Abstract

e13043 Background: NTQ1062 is an oral, potent, and pan-AKT small-molecule inhibitor with favorable pharmacokinetic properties. This phase Ib/II study (NCT06172322) was designed to assess the efficacy and safety of the NTQ1062 in combination with fulvestrant in patients with hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (HER2 - ) metastatic breast cancer (mBC) and to establish the optimal biological dose (OBD) of NTQ1062 for subsequent phase III development. Methods: Eligible patients were women with a histologically confirmed HR + /HER2 - mBC who had experienced disease progression on prior endocrine therapy. Patients were stratified into three dose cohorts: NTQ1062 400 mg or 500 mg once daily (qd), 200 mg twice daily (b.i.d.). Treatment cycles consisted of 21 days of continuous NTQ1062 administration followed by a 7-day rest period, in combination with standard-dose fulvestrant administered per clinical practice guidelines. The primary endpoints were safety and determination of the OBD. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and biomarker analysis. Results: As of the data cutoff (Nov 26, 2025), 56 patients were enrolled to receive study treatment. The cohorts were as follows: 15 patients in 400 mg (qd) cohort, 16 in 500 mg (qd) cohort, and 25 in 200 mg (b.i.d.) cohort. Among the patients, 62.5% had previously received a CDK4/6 inhibitor. Visceral metastases were present in 47 patients (83.9%). A total of 25 patients (44.6%) in the overall population harbored confirmed PIK3CA/AKT1/PTEN alterations. Confirmed partial response (PR) was achieved in 14 patients, resulting in an overall ORR of 25.0% (95% CI, 14.4-38.4), with the 200 mg (b.i.d.) cohort showing a higher response rate (36.0%). In all patients, the median PFS (mPFS) was 6.7 months (95% CI, 3.7-11.1), with 7.4 (95% CI, 3.7-NA) months in the 200 mg (b.i.d.) groups. The most common grade 3 TRAEs (incidence ≥5%) were diarrhea (12.5%, 7/56), maculopapular rash (7.1%, 4/56), and hyperglycemia (7.1%, 4/56). Treatment-related serious adverse events (SAEs) were reported in 5 patients (8.9%), all requiring hospitalization. Conclusions: NTQ1062 combined with fulvestrant demonstrated a favorable and manageable safety profile and encouraging clinical activity in patients with HR + /HER2 - mBC who had progressed on prior endocrine therapy. Based on superior efficacy and a more favorable tolerability profile observed across dose levels, 200 mg (b.i.d.) was determined to be the OBD of NTQ1062 for the combination with fulvestrant. Clinical trial information: NCT06172322 .