Phase II study of trastuzumab-pkrb plus gedatolisib in patients with HER2-positive metastatic breast cancer who progressed after 2 or more HER2-directed chemotherapies (KM-10A/KCSG BR18-13).

Abstract

Background: The prognosis of patients with HER2 positive metastatic breast cancer (MBC) has dramatically improved with the advent of HER2-targeted therapy. However, resistance to anti-HER2 therapies remains inevitable. Aberrations in the PI3K-AKT-mTOR pathway are recognized as a key mechanism of resistance to HER2 directed therapies. This study is a multicenter, prospective, single-arm, phase II study to evaluate the antitumor activity and safety of trastuzumab-pkrb plus gedatolisib in patients with HER2 positive MBC who progressed after 2 or more HER2 directed chemotherapy. Methods: The primary endpoint was the overall response rate (ORR), assumed to be 25% with a type I error rate of 0.05 and a power of 0.9. Although the target enrollment was 62 patients, the study was prematurely terminated after 44 patients due to the drug supply issue of gedatolisib. Patients with HER2-positive MBC and PI3K pathway genomic aberrations, identified via tumor-targeted sequencing or cfDNA analysis, were enrolled after disease progression on at least two HER2-directed therapies. The treatment regimen included trastuzumab-pkrb and gedatolisib. Safety and efficacy outcomes were evaluated, with a data cutoff of December 31, 2024. Results: Primary efficacy and safety data were evaluable in 44 patients. The median age was 59 years (range: 28-72), and the median number of prior palliative treatment lines was 4 (range: 2-10). Genomic aberrations included mutations kinase domain (26 patients), helical domain (11), amplification (1) of PIK3CA, deletion of PTEN (2), and other mutations (4). Among the 44 evaluable patients, the best overall responses were complete response (CR) in 2 patients (4.5%), partial response (PR) in 17 (38.6%), stable disease (SD) in 19 (43.2%), progressive disease (PD) in 5 (11.4%), and non-evaluable (NE) in 1 (2.3%), resulting in an objective response rate (ORR) of 43.2% and a disease control rate (DCR) of 86.4%. The median progression-free survival (mPFS) was 5.8 months. After a median follow-up of 32.5 months, 22 deaths were recorded, and 19 patients were alive. The median overall survival (mOS) after study enrollment was 18.4 months. Common treatment-related adverse events (TRAEs) included oral mucositis (32.3%; 4.1% ≥ grade 3) and skin reactions (14.1%; 1.8% ≥ grade 3). Hyperglycemia was reported in 6.8% (0.5% ≥ grade 3). No fatal adverse event related to trial medications were reported. Conclusions: In this phase II study, the combination of trastuzumab-pkrb and gedatolisib demonstrated a 43.2% response rate with manageable toxicity in patients with HER2 positive MBC and PIK3CA mutations. A translational research study focused on the analysis of cfDNA and PBMC is currently being planned.