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

1021 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. Clinical trial information: NCT03698383 .