Phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple-negative breast cancer.

The PI3K/AKT/mTOR pathway is an important oncogenic driver in triple-negative breast cancer (TNBC). This study investigated the clinical efficacy and safety of the combination of gemcitabine and cisplatin with everolimus (GPE) in patients with metastatic TNBC. In phase I, we assessed the maximum tolerated dose (MTD) of GPE in metastatic TNBC patients. Then, using a seamless design, we conducted a randomized phase II trial to compare GPE to GP in terms of progression-free survival (PFS) and toxicity. In addition, we investigated the mutational status of (E542K, E545K, H1047R) in tumor tissues (n=14) and cell-free DNA (cfDNA) from blood samples (n=23) using droplet digital PCR. In phase I (n=9), we found that the MTD of GPE was gemcitabine 800 mg/m and cisplatin 30 mg/m on days 1 and 8 every 3 weeks along with everolimus 5 mg daily. Phase II was terminated early after 14 patients had been enrolled because of slow recruitment and concerns about efficacy. Results of the combined analysis of phases I and II showed the objective response rate (ORR) of GPE (n=16) was 31.3% and the median PFS was 5.5 months (95% CI, 3.5-7.5). Stomatitis and hematologic toxicities were observed most frequently in the GPE arm. mutations were identified in 8 (57.1%) tumor samples and 17 (73.9%) cfDNA samples; there was no significant association between mutation status and response to GPE treatment. Although the majority of patients with metastatic TNBC demonstrated mutations in cfDNA, the addition of everolimus to gemcitabine/cisplatin did not have a synergistic effect in these patients. Further studies are needed to determine the most effective way to target the PI3K/AKT/mTOR pathway in TNBC patients.