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. 2018 Mar 8;9(7):1145-1151.
doi: 10.7150/jca.24035. eCollection 2018.

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

In Hae Park  1 , Sun-Young Kong  2 , Youngmee Kwon  1 , Min Kyeong Kim  3 , Sung Hoon Sim  1 , Jungnam Joo  4 , Keun Seok Lee  1
Affiliations

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

In Hae Park et al. J Cancer. .

Abstract

Background: 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. Methods: 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 PIK3CA (E542K, E545K, H1047R) in tumor tissues (n=14) and cell-free DNA (cfDNA) from blood samples (n=23) using droplet digital PCR. Results: In phase I (n=9), we found that the MTD of GPE was gemcitabine 800 mg/m2 and cisplatin 30 mg/m2 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. PIK3CA mutations were identified in 8 (57.1%) tumor samples and 17 (73.9%) cfDNA samples; there was no significant association between PIK3CA mutation status and response to GPE treatment. Conclusions: Although the majority of patients with metastatic TNBC demonstrated PIK3CA 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.

Keywords: PIK3CA mutation; Triple negative breast cancer; cell free DNA; mTOR inhibitor.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Study design
Figure 2
Figure 2
Survival analysis for all participants (phase I/II)
See this image and copyright information in PMC

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