Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer

Jin Sun Lee, Susan E Yost, Suzette Blanchard, Daniel Schmolze, Hongwei Holly Yin, Raju Pillai, Kim Robinson, Aileen Tang, Norma Martinez, Jana Portnow, Wei Wen, John H Yim, Heather Ann Brauer, Yuqi Ren, Thehang Luu, Joanne Mortimer, Yuan Yuan, Jin Sun Lee, Susan E Yost, Suzette Blanchard, Daniel Schmolze, Hongwei Holly Yin, Raju Pillai, Kim Robinson, Aileen Tang, Norma Martinez, Jana Portnow, Wei Wen, John H Yim, Heather Ann Brauer, Yuqi Ren, Thehang Luu, Joanne Mortimer, Yuan Yuan

Abstract

Background: Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC.

Methods: The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks).

Results: Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]).

Conclusion: Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle.

Trial registration: ClinicalTrials.gov, NCT02120469. Registered 18 April 2014.

Keywords: Eribulin; Everolimus; Metastatic TNBC; Phase I trial.

Conflict of interest statement

Dr. Yuan has contracted research sponsored by Merck, Eisai, Novartis, Puma, Genentech, and Pfizer; is a consultant for Puma; and is on the Speakers Bureau for Eisai. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Patient accrual and correlative analysis summary. A total of 27 patients were accrued and received treatment on the study. Two of the patients’ on-treatment biopsy revealed HER2+ FISH-amplified tumor, and study treatment was terminated (patients were excluded from the efficacy analysis but included in the toxicity analysis). mRNA profiling was performed for 20 patients with NanoString PanCancer Pathways analysis and 11 patients for BC360™. FoundationOne ® genomic mutation profiles were available for 9 patients
Fig. 2
Fig. 2
Summary of toxicities. a Hematological toxicities: 12/27 (44%) had ≥ grade 3 hematological toxicity, including neutropenia (n = 10), lymphopenia (n = 6), and leukopenia (n = 7). b Non-hematologic toxicities: 9/27 (33%) had grade 3 non-hematological toxicity, including oral mucositis (n = 3), hyperglycemia (n = 3), and fatigue (n = 5). The counts of maximum ≥ grade 2 for each participant was listed for each event type (either ≥ grade 3 toxicity, or 2 participants experienced a grade 2 toxicity)
Fig. 3
Fig. 3
Kaplan-Meier survival analysis. a Median PFS was 2.6 months (95% CI [2.1, 4.0]). b Median OS was 8.3 months (95% CI [5.5, undefined])
Fig. 4
Fig. 4
NanoString PanCancer Pathways® analysis (n = 20). a Volcano plot showing differentially expressed genes with linear fold change > 2 and p < 0.05 comparing SD+PD and PR. b Decreased CDKN2A expression (p = 0.02) in responders. c Increased CALML5 expression (p = 0.01) in responders

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