The CXCR4 antagonist balixafortide plus eribulin achieves responses in metastatic breast cancer.
Major finding: The CXCR4 antagonist balixafortide plus eribulin achieves responses in metastatic breast cancer.
Clinical relevance: Adverse events were consistent with single-agent therapies, and no dose-limiting toxicities occurred.
Impact: Balixafortide plus eribulin warrants further investigation for treatment of HER2− breast cancer.
C-X-C chemokine receptor type 4 (CXCR4) is primarily expressed by hematopoietic stem cells and immune cells, but is also overexpressed in many tumor cell types including primary and metastatic breast cancer. CXCR4 is bound by the ligand SDF-1 and promotes tumor immune evasion and creates a favorable microenvironment for metastatic seeding. In preclinical studies, a CXCR4 antagonist enhanced the efficacy of eribulin chemotherapy in mouse models of triple-negative breast cancer. Thus, Pernas and colleagues evaluated the safety and efficacy of the potent, selective CXCR4 antagonist balixafortide plus eribulin in a phase I dose-escalation study in 56 patients with relapsed HER2-negative metastatic breast cancer, including an expanded cohort of 24 patients at the highest dose of balixafortide. The primary endpoints were dose-limiting toxicities and adverse events, the establishment of a maximum tolerated or recommended phase II dose, and pharmacokinetic parameters. Secondary objectives included progression-free and overall survival, and the proportion of patients achieving an objective response. No dose-limiting toxicities were confirmed, and the safety and tolerability were similar to what had previously been reported with eribulin or balixafortide monotherapy. Serious adverse events occurred in 21 of 56 (38%) patients, and 2 patients (4%) died while receiving study treatment, 1 from septic shock and 1 from pneumonia. Eribulin plus balixafortide exhibited preliminary antitumor activity. In the expanded cohort, receiving the highest dose of balixafortide, objective responses were observed in 9 of 24 (38%) evaluable patients, the median progression-free survival was 6.2 months and the estimated 1-year overall survival was 75%. Median overall survival was not reached. Taken together, the results of this phase I trial demonstrate that balixafortide plus eribulin has promising antitumor activity in patients with HER2-negative metastatic breast cancer and an acceptable tolerability, supporting further investigation in randomized trials.
Pernas S, Martin M, Kaufman PA, Gil-Martin M, Pardo PG, Lopez-Tarruella S, et al. Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial. Lancet Oncol 2018 Apr 26 [Epub ahead of print].
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