Negative Results For Afatinib Regimens in Breast Cancer CNS Metastases Patients

Afatinib regimens fail to provide benefit over investigator’s choice of treatment for patients with human epidermal growth factor receptor 2-positive breast cancer with central nervous system metastases

medwireNews: Negative LUX-Breast 3 trial findings in patients with progressive brain metastases have led to the end of afatinib development as a treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer.

“Patient benefit with afatinib-containing treatments was not different from that in patients given investigator's choice of treatments; however, adverse events were frequent and afatinib-containing treatments seemed to be less well tolerated”, say the study investigators.

The research, published in The Lancet Oncology, focused on 121 patients with HER2-overexpressing breast cancer and central nervous system (CNS) recurrence or progression despite receiving trastuzumab and/or lapatinib.

The primary endpoint of patient benefit at 12 weeks was defined as no CNS or extra-CNS disease progression, no worsening of tumour-related neurological signs and symptoms, or need for an increase in steroid dosage.

This was achieved by 30.0% of the 40 patients given afatinib alone, 34.2% of the 38 patients given afatinib plus vinorelbine, and 41.9% of the 43 patients given the investigator’s choice of any medical treatment approved for advanced or metastatic breast cancer.

And there was no significant difference in overall survival or progression-free survival between the treatment groups, report Javier Cortés, from Vall d’Hebron Institute of Oncology in Barcelona, Spain, and co-authors.

Serious treatment-related adverse events occurred in 13% of afatinib-treated patients, 30% of those treated with afatinib plus vinorelbine, and 5% of those given their investigator’s choice of treatment.

Dose reduction because of adverse events was recorded for 43%, 43% and 7% of patients, respectively, with diarrhoea the most common side effect leading to dose reduction, affecting 23%, 27% and 2%, respectively.

“Overall, no unexpected adverse events were noted and the adverse events that did occur were generally manageable; however, the investigator's choice regimens seemed to be better tolerated, especially when compared with afatinib plus vinorelbine”, the team concludes.

Despite the negative result, Nancy Lin, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, says that “this well-designed study provides important lessons for drug development and clinical care.”

She notes in an associated comment that the median overall survival of patients in the afatinib and investigator’s choice group was about 1 year and 14% of the latter group achieved an objective response in the CNS that was sustained for almost 200 days.

“Together with data from other studies, these results support the practice of treating patients with systemic agents as an alternative to repeated courses of radiation”, writes Nancy Lin.

Furthermore, she believes that the “results of LUX-Breast 3 reinforce the idea that extracranial drug activity cannot merely be extrapolated to the brain”.

The commentator concludes that “[i]n view of the high prevalence of CNS metastases in patients with advanced HER2-positive breast cancer, assessment of CNS activity should not be an afterthought—our patients deserve better.”


Cortés J, Dieras V, Ro J, et al. Afatinib alone or afatinib plus vinorelbine versus investigator’s choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial. Lancet Oncol 2015; Advance online publication 16 November. DOI:

Lin NU. Better treatments needed for breast cancer brain metastases. Lancet Oncol 2015; Advance online publication 16 November. DOI:

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