Continued HER-2 Blockade Best For Metastatic Breast Cancer After Trastuzumab Progression

Trastuzumab-based treatment better than an afatinib-based regimen for trastuzumab-resistant metastatic breast cancer

medwireNews: Afatinib plus vinorelbine does not offer better progression-free survival (PFS) than trastuzumab plus vinorelbine for metastatic breast cancer patients who have already progressed while using trastuzumab, LUX-Breast 1 trial findings indicate.

Recruitment to the open-label, phase III trial was halted after the benefit–risk assessment found the afatinib arm of the trial to be unfavourable, with comparable PFS to the trastuzumab combination but a higher rate of adverse events (AEs).

“Trastuzumab-based therapy remains the treatment of choice in patients with HER2-positive metastatic breast cancer progressing on or after trastuzumab”, say Binghe Xu, from the Chinese Academy of Medical Sciences in Beijing, China, and fellow investigators in The Lancet Oncology.

“These results also provide new insights into potential mechanisms of resistance to trastuzumab”, they write, adding that the definition of trastuzumab resistance “remains challenging”, with the possibility of patients retaining sensitivity to the drug despite refractory disease having “implications for future studies in this area”.

The 339 patients assigned to receive the afatinib 40 mg/day plus vinorelbine 25 mg/m2 per week achieved a median PFS of 5.5 months compared with 5.6 months for 169 patients given a 4 mg/kg loading dose of trastuzumab followed by a dose of 2 mg/kg per week plus vinorelbine.

The epidermal growth factor receptor–tyrosine kinase inhibitor (TKI) and HER2/neu receptor inhibitor treatment groups also had comparable outcomes in terms of objective response rate (46 and 47%, respectively ) and median duration of response (3.7 and 3.8 months).

However, patients given afatinib plus vinorelbine had a higher rate of drug-related AEs than the trastuzumab plus vinorelbine group (98 vs 93%), and were more likely to experience AEs that led to dose reduction (55 vs 3%) or discontinuation (15 vs 7%).

The most common grade 3 or more severe AEs in the afatinib and trastuzumab treatment groups were neutropenia (56 vs 60%), leukopenia (19 vs 21%) and diarrhoea (18 vs 0%). Serious AEs occurred in 36% and 26% of patients, respectively, and three patients in the afatinib group died from treatment-related AEs.

Ian Krop, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, writes in an accompanying comment that trastuzumab’s superiority to TKI therapy in LUX-Breast 1 and other trials may be due to its immunomodulatory effects.

The “consistently negative results” for TKIs versus trastuzumab in metastatic breast cancer “strongly suggest that further attempts to improve outcomes by substituting a [TKI] for trastuzumab are unlikely to be successful”, he believes.

Ian Krop therefore recommends that research should focus on the use of TKIs with trastuzumab or other agents, or in “niche” indications.

“In addition, a better understanding of why trastuzumab repeatedly outperforms even the most potent [TKIs] might provide important insights into the biology and resistance mechanisms of HER2-positive breast cancer”, he concludes.


Harbeck N, Huang C-S, Hurvitz S, et al. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial. Lancet Oncol 2016; Advance online publication 25 January. DOI:

Krop IE. Lessons from breast cancer trials of HER2-kinase inhibitors. Lancet Oncol 2016; Advance online publication 25 January. DOI:

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