Neratinib Equals Trastuzumab PFS For Recurrent, Metastatic ERBB2-Positive Breast Cancer

Progression-free survival is comparable with first-line neratinib- and trastuzumab-based chemotherapy regimens for recurrent and metastatic ERBB2-positive breast cancer

medwireNews: The NEfERT-T trial has failed to show superior progression-free survival (PFS) with neratinib plus paclitaxel versus trastuzumab plus paclitaxel in women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer.

The primary endpoint of PFS was a median of 12.9 months for both the 242 patients given neratinib 240 mg/day plus paclitaxel and the 237 patients given trastuzumab plus paclitaxel, say Ahmad Awada, from Jules Bordet Institute in Brussels, Belgium, and co-investigators.

However, the team notes that symptomatic or progressive central nervous system (CNS) recurrence occurred in significantly fewer patients given the irreversible pan-ERBB tyrosine kinase inhibitor (TKI) neratinib than those given the ERBB receptor inhibitor trastuzumab.

This secondary endpoint was reported for 8.3% and 17.3% of the treatment groups, respectively, with a relative risk of 0.48. And the estimated 2-year incidence of CNS recurrence was 16.3% with neratinib versus 31.2% with trastuzumab, giving a hazard ratio of 0.45.

The authors acknowledge that patients were not stratified by CNS disease at baseline, resulting in CNS metastases affecting 2.5% of neratinib- versus 5.1% of trastuzumab-treated patients.

Nevertheless, after adjusting for this imbalance, neratinib was significantly associated with both a lower rate of CNS progression and a longer time to CNS progression in patients with and without brain metastases at time of trial enrolment.

As previously reported, diarrhoea was the most common side effect associated with neratinib, affecting 92.5% of patients versus 33.3% of those given trastuzumab, prompting the authors to say that “this drug regimen requires aggressive primary prophylaxis of this adverse effect for the first cycle of therapy.”

Grade 3 diarrhoea symptoms occurred in 30.4% versus 3.8% of the neratinib and trastuzumab groups, respectively, with grade 3 neutropenia reported in 11.3% and 12.4%, and leukopenia in 6.7% and 10.3%.

Writing in an accompanying editorial, Mark Pegram, from Stanford Women’s Cancer Center in California, USA, says that “because of the devastating consequences of CNS metastasis, the results observed for reduction in CNS events are judged to be compelling and are not without historical precedent with other EGFR/ERBB2 TKIs.”

He encourages further investigation of neratinib, in combination with diarrhoeal prophylaxis, as well as other ERBB2 TKIs, and highlights the need to identify biomarkers for CNS metastases risk in this patient population.

“Only through focused clinical and/or translational research will important advances be made that exploit new insights into the tumor biology of ERBB2-positive brain metastasis”, Mark Pegram concludes.


Awada A, Colomer R, Inoue K, et al. Neritinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer. The NEfERT-T randomized clinical trial. JAMA Oncol 2016; Advance online publication 14 April. doi:10.1001/jamaoncol.2016.0237

Pegram M. Neratinib in ERBB2-positive brain metastases. JAMA Oncol 2016; Advance online publication 14 April. doi:10.1001/jamaoncol.2016.0238.

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