Neratinib plus capecitabine for the treatment of advanced HER2-positive breast cancer

ABSTRACT

Introduction

Several agents are being developed for advanced HER2-positive breast cancer, such as potent tyrosine kinase inhibitors (TKI) targeting ErbB family receptors, novel antibody-drug conjugates, higher affinity anti-HER2 antibodies, among others. Neratinib is an irreversible pan-HER (EGFR, ERBB2, and ERBB4) TKI being tested in early and advanced HER2-positive breast cancer. In the NALA trial, neratinib plus capecitabine led to increased PFS and time to intervention for central nervous system disease over the standard regimen of lapatinib plus capecitabine. The main adverse event in the neratinib arm was diarrhea, which mandates for prophylactic treatment with loperamide.

Areas covered

In this review, we analyze and discuss preclinical and clinical data with neratinib plus capecitabine. We summarize efficacy and safety results from phase I/II and III trials, and discuss this regimen within the landscape of treatment for patients with HER2-positive metastatic breast cancer progressing after two lines of HER2-directed treatment.

Expert opinion

Neratinib plus capecitabine is a valid treatment option for patients with advanced HER2-positive breast cancer, after progression to at least two anti-HER2-based regimens. Given the multiple options that are being developed in this context, efforts should be employed to establish strong predictive biomarkers of efficacy to each drug and combination.

KEYWORDS:

• HER2-positive metastatic breast cancer
• neratinib
• capecitabine
• CNS disease

Article highlights

• Neratinib is a potent, irreversible inhibitor of HER2, EGFR, and HER4.

• When compared to lapatinib plus capecitabine, neratinib plus capecitabine significantly improves PFS in patients with advanced HER2-positive breast cancer that had progressed to at least two prior anti-HER2 regimens.

• In the phase III NALA trial, mean PFS was 8.8 months for neratinib plus capecitabine and 6.6 months for lapatinib plus capecitabine (HR 0.76; 95% CI 0.63–0.93; stratified log-rank p=0.0059). Differences in OS were not statistically significant.

• The cumulative incidence of intervention to the CNS was lower in the neratinib plus capecitabine arm than in the lapatinib plus capecitabine arm (22.8% vs 29.2%, p=0.043).

• Despite the use of mandatory loperamide, the main adverse event of the combination is diarrhea. In NALA, incidence of diarrhea was 83.2%, being G3 in 24%. Of note, this did not translate in an increase in treatment discontinuation or changes in QoL scores.

• Other adverse events of neratinib plus capecitabine are palmar-plantar erythrodysesthesia (46%, grade 3/4 10%), nausea (4%, grade 3/4 53%), vomiting (46%, grade 3/4 4%), decrease appetite (35%, grade 3/4 3%), and fatigue (34%, grade 3/4 3%).

• Based on the results of the NALA trial, the combination of neratinib and capecitabine has been approved by the FDA in February 2020 and the file will be sent for EMA evaluation later this year.

• Given the multiple treatment options that are being developed for advanced HER2-positive breast cancer, efforts should be employed to establish strong predictive biomarkers of efficacy to the combination of neratinib plus capecitabine.

Declaration of interest

M Oliveira reports grants, personal fees and non-financial support from Roche, grants, and personal fees from Genentech, grants, and personal fees from GSK, grants, and personal fees from PUMA Biotechnology, grants, and personal fees from Astra Zeneca, grants, and personal fees from Seattle Genetics, grants from lmmunomedics, grants from Boehringer-lngelheim, non-financial support from Pierre-Fabre, non-financial support from Eisai, non-financial support from GP. Pharma, non-financial support from Gronenthal, grants, personal fees and non-financial support from Novartis, outside the submitted work. L Garrigos reports non-financial support from Roche. S Escriva-de-Romani reports grants, personal fees and non-financial support from Roche, personal fees and non-financial support from Pierre-Fabre, personal fees from Kyowa-Kirin, personal fees from Eisai, personal fees from Celgene, non-financial support from Daiichi-Sankyo, grants from Synthon. C Saura reports personal fees from Puma biotechnology, personal fees from Pfizer, personal fees from Roche, personal fees from Astra Zeneca, personal fees from Celgene, personal fees from Daiichi Sankyo, personal fees from Eisai, personal fees from Genomyc health, personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Synthon biopharmaceuticals, grants from Roche-Genentech, grants from Macrogenics, grants from Pfizer, grants from Piqur therapeutics, grants from Puma biotechnology, grants from Synthon biopharmaceuticals, grants from Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.