Breast Cancer Coverage from Every Angle

(UPDATE) Neratinib in Breast Cancer

Updated: Friday, February 11, 2022
Posted: Friday, January 26, 2018

Commentary by Breast Cancer Site Editor for JNCCN 360


Director, Clinical Network; Chief, Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago

Neratinib is an agent with potential application in both early-stage and advanced HER2-positive breast cancer. An early concern about the use of neratinib had been the associated prohibitive gastrointestinal symptoms, particularly diarrhea. With more experience, practical strategies are now routinely utilized from the outset, which significantly mitigate the frequency of high-grade diarrhea and make the drug more tolerable. Nevertheless, for most oncologists, the use of neratinib remains relatively limited. With the recent approval of new anti-HER2 agents, including tucatinib and fam-trastuzumab deruxtecan-nxki, in the advanced disease setting, consideration for the use of neratinib has moved to later lines of therapy. In the early-stage breast cancer setting, the use of neratinib has largely been considered for select, high-risk patients after standard, adjuvant HER2-directed treatment, particularly for those with node-positive, hormone receptor–positive disease and for those with residual disease after neoadjuvant HER2-directed therapy.


Dr. Gradishar has served on a scientific advisory board or as a consultant or expert witness for Genentech, AstraZeneca, Gilead, Daiichi Sankyo, and MacroGenics.


The use of neratinib for the treatment of breast cancer has increased since its 2017 approval for extended adjuvant treatment of adults with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer following adjuvant trastuzumab-based therapy.1

Neratinib has now been approved in the advanced or metastatic breast cancer setting, based on results from the phase III NALA trial.2 On February 25, 2020, the U.S. Food and Drug Administration (FDA) approved neratinib in combination with capecitabine for adults with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2–based regimens in the metastatic setting.3

Important Clinical Trial Updates

The NALA trial randomly assigned patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens to either neratinib plus capecitabine or lapatinib plus capecitabine. Results showed significantly prolonged progression-free survival with the neratinib combination, leading to the FDA approval of the drug combination in this setting. However, the study showed no significant improvement in the co-primary endpoint of overall survival; a numeric benefit in overall survival was observed (192 vs. 218 deaths). Additionally, no new safety signals were noted with the combination of neratinib/capecitabine.

According to the investigators: “NALA is the first study to demonstrate superiority of one HER2-directed tyrosine kinase inhibitor over another in metastatic breast cancer and provides evidence for the efficacy and tolerability of [neratinib plus capecitabine] in this setting.”

The large phase III ExteNET trial assessed whether neratinib would be of value in the adjuvant setting for patients with hormone receptor (HR)-positive, HER2-positive early breast cancer.4 In the double-blind trial, nearly 3,000 patients were randomly assigned to receive either oral neratinib or placebo for 1 year or until disease recurrence, new breast cancer, or intolerable toxicity.

Final efficacy results from the trial, reported at 5 years of follow-up, demonstrated that 1 year of extended adjuvant therapy with neratinib administered after chemotherapy and trastuzumab significantly reduced the proportion of clinically relevant breast cancer relapses (ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast), without increasing the risk of long-term toxicity.

Neratinib also significantly improved invasive disease–free survival in the HER2-positive/HR-positive/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment.5

Although the numbers did not reach statistical significance, numerical improvements in central nervous system events and overall survival in the ExteNET trial were observed and were consistent with invasive disease–free survival benefits. According to the investigators, these improvements suggest long-term benefit with neratinib in this population.

After Disease Progression on Dual-Antibody Therapy

Patients with HER2-positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab, limiting their treatment options. However, a phase Ib/II FB-10 clinical trial of neratinib given in combination with the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) after disease progression (in patients with metastatic disease) on trastuzumab, pertuzumab, and a taxane demonstrated an objective response rate of 56% in 16 evaluable patients.6

A total of three patients had a complete response lasting 17.1 months, 11.9 months, and more than 12 months; six patients had a partial response; three patients had stable disease; and four patients had progressive disease. The most frequently observed grade 3 adverse events were diarrhea, nausea, thrombocytopenia, and hypertension.

Based on these findings, the investigators recommended a phase II dose of T-DM1 at 3.6 mg/kg and neratinib at 160 mg/day for this combination; they maintain that these data provide support for an ongoing phase II study to better define the activity of this regimen.

Treating Resistant ER-Positive Metastatic Disease

Resistant estrogen receptor (ER)-positive metastatic breast cancer is a common cause of breast cancer death, because patients eventually develop resistance to ER-targeted therapies and stop responding to treatment.

Based on data presented at a media preview for the 2018 American Association for Cancer Research (AACR) Annual Meeting,7 acquired mutations in HER2 were found to confer resistance to hormone therapy in some patients with ER-positive metastatic breast cancer. However, that resistance may be reversed by dual treatment with neratinib and the hormone therapy fulvestrant. According to the investigators, this dual treatment may be an effective therapeutic strategy for patients with breast cancer who are resistant to ER-directed therapies with acquired HER2 mutations.

Triplet Therapy With Neratinib

In the SUMMIT study, a phase II basket trial of neratinib in HER2-mutant solid tumors, the combination of neratinib, trastuzumab, and fulvestrant demonstrated encouraging clinical activity in patients with heavily pretreated HER2-mutant, HR-positive, HER2-nonamplified metastatic breast cancer, including in patients who had previously received either fulvestrant and/or CDK4/6 inhibitor–based therapies ( identifier NCT01953926). 

Although the rate of grade 3 diarrhea was higher than that observed with single-agent neratinib, it was manageable with loperamide prophylaxis, and no patients discontinued study treatment due to diarrhea.

As of December 2020, the SUMMIT study was amended to evaluate neratinib, trastuzumab, and fulvestrant versus trastuzumab plus fulvestrant versus fulvestrant alone (1:1:1 randomization) and continues to enroll patients. Patients who receive single-agent fulvestrant or fulvestrant plus trastuzumab are eligible to cross over to triplet therapy upon disease progression.

Neratinib Active in Patients With Brain Metastases

Evidence-based treatments for patients with metastatic HER2-positive breast cancer and brain metastases are limited, but a phase II trial showed that neratinib plus capecitabine was active in this refractory population.8 Diarrhea was the most common grade 3 toxicity, so efforts should be taken to minimize diarrhea and optimize tolerance to this drug combination.

According to the research team, these findings contribute additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy.



  1. Novel Drug Approvals for 2017. Available at Accessed December 2, 2021.
  2. Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine vs lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Phase III NALA Trial. J Clin Oncol 2020; 38:3138–3149.
  3. FDA approves neratinib for metastatic HER2-positive breast cancer. Available at Accessed December 2, 2021.
  4. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1688–1700.
  5. Chan A, Moy B, Mansi J, et al. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the Phase III ExteNET trial. Clin Breast Cancer 2021;21:80–91.
  6. Abraham J, Montero AJ, Jankowitz RC, et al. Safety and efficacy of T-DM1 plus neratinib in patients with metastatic HER2-positive breast cancer: NSABP Foundation Trial FB-10. J Clin Oncol 2019;37:2601–2609.
  7. American Association for Cancer Research (AACR) 2018 Annual Meeting Media Preview. Available at Accessed January 31, 2022.
  8. Freedman RA, Gelman RS, Anders CK, et al. TBCRC 022: A phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol 2019;37:1081–1089.

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