Neratinib in Previously Treated HER2-Positive Metastatic Breast Cancer: Point of View From the NALA Trial

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Kimberley T. Lee, MD, MHS

Kimberley T. Lee, MD, MHS

Cesar A. Santa-Maria, MD, MSCI

Cesar A. Santa-Maria, MD, MSCI

Neratinib is an oral pan-HER tyrosine kinase inhibitor that is approved by the U.S. Food and Drug Administration (FDA) for two indications. The first is as adjuvant treatment of early-stage HER2-positive breast cancer following adjuvant trastuzumab therapy. The second is in combination with capecitabine for the treatment of HER2-positive advanced or metastatic breast cancer in the third-line setting or later. The latter approval was based on findings from the randomized, controlled, phase III NALA trial, reported in the Journal of Clinical Oncology by Saura et al1 and reviewed in this issue of The ASCO Post. NALA compared neratinib and capecitabine against lapatinib and capecitabine in patients with HER2-positive metastatic breast cancer. Notably, NALA enrolled patients with asymptomatic or stable brain metastases, treated or untreated.

Tyrosine Kinase Inhibitors: Comparing Results in the Metastatic Setting

There are two other anti-HER2 tyrosine kinase inhibitors currently approved by the FDA for use in the metastatic setting, and all demonstrated improvements in progression-free survival over comparator treatments. Lapatinib plus capecitabine demonstrated an approximately 1.96-month improvement in the median time to disease progression compared with capecitabine (hazard ratio [HR] = 0.57, 95% confidence interval [CI] = 0.43–0.77).2 NALA demonstrated a 2.2-month improvement in mean progression-free survival in favor of neratinib and capecitabine compared with lapatinib and capecitabine.

Finally, HER2CLIMB showed a 2.2-month median improvement in progression-free survival (HR = 0.54, 95% CI = 0.42–0.71) with tucatinib, trastuzumab, and capecitabine compared with trastuzumab and capecitabine.3 Tucatinib in combination with trastuzumab and capecitabine is the only tyrosine kinase inhibitor to date to demonstrate an overall survival benefit, with a 4.5-month improvement in median overall survival (HR = 0.66, 95% CI = 0.50–0.87). However, it is important to note that HER2CLIMB did not include a tyrosine kinase inhibitor control group.

Although neratinib plus capecitabine has been shown to be superior to lapatinib plus capecitabine, the question remains as to where neratinib fits in the HER2-positive metastatic breast cancer treatment paradigm in relation to tucatinib. There are no direct comparison trials of neratinib combination therapy vs tucatinib combination therapy, so the relative efficacy of these two drugs remains unknown. Furthermore, the efficacy of a newer-generation HER2 tyrosine kinase inhibitor after any previous tyrosine kinase inhibitor is unknown.

Clinical Decision-Making: Factors to Consider

Given such limitations of data, side-effect profiles may be considered in clinical decision-making. In HER2CLIMB, 12.5% of patients experienced grade 3 or 4 diarrhea, and prophylactic antidiarrheals were not required. This is in contrast to NALA, where grade 3 or 4 diarrhea occurred in 24% of patients in the neratinib arm, even with antidiarrheal prophylaxis in the first cycle.

Prior treatment is another factor to consider. The current standard of care for HER2-positive metastatic breast cancer includes pertuzumab, trastuzumab, and taxane in the first-line setting and trastuzumab emtansine (T-DM1) in the second-line setting. In NALA, just 33% of patients had prior treatment with pertuzumab and T-DM1, whereas in HER2CLIMB, which of course was designed later, 100% of patients included in the endpoint analysis received prior pertuzumab and T-DM1. Furthermore, although the control treatment used in HER2CLIMB is likely inferior to what was used in NALA, tucatinib is the only HER2-targted tyrosine kinase inhibitor with a proven overall survival benefit.

Perhaps one situation in which neratinib may play a role is in patients with cardiomyopathy. Tucatinib was evaluated with trastuzumab, and even though patients were previously treated with trastuzumab, the efficacy of tucatinib with capecitabine compared with capecitabine alone or with another tyrosine kinase inhibitor is unknown.

Future Directions and Conclusions

The neratinib group had a lower cumulative incidence of requiring interventions for central nervous system (CNS) disease compared with the lapatinib group; thus, neratinib may play a role in the treatment of CNS disease. The TBCRC 022 study ( identifier NCT01494662) is a phase II trial of neratinib and capecitabine for treatment of HER2-positive metastatic breast cancer with progressive disease in the brain after prior CNS-directed therapy.4 Initial data found a CNS overall response rate of 49% in patients without prior exposure to lapatinib and 33% in those with prior lapatinib use, with a median progression-free survival of 13.3 and 15.1 months, respectively; the study continues to accrue patients.

In summary, NALA demonstrates superior progression-free survival with neratinib combination therapy compared with lapatinib combination therapy. However, the clinical utility of neratinib may be limited with the recent approval of tucatinib, given the overall survival benefit and lower toxicity associated with the tucatinib regimen. 

Dr. Lee is employed by Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins University Bloomberg School of Public Health. Dr. Santa-Maria is employed by Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.

DISCLOSURE: Dr. Lee has received institutional research funding from Pfizer. Dr. Santa-Maria has served as a consultant or advisor to Polyphor, Genomic Health, Halozyme, Bristol Myers Squibb, Athenex, and Seattle Genetics; and has received institutional research funding from Pfizer, Astrazeneca, Bristol Myers Squibb, and Tesaro/GSK.


1. 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. July 17, 2020 (early release online).

2. Geyer CE, Forster JF, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006.

3. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382:597-609, 2019.

4. 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 37:1081-1089, 2019.

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