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Neratinib Improves PFS in HER2+ Metastatic Breast Cancer

Gina Columbus @ginacolumbusonc
Published: Tuesday, Dec 18, 2018

Alan H. Auerbach

Alan H. Auerbach

Neratinib (Nerlynx) led to a statistically significant improvement in centrally confirmed progression-free survival (PFS) compared with lapatinib (Tykerb) and capecitabine in patients with HER2-positive metastatic breast cancer who have failed 2 or more prior lines of HER2-directed therapy, according to topline findings of the phase III NALA trial (NCT01808573).1

Additionally, Puma Biotechnology, the manufacturer of the TKI, reported that neratinib and capecitabine also improved overall survival (OS), but it was not found to be statistically significant (P = .21). Full findings of the study will be presented at an upcoming medical meeting. Additionally, the data will be submitted to the FDA and European Medicines Agency (EMA), Puma Biotechnology noted in a press release.

"We are highly encouraged by these results from the NALA trial with the combination of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer who have failed 2 or more prior lines of HER2-directed treatments,” said Alan H. Auerbach, chief executive officer and president of Puma Biotechnology, in the press release. “We look forward to working with the regulatory authorities in the hope of bringing another potential treatment option to patients with HER2-positive metastatic breast cancer as soon as possible.”

In the international, multicenter, open-label, active-controlled, parallel design phase III NALA trial, 621 patients with HER2-positive metastatic breast cancer were randomized 1:1 to receive oral neratinib at 240 mg once daily plus capecitabine at 1500 mg/m2 daily in 2 doses or oral lapatinib at 1250 mg once daily combined with capecitabine at 2000 mg/m2 daily in 2 doses.

The co-primary endpoints of the trial were centrally confirmed PFS and OS; an alpha level of 1% was allocated to PFS and 4% allocated to OS. Secondary endpoints were investigator-assessed PFS, objective response rate, clinical benefit rate, duration of response, time to intervention for symptomatic metastatic central nervous system (CNS) disease, safety, and health outcome assessments.

The phase III trial design was agreed upon between Puma Biotechnology and the FDA under a Special Protocol Assessment, and between Puma and the EMA with scientific advice.

To be eligible for enrollment, adult patients with stage IV HER2-positive metastatic breast cancer had to have received ≥2 prior HER2-directed therapies. Those who previously received treatment with capecitabine, neratinib, lapatinib, or any other HER2-directed TKI were excluded.

For the primary analysis of centrally confirmed PFS, the improvement in centrally confirmed PFS was statistically significant with neratinib/capecitabine treatment (P = .0059) versus lapatinib/capecitabine.

For the secondary endpoint of time to intervention for symptomatic CNS disease, neratinib/capecitabine also showed an improvement versus lapatinib/capecitabine (P = .043).

Neratinib was initially approved by the FDA in July 2017 for the extended adjuvant treatment of patients with early-stage, HER2-positive breast cancer following postoperative trastuzumab (Herceptin). The approval was based on data from the phase III ExteNET trial and the phase II CONTROL trial. In the primary analysis of ExteNET, the invasive disease-free survival (iDFS) rate at 2 years was 94.2% with neratinib compared with 91.9% with placebo (stratified HR, 0.66; 95% CI, 0.49-0.90; stratified log-rank P-value [two-sided] =.008).2

The data showed that the iDFS benefit may vary based on hormone receptor (HR) status. Moreover, an exploratory subgroup analysis indicated that neratinib decreased the risk of recurrence by 51% (HR, 0.49; 95% CI, 0.31-0.75) in HR-positive patients versus 7% in HR-negative patients (HR, 0.93; 95% CI, 0.60-1.43).

Overall, diarrhea was the primary safety concern associated with neratinib, as 95% of patients in the ExteNET trial who received the TKI experienced this type of adverse event, including grade 3 diarrhea in 40% of patients. Moreover, diarrhea led to study discontinuation for 16.8% of patients.

However, data from the ongoing phase II CONTROL trial (NCT01008150) suggest that antidiarrheal prophylaxis can control the occurrence and severity of diarrhea among patients receiving neratinib. In data presented at the 2018 San Antonio Breast Cancer Symposium, adjuvant treatment with neratinib with or without anti-diarrheal prophylaxis was associated with small decreases in health-related quality of life (HRQoL).3 Additionally, aside from the Functional Assessment of Cancer Therapy–Breast (FACT-B), v4.0, the HRQoL changes did not reach clinically meaningful thresholds.

Results of the analysis demonstrated that, in both the EXTENT and CONTROL studies, FACT-B total score decreases were seen in early months followed by recovery towards baseline levels.


  1. Puma Biotechnology Announces Top Line Results of the Phase III NALA Trial of Neratinib in Patients with HER2-Positive Metastatic Breast Cancer. Puma BioTechnology. Published December 17, 2018." . Accessed December 17, 2018.
  2. Singh H, Walker AJ, Amiri-Kordestani L, et al. U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer. Clin Cancer Res. 2018;24(15):3486-3491. doi: 10.1158/1078-0432.CCR-17-3628.
  3. Delalogue S, Hurvitz S, Chan N, et al. The impact of neratinib with or without anti-diarrheal prophylaxis on health-related quality of life in HER2+ early-stage breast cancer: Analyses from the ExteNET and CONTROL trials. In: Proceedings from the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. Abstract P2-13-03.

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