NCCN Guidelines Now Include Neratinib For Metastatic Breast Cancer


The National Comprehensive Cancer Network has updated their guidelines to include neratinib for patients with HER2-negative metastatic breast cancer.

The National Comprehensive Cancer Network (NCCN) has updated its guidelines for metastatic breast cancer treatment. The new guidelines now advise providers to consider neratinib for those with HER2-negative metastatic breast cancer, regardless of estrogen receptor (ER) status, with activating mutations in the HER2 gene as detected by next-generation sequencing of tumor tissue or circulating tumor DNA.1

Neratinib is recommended with or without fulvestrant (Faslodex), and with or without fulvestrant/trastuzumab (Herceptin). The NCCN designated the tyrosine kinase inhibitor (TKI) as useful in certain circumstances in the ER-negative population and useful in certain circumstances in patients with ER-positive/HER2-negative disease who have already received a CDK4/6 inhibitor.

The guidelines also state that olaparib (Lynparza) is useful in certain circumstances for patients with somatic BRCA1/2 mutations or germline PALB2 alterations. Both recommendations received a 2B grade, which means that there is NCCN consensus that the agent is appropriate based on “lower level” evidence.

“We are pleased with the additional inclusion of neratinib in the NCCN Guidelines for Breast Cancer for patients with HER2 activating mutations,” Alan H. Auerbach, president and chief executive officer of Puma Biotechnology, said in a news release.2 “Physicians use the NCCN Guidelines as the standard resource for determining the best course of treatment for patients. We believe the updated NCCN guidelines will increase awareness, which will help assist patients, their caregivers and their healthcare providers in making informed decisions while treating this significant unmet need in advanced breast cancer.”

The NCCN based its decision on data from the phase 2 SUMMIT (NCT01953926) and MutHER trials (NCT01670877).

In data from SUMMIT presented at the 2022 ASCO Annual Meeting, which enrolled patients with hormone receptor (HR)–positive, HER2-mutated metastatic breast cancer who had previously received CDK4/6 inhibitors (n = 45), neratinib plus fulvestrant and trastuzumab had an objective response rate of 38%, including 1 complete response (CR; 2%) and 16 partial responses (PR; 36%). The clinical benefit rate was 47% (95% CI, 32%-62%). The median duration of response was 14.4 months (95% CI, 6.4-not evaluable [NE]) with a median progression-free survival (PFS) of 8.2 months (95% CI, 4.2-15.1).3

In MutHER, 40 patients with ER-positive/HER2-mutated metastatic breast cancer received neratinib plus fulvestrant. The median age was 63 years and patients had a median of 3 prior lines of therapy in the metastatic setting.4

The median progression-free survival was 24.0 weeks (95% CI, 15.7-31.0). Investigators observed 3 partial responses and 1 case of stable disease at progression with the addition of trastuzumab for 24 weeks or more.

The FDA first approved neratinib in 2017 as extended adjuvant treatment for patients with early-stage, HER2-positive breast cancer based on results from the phase 3 ExteNET trial (NCT00878709).5 The 5-year invasive disease-free survival (IDFS) rate with neratinib was 90.2% (95% CI, 88.3%-91.8%) compared with 87.7% (95% CI, 85.7%-89.4%) with placebo. After a median follow-up of 5.2 years (interquartile range, 2.1-5.3), patients in the neratinib group had 116 IDFS events compared with 163 for those in the placebo group (HR, 0.73; 95% CI, 0.57-0.92; P = .0083).6


  1. NCCN Clinical Practice Guidelines in Oncology. January 27, 2023. Accessed February 1, 2023.
  2. Puma Biotechnology’s NERLYNX® included in NCCN Clinical Practice Guidelines for the treatment of breast cancer with a HER2 mutation. News release. Puma Biotechnology. February 1, 2023. Accessed February 1, 2023.
  3. Jhaveri KL, Goldman JW, Hurvitz SA, et al. Neratinib plus fulvestrant plus trastzuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): outcomes and biomarker analysis from the SUMMIT trial. J Clin Oncol. 2022;40(suppl 16):1028. doi:10.1200/JCO.2022.40.16_suppl.1028
  4. Ma CX, Luo J, Freedman RA, et al. The phase II MutHER study of neratinib alone and in combination with fulvestrant in HER2-mutated, non-amplified metastatic breast cancer. Clin Cancer Res. 2022;28(7):1258-1267. doi:10.1158/1078-0432.CCR-21-3418
  5. FDA approves new treatment to reduce the risk of breast cancer returning. News release. FDA. July 17, 2017. Accessed February 1, 2023.
  6. 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(12):1688-1700. doi:10.1016/S1470-2045(17)30717-9

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