Updated NCCN Guidelines Now Include Neratinib for HER2+ Breast Cancer


The update is in agreement with the FDA approval of a labeling supplement in June 2021 to the United States Prescribing Information for neratinib in HER2-positive breast cancer.

Joyce A. O’Shaughnessy, MD

Joyce A. O’Shaughnessy, MD

Updates to the National Comprehensive Cancer Network (NCCN) guidelines now include 2 recommendations involving neratinib (Nerlynx) for the treatment of patients with HER2-positive breast cancer, according to a news release from Puma Biotechnology.1

The first update recommends neratinib for the adjuvant treatment of patients with HER2-positive breast cancer under the designation of Useful in Certain Circumstances. The guideline indicates that extended adjuvant neratinib is recommended for patients with hormone receptor (HR)–positive, HER2-positive disease who have a perceived high risk of disease recurrence.

The second guideline recommends a dose-escalation strategy with neratinib to improve tolerability when the agent is utilized in the adjuvant setting for patients with HER2-positive disease.

Notably, this update is in agreement with the FDA approval of a labeling supplement in June 2021 to the United States Prescribing Information for neratinib. The labeling update includes the dose-escalated use of the agent in patients with HER2-positive breast cancer, as examined in the phase 2 CONTROL trial (NCT02400476), and the new 133-count commercial Nerlynx SKU.2

“Oncologists should be aware of an important recent update to the NCCN guidelines that now include adjuvant neratinib to be used in certain circumstances, [including] high-risk HR-positive, HER2-positive, early-stage breast cancer patients,” Joyce A. O’Shaughnessy, MD, co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center and The US Oncology Network said in the news release.1

“These high-risk patients need access to every available treatment option proven to decrease their risk of recurrence, and the new NCCN guidelines update supports neratinib in this context,” O’Shaughnessy added.

Single-agent neratinib is associated with the following adverse events (AEs): diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, increased AST/ALT, nail disorder, dry skin, abdominal distention, epistaxis, decreased weight, and urinary tract infection.

Furthermore, patients who receive neratinib in combination with capecitabine have reported diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms.

Patients should not receive neratinib with proton pump inhibitors. Similarly, neratinib should be separated from antacids by at least 3 hours and should be separated from H2-receptor antagonists by at least 2 hours before or 10 hours after. Patients should not breastfeed while receiving this medication.

Neratinib has 2 FDA indications in breast cancer. The first is as a single agent for extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer following adjuvant trastuzumab (Herceptin)-based therapy. The second indication is in combination with capecitabine (Xeloda) for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.

The NCCN guideline updates are supported by findings from the pivotal phase 3 ExteNET trial (NCT00878709), which randomized 2840 women with early-stage HER2-positive breast cancer who had prior trastuzumab-based therapy to 1 year of neratinib given once daily at 240 mg (n = 1420) vs 1 year of placebo (n = 1420).3

In patients who completed prior trastuzumab-based therapy within 1 year prior to randomization, the results of the study demonstrated a 5.1% absolute benefit in invasive disease-free survival (iDFS) at 5 years with neratinib vs placebo, as well as a 42% reduction in the risk of disease recurrence. The 5-year iDFS rate was 90.8% (95% CI, 88.1%-93.0%) with neratinib vs 85.7% (95% CI, 82.6%-88.3%) with placebo (HR, 0.58; 95% CI, 0.41-0.82).

In the intention-to-treat population, the 2-year iDFS rate was 94.2% with neratinib vs 91.9% with placebo (HR, 0.66; 0.49-0.90; P = .008).4

Notably, neratinib demonstrated iDFS improvement vs placebo across several prespecified subgroups, including nodal status, hormone receptor status, and age at randomization.

Regarding safety, neratinib was not found to induce cardiac or serious pulmonary toxicity or increase a patient’s risk for secondary malignancy.

“The NCCN guidelines are utilized by many institutions, practices, and clinicians who treat [patients with] breast cancer. These updates help to increase the awareness of neratinib within the guidelines and should further support neratinib as an appropriate option to reduce the risk of recurrence for patients battling HER2-positive breast cancer,” Alan H. Auerbach, chief executive officer and president of Puma Biotechnology, concluded in the news release.1


  1. Puma Biotechnology’s NERLYNX included in two important NCCN clinical practice guideline updates for the treatment of breast cancer. News release. Puma Biotechnology, Inc. January 12, 2022. Accessed January 14, 2022. https://bit.ly/3K9CzzA
  2. FDA approves dose escalation label update for Puma Biotechnology’s NERLYNX (neratinib) in HER2-positive early stage and metastatic breast cancer. News release. Puma Biotechnology, Inc. July 1, 2021. Accessed January 14, 2022. https://bwnews.pr/3A0gn6a
  3. 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(1):80-91.e7. doi:10.1016/j.clbc.2020.09.014
  4. Puma Biotechnology. US Food and Drug Administration Oncologic Drugs Advisory Committee. Accessed January 17, 2021. https://www.fda.gov/media/105941/download

This article was originally published on OncLive as “NCCN Guidelines Include Neratinib-Based Recommendations for HER2+ Breast Cancer”

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