FDA Approval Watch: First Extended Adjuvant Therapy for HER2-Positive Breast Cancer

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Approval Information

Brand Name: Nerlynx

Generic Name: Neratinib

Sponsor: Puma Biotechnology Inc. [1]

Date: July 17, 2017

Outcome: Approval for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer [2]. Adjuvant therapy is a form of therapy that is taken after an initial treatment to lower the risk of the cancer recurrence.

Mechanism of Action: Neratinib is a potent irreversible tyrosine kinase inhibitor (TKI) that blocks signal transduction through the epidermal growth factor receptors (EGFR), HER1, HER2 and HER4 [18].

Side Effects: Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, swollen and sore mouth (stomatitis), decreased appetite, muscle spasms, indigestion (dyspepsia), liver damage (AST or ALT enzyme increase), nail disorder, dry skin, abdominal swelling (distention), weight loss and urinary tract infection [2].

Chain of Command: Preclinical development and Phase I/II clinical trials at Wyeth, prior to the company’s acquisition by Pfizer for $68 billion in 2009 [3,4]. Pfizer initially financed the progression of neratinib through Phase III clinical trials, before selling the drug to Puma Biotechnology in 2011 [5,6].

Prevalence and Pathophysiology of HER2-positive Breast Cancer

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute (NCI) estimates approximately 252,710 women will be diagnosed with breast cancer this year and 40,610 will die of the disease [7]. According to the NCI and the American Society of Clinical Oncology (ASCO), approximately 15-20% of patients with breast cancer have tumors that are HER2-positive [2,8].

A HER2-positive cancer cell has approximately two million HER2 proteins on its surface, around 100 times more than a normal cell. This HER2 overexpression causes cells to grow and divide more rapidly. Pairing of HER proteins (also called dimerisation) is a vital step in the signalling pathway that leads to cancer cell growth. There are four proteins in the HER family (HER1, HER2, HER3, HER4), and HER2 has been found to pair with other HER family members, including other HER2 proteins. This act of pairing can send additional signals to encourage the cancer cell to grow and multiply [9,10].

Phase I/II Clinical Trial Outcomes [11,12]  

Evaluated the safety and efficacy of a daily 240 mg oral dose of neratinib in 127 women diagnosed with HER2-positive locally advanced or metastatic breast cancer (stage IIIB, IIIC or IV). Major efficacy outcomes include 16-week progression-free survival (PFS), median PFS, objective response rate, and clinical benefit rate.

Progression-free survival (PFS) is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse [13]. Objective response rate is the percentage of patients whose cancer shrinks or disappears after treatment [14]. Clinical benefit rate is the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents [15].

Patients were assigned to one of two study arms based on prior treatment with trastuzumab (Herceptin, Genentech), the standard of care for the treatment of advanced HER2-positive breast cancer:

  • Arm A (n=66): Women that had either (1) previously received at least 6 weeks of standard trastuzumab treatment or (2) had experienced disease progression during or following trastuzumab-containing adjuvant therapy.
  • Arm B (n=70): Women that have not received prior treatment with any HER2-targeted therapy, including trastuzumab.
Arm A Arm B
16-week PFS 60% 77%
Median PFS 23 weeks 40 weeks
Objective Response Rate 26% 56%
Clinical Benefit Rate 36% 68%

Phase III Clinical Trial Outcomes [16,17]

A multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment. Evaluated the safety and efficacy of a daily 240 mg oral dose of neratinib in 2,840 women early-stage HER2-positive breast cancer and within two years of completing adjuvant trastuzumab. The major efficacy outcome measures were invasive disease-free survival (iDFS) survival rate, and iDFS events.

Invasive disease-free survival (iDFS) survival rate is the time duration  (represented as a proportion of the 2 year, 28 day follow-up period) between the randomization date to the first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distant recurrence, or death from any cause. Invasive disease-free survival (iDFS) events are the number of patients who displayed occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distant recurrence, or death from any cause, within 2 year and 28 day follow-up period.

Patients were randomly assigned to one of two study arms:

  • Arm A (n=1420): Patients received placebo for one year.
  • Arm B (n=1420): Patients received neratinib for one year.
Arm A Arm B
2-year iDFS Survival Rate 91.9% 94.2%
2-year iDFS Events 109 70



  1. http://www.pumabiotechnology.com/
  2. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm567309.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery
  3. Gandhi, Leena, et al. “Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2–dependent and other solid tumors.” Journal of Clinical Oncology 32.2 (2013): 68-75.
  4. http://www.nytimes.com/2009/01/26/business/worldbusiness/26iht-drug.4.19689943.html
  5. http://www.genengnews.com/gen-news-highlights/puma-acquires-global-rights-to-pfizer-s-phase-iii-breast-cancer-drug-neratinib/81245787
  6. http://www.onclive.com/web-exclusives/extended-adjuvant-neratinib-improves-dfs-in-phase-iii-breast-cancer-study
  7. https://www.cancer.gov/types/common-cancers
  8. Wolff, Antonio C., et al. “Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.” Journal of clinical oncology 31.31 (2013): 3997-4013.
  9. Phillips, Gail D. Lewis, et al. “Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody–cytotoxic drug conjugate.” Cancer research 68.22 (2008): 9280-9290.
  10. http://www.roche.com/dam/jcr:2ac14009-bbe8-4991-a460-acfa600d7e2a/en/med-her2-cancer.pdf
  11. Swaby, R., et al. “Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: a phase I/II study.” Journal of Clinical Oncology 27.15_suppl (2009): 1004-1004.
  12. http://www.fiercebiotech.com/biotech/wyeth-announces-positive-data-from-phase-2-study-of-neratinib-advanced-her-2-positive
  13. https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=44782
  14. https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=43983
  15. Sznol, Mario. “Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype?.” (2010): 1340-1341.
  16. Chan, Arlene, et al. “Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.” The Lancet Oncology 17.3 (2016): 367-377.
  17. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm567259.htm
  18. http://app.quotemedia.com/data/downloadFiling?ref=10782143&type=HTML&symbol=PBYI&companyName=Puma+Biotechnology+Inc&formType=10-K&formDescription=Annual+report+with+a+comprehensive+overview+of+the+company&dateFiled=2016-02-29
  19. Image: http://photos.prnewswire.com/prnfull/20151222/317925LOGO

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