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Puma should invest in developing an escalating-dose schedule for neratinib (Nerlynx). If one plans on giving a drug for a year, and starts after finishing a year of effective adjuvant therapy, there is no hurry to begin at full, intolerable doses. Starting at a lower dose and escalating slowly as tolerated seems a less dramatic and more humane way to begin treatment of women without symptoms, only a small fraction of whom will benefit from neratinib. One needs to remember that 84% of node-positive women given ACTH (doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab [Herceptin]) in the NCCTG N9831/NSABP B-31 trials were alive 10 years after diagnosis without neratinib!1

Puma needs to confirm the benefit of extended adjuvant neratinib in patients with estrogen receptor–positive, node-positive patients (those who seemed to benefit to some extent in ExteNET) given a tolerable schedule. It seems reasonable to investigate the activity of neratinib together with trastuzumab, pertuzumab (Perjeta), and chemotherapy, alone or concurrently, both for metastatic and for adjuvant treatment of HER2-positive breast cancer. 

The Systemic Problem

Neratinib has been developed as a refugee drug, repeatedly starved of funding and abandoned by large drug companies. Before physicians advocate its use to patients, we should demand good data supporting clinically significant benefits of tolerable regimens in well-defined target patient populations. This means a benefit in overall survival, or at least distant disease–free survival, in HER2-positive, estrogen receptor–positive, node-positive resected breast cancer. 

Puma, or whatever larger company purchases Puma, may decide its stockholders are not well served by starting an expensive, long-term study whose outcome is uncertain, especially with the “patent-expiration clock” ticking. Instead, Puma may decide to invest in an attractive sales force, present its weak data in a forceful way, and offer heavy discounts that yield profits for insurance companies and pharmacy benefit managers that can pass inflated costs through to the U.S. Treasury or other entities like unions and self-insured employers. This calculation could be changed, and we could get the studies we need to care for our patients well, if the ultimate payers refused to pay prices like $10,400 per month unless and until solid evidence of long-term benefit is presented. 

It would make sense to offer drug companies patent extensions and high-dollar payment rates in return for the support and conduct of needed studies with proper endpoints. Alas, it remains uncertain whether the United States will ever have a Congress not dependent on campaign contributions by drug and insurance companies. Such a Congress could legislate to limit payments for weak drugs and raise payments for good ones. ■

DISCLOSURE: Dr. Vogl reported no conflicts of interest.


1. Perez EA, Romond EH, Suman VJ, et al: Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: Planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 32:3744-3752, 2014.

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Neratinib Is Approved: Should We Reject It Anyway?

Steven Vogl, MD

Steven Vogl, MD

The U.S. Food and Drug Administration (FDA) approved 1 year of extended adjuvant neratinib (Nerlynx) after chemotherapy and a year of trastuzumab (Herceptin) for HER2-positive breast cancer this summer on the basis of the ExteNET trial. Many were surprised at the approval,...




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