Neratinib (PB27) is an orally administered compound under development by Puma Biotechnology as a treatment for HER2-positive (HER2+) breast cancer, and which has shown promising activity in clinical trials.

Puma has applied to the U.S. Food and Drug Administration (FDA) for approval of the drug. An FDA advisory committee voted in late May in favor of approval, although a final decision has not yet been reached.

How neratinib works

Neratinib is an irreversible tyrosine kinase inhibitor (TKI), a small molecule that works by blocking signal transduction through the epidermal growth factor receptor HER2, among other receptors. HER2 has long been associated with some forms of breast cancer, including several aggressive types. The receptor has been widely studied because of its predictive and prognostic value in the formation of breast tumors.

Puma’s initial focus is on developing neratinib to treat HER2+ breast cancer or breast cancer with overexpression of the HER2 protein (produced by the HER2 gene) on its cells. Neratinib is designed to inhibit HER2 to prevent cancer cell proliferation and induce cell death.

Clinical trials of PB272 (neratinib)

A Phase 2 open-label clinical trial (NCT00300781) assessed the safety and benefits of neratinib administered as a single agent to 136 patients with HER2+ metastatic breast cancer. Some patients had received prior treatment with the FDA-approved cancer drug Herceptin (trastuzumab). Trial results found that neratinib was reasonably well-tolerated both by pre-treated patients and those never previously treated with Herceptin.

Early results of the ExteNET Phase 3 double-blind, placebo-controlled trial (NCT00878709) of neratinib in 2,840 patients with early stage HER2+ breast cancer — stage 2 or 3 cancers who had finished  chemotherapy and Herceptin-based adjuvant therapy prior to starting this study — showed that extending treatment with neratinib for one year significantly improved their disease-free survival (DFS) rates.

Diarrhea was the most common adverse effect seen in the ExteNET trial, with 95.4% of neratinib-treated patients experiencing it in some form (39.9% had severe diarrhea).

To investigate this, Puma is conducting an open-label Phase 2 CONTROL trial (NCT02400476) to characterize the incidence and severity of diarrhea after administration of antidiarrheal agents. Puma reported positive interim results from the trial at the 2017 American Association for Cancer Research Annual Meeting (AACR). The CONTROL study saw a significant reduction in the incidence of diarrhea and a reduction in the re-occurrence over a 12-month period.

Based on the results of these two studies, Puma Biotechnology announced in April that the FDA has accepted the company’s New Drug Application (NDA) for neratinib, the first step in securing approval for treatment. The Oncologic Drugs Advisory Committee (ODAC) – a panel of experts that evaluate data concerning the efficacy and safety of marketed and investigational products used in cancer treatment – met on May 24, 2017, to evaluate the treatment.

 The advisory committee voted to recommend approval of neratinib, with restrictions in place for who will receive the treatment. The panel believes the treatment should be restricted to patients who have received post-operative Herceptin within the past two years until further clinical trials have been completed.

The FDA is considering the panel’s recommendations in evaluating neratinib for possible approval.

Neratinib is also being investigated in clinical trials as a neoadjuvant therapy, or a first treatment given to shrink a tumor before a main treatment, for patients with HER2+ breast cancer, and as a treatment for patients with metastatic HER2+ breast cancer. It is also under development as a potential treatment for gastric cancer.

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