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Neratinib, an irreversible pan erB receptor tyrosine kinase inhibitor active for advanced HER2+breast cancer

Neratinib (HKI-272) is a dual inhibitor of the tyrosine kinase receptors, erbB1 (EGFR) and erbB2 (HER2). In a phase I study, neratinib was tolerable and demonstrated antitumor activity in patients with solid tumors, including 8 of 25 evaluable patients with erbB2-positive advanced breast cancer. In an open-label, two-arm phase II study, patients with stage IIIB, IIIC or IV erbB2-positive advanced breast cancer were evaluated to further characterize the safety and efficacy of neratinib. The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 IHC staining intensity of 2+ or 3+.

Neratinib has demonstrated a potent activity against trastuzumab-resistant and trastuzumab-naive HER2-positive breast cancer in a phase II study that evaluated the safety and efficacy of a daily 240 mg oral dose on 136 women with locally advanced or metastatic breast cancer (stage IIIB, IIIC or IV). The 16-week progression-free survival (PFS) rate was the primary end point. Secondary end points included safety, objective response rate and clinical benefit rate. Patients were assigned to one of two study arms based on prior treatment with trastuzumab. The efficacy analysis included 127 evaluable patients, 61 in arm A and 66 in arm B. In patients who were previously treated with trastuzumab (arm A), the 16-week PFS rate was 60%, and the median PFS was 23 weeks. The objective response rate was 26%, and the clinical benefit rate was 36%.

At the present time, several phase II studies of neratinib in combination with chemotherapy (capacitabine, vinorelbine, paclitaxel and doxorubicin) are ongoing, some of them already finished. The tolerance and efficacy will be presented. A large worldwide randomized phase III study of the combination of trastuzumab versus neratinib plus paclitaxel in chemonaïve advanced HER2-positive breast cancer patients will start very soon in order to determine the efficacy of neratinib compared with standard treatment.


  1. Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Jänne PA, Eder JP, Naughton MJ, Ellis MJ, et al: A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res. 2009, 15: 2552-2558. 10.1158/1078-0432.CCR-08-1978.

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  2. Burstenin HJ, Sun Y, Tan AR, Dirix L, Vermette JJ, Powell C, Zacharchuk C, Badwe RA: Neratinib (HKI-272), an irreversible pan erbB receptor tyrosine kinase inhibitor: phase 2 results in patients with advanced HER2+ breast cancer [abstract 37]. SABCS. 2008

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Cortés-Funes, H., Mendiola, C., Manso, L. et al. Neratinib, an irreversible pan erB receptor tyrosine kinase inhibitor active for advanced HER2+breast cancer. Breast Cancer Res 11 (Suppl 1), S19 (2009).

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