Two Studies on Novel Drug Neratinib (HKI-272) Demonstrate Clinical Benefit in HER2-Positive Breast Cancer

Trastuzumab (Herceptin) is used to treat women with HER2-positive breast cancer. One of the problems with trastuzumab is that, over time, nearly 50% of patients develop resistance, and their disease resumes progression. Researchers at Fox Chase Cancer Center in Philadelphia, PA, believe the experimental drug neratinib (HKI-272) may offer a new treatment option for these women.

Like trastuzumab, neratinib inhibits the HER2 receptor (ErbB2) found on the surface of HER2-positive tumor cells. Trastuzumab targets the extramembrane epitope, whereas neratinib blocks the intracellular domain.

Researchers enrolled 45 women whose HER2-positive breast tumors progressed after treatment with trastuzumab. In a phase I trial to determine the maximum tolerated dose of neratinib, the patients received a 4mg/kg intravenous loading dose of trastuzumab followed by 2mg of trastuzumab weekly; patients also received either 160mg or 240mg of neratinib daily. With no evidence of dose-limiting toxicities or cardiotoxicity, researchers advanced patients to phase II of the trial, in which they received weekly trastuzumab plus 240mg of daily neratinib.

The preliminary analysis included data for 33 evaluable patients. A total of nine patients (27%) demonstrated objective response to the combination regimen. The trial’s primary endpoint was progression-free survival at 16 weeks, and 47% of patients met or exceeded this endpoint, with median progression-free survival of 19 weeks. In addition, 7% of evaluable patients demonstrated complete response, and 21% showed partial response. The research team said seven women are continuing on the dual therapy regimen. The most common adverse effect was diarrhea, observed in 91% of patients. In the 240mg dose group, two patients discontinued because of treatment-related adverse effects.

Ramona Swaby, MD, medical oncologist and attending physician, Fox Chase, was lead investigator for the phase I/II trial. She is presenting full study results on Monday, June 1. She noted in a press release that neratinib is a small molecule agent able to cross the blood—brain barrier, which may mean it could be used to treat brain metastasis. As a monoclonal antibody, trastuzumab is unable to cross the blood–brain barrier. Dr. Swaby said phase III trials are already underway.

A second study investigated neratinib plus paclitaxel (Taxol) in various solid tumors, including endometrial, cervical, colorectal, breast, and esophageal cancers. This was a phase I/II open-label study. In phase I, investigators administered an escalating dose of neratinib combined with 70 or 80mg/m2 of intravenous paclitaxel. No dose-limiting toxicities were observed at the highest dose used, which was neratinib 240mg combined with paclitaxel 8mg/m2.

Tumors were measured at baseline and after every two cycles of treatment using modified RECIST criteria. Investigators confirmed clinical benefit, as measured by partial response or disease stabilization, in one patient with endometrial cancer and one with cervical cancer.

Phase II of the study included only those patients in phase I who had ErbB-2-positive breast cancer. Of the 102 patients enrolled, 97 were available for efficacy analysis. At 16 weeks, investigators observed overall response rate of 63%. Adverse events included diarrhea, alopecia, infection, peripheral neuropathy, leucopenia, anemia, nausea, rash, fatigue, and vomiting, at rates and degrees similar to those documented when using each agent singly. As in the previous trial, diarrhea was the most common adverse event, experienced by 89% of patients in the phase II study. Dose reductions were required for 14 patients, and one patient discontinued treatment.

With both studies suggesting clinical benefit to treatment regimens containing neratinib in patients with HER2-positive breast cancer, promising antitumor activity in other solid tumors, and a tolerable safety profile, this investigational agent is likely to be the focus of additional studies.

ASCO Abstract 1004 and Abstract 3557.