Neratinib Improves Invasive Disease-Free Survival in Centrally Confirmed HER2-Positive Breast Cancer

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Neratinib significantly improves invasive disease-free survival (iDFS) in trastuzumab (Herceptin)-treated, early-stage, human epidermal growth factor receptor 2-positive (HER2+) breast cancer patients, with an enhanced treatment effect observed in women with centrally confirmed HER2+ tumors.

Despite survival benefits with adjuvant chemotherapy plus trastuzumab, “up to one-quarter of patients have a breast cancer event,” said Arlene Chan, MD, Adjunct Associate Professor at Curtin University in Perth, Australia, at the 2015 American Society of Clinical Oncology (ASCO) Breast Symposium in San Francisco.

She presented further data on the ExteNET phase III randomized, placebo-controlled trial, sharing results on the proportion of patients who underwent central HER2 testing (Abstract 117).

Earlier this year at the ASCO annual meeting, Chan presented the primary analysis of the intent-to-treat (ITT) population of 2840 patients; 1420 taking neratinib and 1420 on placebo. That analysis showed that this oral tyrosine kinase inhibitor of HER led to a statistically significant absolute benefit of 2.3% in iDFS at 2 years (93.3% neratinib versus 91% placebo), which was the primary endpoint.

In a subset of hormone receptor-positive (HR+) patients, there was an even greater benefit of 4.2% in iDFS with neratinib (95.4% neratinib versus 91.2% placebo). Distant recurrence was also reduced in those patients receiving neratinib.

Of the tumor samples analyzed, 1463 (86%) were centrally confirmed as HER2+, including 741 neratinib patients and 722 placebo patients. Among these centrally confirmed HER2+ patients, “there was a sustained and statistically significant benefit in those who received 12 months of neratinib (94.7% neratinib versus 90.6% placebo),” Chan said.

In the centrally confirmed HER2+ population, those with distant metastatic disease showed a 4% absolute benefit if they received neratinib as compared to placebo.

Subgroup analyses also show neratinib was superior to placebo, in particular for those patients with HER2+ disease, sequential disease, and premenopausal status.

Among 765 patients with centrally confirmed breast cancer, HER2+, and HR+ disease, there was a significant absolute benefit at 2 years of 8.6% in favor of the neratinib group (97% neratinib versus 88.4% placebo).

Preclinical and clinical evidence show that anti-HER2+ and antiestrogen receptor agents may be synergistic, she said.

Safety data show the predominant side effect was diarrhea, with up to 40% of patients with grade 3 diarrhea. This largely occurred in the first 2 months of neratinib therapy. “We are cognizant that diarrhea is an important side effect to address,” she said, noting that prophylaxis with loperamide concurrent with the first 30 days of neratinib reduces the rate of grade 3 diarrhea. Better patient education may reduce high discontinuation rates, she said.

In conclusion, Chan said “the primary analysis demonstrates a statistically significant improvement in iDFS in the ITT population, with a hazard ratio of 0.67,” with neratinib therapy. In centrally confirmed patients with HER2+ disease, the iDFS improvement held up, with a hazard ratio of 0.51 with neratinib. The greater benefit seen in HR+ disease requires further evaluation, she said.

Chan noted that “diarrhea was predictably the most common adverse event. Intensive prophylaxis with loperamide is effective and recommended.”