Final Overall Survival Analysis from the Randomized Phase 3 ExteNET Trial of Neratinib in Patients with HER2-Positive Early-Stage Breast Cancer

Conference Correspondent 

When given as extended adjuvant therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer after trastuzumab (Herceptin)-based adjuvant therapy, neratinib (Nerlynx) significantly improved invasive disease-free survival.

This irreversible pan-HER inhibitor has demonstrated in the phase 3 ExteNET trial, a 2.5% absolute invasive disease-free survival benefit and a 1.7% distant disease-free survival benefit after 5 years of follow-up.

Neratinib has been indicated for use by the European Medicines Agency. In the trial leading to approval, patients with hormone receptor (HR)-positive disease who received neratinib treatment within 1 year of completing trastuzumab experienced an absolute invasive disease-free survival benefit of 5.1% and a distant disease-free survival benefit of 4.7% at 5 years.

In patients with HR-positive disease ≤1 year with residual disease after neoadjuvant therapy, absolute 5-year invasive disease-free survival benefits were 7.4% and distant disease-free survival benefits were 7.0%.

Frankie Ann Holmes, MD, FACP, Past Associate Director, Breast Oncology Research, US Oncology, Houston, TX, and colleagues described the final protocol-defined analysis of overall survival from ExteNET and provided a descriptive examination of subgroups of primary interest based on the European Union label as well as the current clinical practice in early-stage HER2-positive disease.

ExteNET was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial. For 1 year, women with early-stage HER2-positive breast cancer who had completed neoadjuvant or adjuvant trastuzumab plus chemotherapy were randomized to receive oral neratinib 240 mg daily or placebo. Based on the approved indication in the European Union, descriptive analyses were performed in the HR-positive disease ≤1-year subgroup. Higher-risk patients were those who had HR-positive disease ≤1 year and had residual disease after neoadjuvant therapy (ie, those who did not achieve a pathologic complete response).

In this study, a total 2840 patients were randomized with 1420 in each arm. Death occurred in 8.9% of patients in the neratinib arm and 9.8% of placebo patients after a median follow-up of 8.1 years.

In neratinib and the placebo groups, the 8-year overall survival rates were comparable at approximately 90%. In the prespecified hormone receptor–positive subgroup (N = 1631), a positive trend was seen, which suggested greater benefits with neratinib in the hormone receptor–positive disease ≤1-year subgroup (N = 1334) and in the hormone receptor–positive disease ≤1-year subset with no pathologic complete response after neoadjuvant therapy (N = 295). Even in the long-term follow-up, new safety signals were not seen.

The authors concluded that in the final overall survival analysis of ExteNET, while the results did not reach statistical significance, there were fewer deaths with neratinib than placebo in the intent-to-treat population. In the subgroups including the hormone receptor–positive disease ≤1-year group and hormone receptor–positive disease ≤1 year with residual disease after neoadjuvant therapy group, analyses showed greater overall survival improvements with neratinib. These results match previous findings as well as the primary end point of invasive disease-free survival and support the use of neratinib in clinical practice in these patients.

Source: Holmes FA, Moy B, Delaloge S, et al. Continued efficacy of neratinib in patients with HER2-positive early-stage breast cancer: Final overall survival analysis from the randomized phase 3 ExteNET trial. Presented at: San Antonio Breast Cancer Symposium, December 8-11, 2020. Abstract PD3-03.

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