Abstract PD3-03: Continued efficacy of neratinib in patients with HER2-positive early-stage breast cancer: Final overall survival analysis from the randomized phase 3 ExteNET trial
Authors: Holmes Frankie Ann , Moy Beverly , Delaloge Suzette , Chia Stephen , Ejlertsen Bent , Mansi Janine , Iwata Hiroji , Gnant Michael , Buyse Mark , Barrios Carlos , Silovski Tajana , Separovic Robert , Bashford Anna , Guerrero-Zotano Angel , Denduluri Neelima , Patt Debra , Gokmen Erhan , Gore Ira , Smith John , Bryce Richard , Xu Feng , Wong Alvin , Martin Miguel , Chan Arlene 
Published: February 2021

Abstract
Background: Neratinib (NERLYNX®) is an irreversible pan-HER inhibitor that significantly improves invasive disease-free survival (iDFS) compared with placebo when given as extended adjuvant therapy in patients with HER2-positive (HER2+) early breast cancer after trastuzumab-based adjuvant therapy. In the phase 3 ExteNET trial, an absolute iDFS benefit of 2.5% and distant disease-free survival (DDFS) benefit of 1.7% were observed with neratinib after 5 years’ follow-up. As reflected in the approved indication by the European Medicines Agency (EMA), patients with hormone receptor-positive (HR+) disease who initiated neratinib treatment within 1 year of completing trastuzumab (HR+/≤1 year) experienced an absolute iDFS benefit of 5.1% and DDFS benefit of 4.7% at 5 years. In HR+/≤1 year patients with residual disease after neoadjuvant therapy, absolute 5-year iDFS and DDFS benefits of 7.4% and 7.0%, respectively, were observed. Here we report the final protocol-defined, event-driven analysis of overall survival (OS) from ExteNET, and provide descriptive analyses of subgroups of primary interest according to the EU label and current clinical practice in early-stage HER2+ disease.
Methods: ExteNET was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of women with early-stage HER2+ breast cancer who had completed neoadjuvant or adjuvant trastuzumab plus chemotherapy (NCT00878709). Patients were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year. Hazard ratios (HR) for OS were estimated from Cox proportional hazards models, and survival rates by the Kaplan-Meier method. The OS analysis was event-driven and powered for the intention-to-treat (ITT) population with a target of 248 events. Descriptive analyses were performed in the HR+/≤1 year subgroup per the approved indication in the EU, and in higher-risk patients, i.e. HR+/≤1 year who have residual disease after neoadjuvant therapy [i.e. those who did not achieve a pathologic complete response (pCR)]. Cut-off date: July 2019.
Results: 2840 patients were randomized to study treatment (1420 per group). After a median follow-up of 8.1 years, 127 (8.9%) and 137 (9.6%) patients in the neratinib and placebo ITT groups had died, respectively. The 8-year OS rates were 90.1% (95% CI, 88.3–91.6) in the neratinib group and 90.2% (95% CI, 88.4–91.7) in the placebo group (absolute difference at 8 years -0.1%; stratified HR=0.95; 95% CI, 0.75–1.21; p=0.6914). A positive trend was seen in the prespecified HR+ subgroup (n=1631; absolute difference at 8 years 1.5%; HR=0.80; 95% CI, 0.58–1.12), and within this population, descriptive analyses suggested greater benefits with neratinib in the HR+/≤1 year subgroup (n=1334; absolute difference at 8 years 2.1%; HR=0.79; 95% CI, 0.55–1.13) and in the HR+/≤1 year subset with no pCR after neoadjuvant therapy (n=295; absolute difference at 8 years 9.1%; HR=0.47; 95% CI, 0.23–0.92). No new safety signals were reported with this long-term follow-up to 8 years.
Conclusions: In this final OS analysis of ExteNET, there were fewer deaths with neratinib than placebo in the ITT population, but the results did not reach statistical significance. Analyses showed greater OS improvements with neratinib in subgroups including HR+/≤1 year, and HR+/≤1 year with residual disease after neoadjuvant therapy. These findings are consistent with the results based on the primary endpoint of iDFS, and support the use of neratinib in clinical practice in these patients.
Citation Format: Frankie Ann Holmes, Beverly Moy, Suzette Delaloge, Stephen Chia, Bent Ejlertsen, Janine Mansi, Hiroji Iwata, Michael Gnant, Mark Buyse, Carlos Barrios, Tajana Silovski, Robert Separovic, Anna Bashford, Angel Guerrero-Zotano, Neelima Denduluri, Debra Patt, Erhan Gokmen, Ira Gore, John Smith, Richard Bryce, Feng Xu, Alvin Wong, Miguel Martin, Arlene Chan. Continued efficacy of neratinib in patients with HER2-positive early-stage breast cancer: Final overall survival analysis from the randomized phase 3 ExteNET trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-03.