Abstract P1-13-11: Neratinib in the extended adjuvant treatment of patients from Asia with early-stage HER2+ breast cancer after trastuzumab-based therapy: Exploratory analyses from the phase III ExteNET trial
Authors: Iwata H , Masuda N , Kim S-B , Inoue K , Rai Y , Fujita T , Shen Z-Z , Chiu JW , Ohtani S , Takahashi M , Yamamoto N , Miyaki T , Sun Q , Yen-Shen L , Xu B , Yap YS , Bustam AZ , Lee JR , Zhang B , Bryce R , Chan A 
Published: February 2018

Abstract
Background: Current breast cancer knowledge is based largely on studies conducted in western populations. Their findings may not be generalizable to Asian women because of ethnic, genetic and lifestyle differences. Neratinib (N) is an irreversible tyrosine kinase inhibitor of HER1, 2 and 4. The international, randomized, placebo (P)-controlled phase III ExteNET trial showed that 1 year (yr) of N after trastuzumab (T)-based adjuvant therapy significantly improved 2-yr invasive disease-free survival (iDFS) in patients (pts) with early-stage HER2+ breast cancer (HR 0.67; 95% CI 0.50–0.91; p=0.009) [Chan et al. Lancet Oncol 2016]. The significant iDFS benefit with N was shown to be durable after 5 yrs' follow-up (HR 0.73; 95% CI 0.57-0.92; p=0.008) [Martin et al. ESMO 2017]. We report efficacy and safety findings from pts enrolled from Asian centers (China, Hong Kong, Japan, Korea, Malaysia, Singapore, and Taiwan) on the ExteNET trial to better characterize the effects of N in Asian women.
Methods: Pts with early-stage HER2+ breast cancer were randomly assigned to oral N 240 mg/day or P for 1 yr after standard primary therapy and T-based adjuvant therapy. Antidiarrheal prophylaxis was not required by protocol. Data concerning disease recurrences were collected prospectively during yr 1-2 post-randomization, and from medical records during yr 3–5 post-randomization. Primary endpoint: iDFS. HR (95% CI) estimated using Cox proportional-hazards models stratified by nodal status, hormone-receptor status and prior T regimen. Data cut-off: 2-yr analysis, July 2014; 5-yr analysis, March 2017. Clinicaltrials.gov:NCT00878709.
Results: Of 2840 randomized pts (N, n=1420; P, n=1420), 341 (12%) were enrolled from Asian centers (N, n=165; P, n=176). Baseline characteristics: median age 53 yr; hormone receptor-positive 48%. Median treatment duration was similar in both groups (N, 351 days; P, 352 days). iDFS events in Asian vs ITT populations are shown in the Table.
Primary 2-yr analysisa5-yr analysis NPNPAsian population, n165176165176iDFS events, n10151222HR (95% CI)b0.71 (0.31-1.57)0.54 (0.26-1.08)P-value (2-sided)0.4040.085ITT population, n1420142014201420iDFS events, n67106116163HR (95% CI)b0.66 (0.49-0.90)0.73 (0.57-0.92)P-value (2-sided)0.0080.008a. Primary study endpoint; b. Neratinib vs placebo
The incidence of grade 3/4 diarrhea with N was slightly higher in Asian pts (46.1% vs ITT, 39.8%). All other grade 3/4 adverse events with N were rare among Asian pts (elevated ALT, mucosal inflammation, 2 pts each; other events, 1 pt each). Compliance with N in Asian pts was also improved (71% vs ITT, 61%).
Conclusions: In Asian pts enrolled into ExteNET, compliance with N was better and the magnitude of N effect was similar or greater that that observed in the ITT population. Although N-related grade 3/4 diarrhea was more common in Asian pts than in the ITT population, all other grade 3/4 events were rare. Despite small pt numbers, our analyses suggest that the findings from ExteNET are applicable to Asian pts, and support the conclusion that N reduces disease recurrences in Asian pts with early-stage HER2+ breast cancer after T-based adjuvant therapy.
Citation Format: Iwata H, Masuda N, Kim S-B, Inoue K, Rai Y, Fujita T, Shen Z-Z, Chiu JW, Ohtani S, Takahashi M, Yamamoto N, Miyaki T, Sun Q, Yen-Shen L, Xu B, Yap YS, Bustam AZ, Lee JR, Zhang B, Bryce R, Chan A. Neratinib in the extended adjuvant treatment of patients from Asia with early-stage HER2+ breast cancer after trastuzumab-based therapy: Exploratory analyses from the phase III ExteNET trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-11.