Bryce, R

Bustam, A

Chan, A

Chiu, WYJ

Fujita, TCC

Inoue, K

Iwata, H

Kim, S-B

Lu, YS

Masuda, N

Miyaki, T

Ohtani, S

Rai, TY

Shen, Z-Z

Sun, Q

Takahashi, M

Xu, B

Yamamoto, N

Yap, YS

Yee, Y

Zhang, B

HKU Scholars Hub

TitleNeratinib in the extended adjuvant treatment of patients fromAsia with early-stage HER2+ breast cancer after trastuzumab-based therapy: exploratory analyses from the phase III ExteNETtrialAuthor(s)Iwata, H; Masuda, N; Kim, S-B; Inoue, K; Rai, TY; Fujita, TCC;Shen, Z-Z; Chiu, WYJ; Ohtani, S; Takahashi, M; Yamamoto, N;Miyaki, T; Sun, Q; Lu, YS; Xu, B; Yap, YS; Bustam, A; Yee, Y;Zhang, B; Bryce, R; Chan, ACitation San Antonio Breast Cancer Congress (SABCS) 40th AnnualMeeting, San Antonio, TX, 5-9 December 2017Issued Date 2017URL http://hdl.handle.net/10722/249353Rights This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Neratinib in the extended adjuvant treatment of patients from Asia with early stage HER2-positive breast cancer after trastuzumab-based therapy: exploratory analyses from the phase III ExteNET trial Hiroji Iwata,1 Norikazu Masuda,2 Sung-Bae Kim,3 Kenichi Inoue,4 Yoshiaki Rai,5 Takashi Fujita,6 Zhen-Zhou Shen,7 Joanne Chiu,8 Shoichiro Ohtani,9 Masato Takahashi,10 Naohito Yamamoto,11 Toshiko Miyaki,11 Qiang Sun,12 Yen-Shen Lu,13 Binghe Xu,14 Yoon Sim Yap,15  Anita Bustam,16 Yining Yee,17 Bo Zhang,17 Richard Bryce,17 Arlene Chan181Aichi Cancer Center, Nagoya, Japan; 2National Hospital Organization Osaka National Hospital, Osaka, Japan; 3Asan Medical Center, University of Ulsan, Seoul, Korea; 4Saitama Cancer Center, Ina, Japan; 5Hakuaikai Medical Corporation Sagara Hospital, Kagoshima City, Japan; 6Jichi Medical University Hospital, Yakushiji, Japan; 7Shanghai Cancer Center,  Fudan University, Shanghai, China; 8Queen Mary Hospital, Hong Kong Island, Hong Kong; 9Hiroshima City Hospital, Hiroshima, Japan; 10National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan; 11Chiba Cancer Center, Chiba, Japan; 12Peking Union Medical College Hospital, Beijing, China; 13National Taiwan University Hospital, Taipei City, Taiwan; 14National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 15National Cancer Centre Singapore, Singapore; 16University Malaya Medical Centre, Kuala Lumpur, Malaysia; 17Puma Biotechnology Inc., Los Angeles, CA, USA; 18Breast Cancer Research Centre-WA & Curtin University, Perth, Australia.Introduction■  Neratinib, an irreversible tyrosine kinase inhibitor of HER1, HER2 and HER4,1  is used for the extended adjuvant treatment of early-stage HER2-positive (HER2+) breast cancer after trastuzumab-based adjuvant therapy.‒  The primary analysis of the international, randomized, placebo-controlled phase III ExteNET trial showed that 1 year of neratinib given after trastuzumab-based (neo)adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) compared with placebo in women with early-stage HER2-positive breast cancer (stratified hazard ratio [HR] 0.67; 95% confidence intervals [CI] 0.50–0.91; p=0.0091).2‒  Furthermore, the significant iDFS benefits of neratinib were maintained after  a median of 5 years’ follow-up (stratified hazard ratio 0.73; 95% CI 0.57‒0.92; p=0.008).3■  Current knowledge about breast cancer is based largely on studies conducted in western populations.4 –  As the genetic background, socio-economic profile, lifestyle, and health beliefs of Asian and western women differ, the findings from such studies may not be applicable to Asian women.4‒  We report exploratory analyses from the ExteNET trial of patients enrolled from Asian centers to better understand the efficacy and safety of neratinib compared with placebo in Asian women with early-stage HER2-positive breast cancer.MethodsStudy overview■  ExteNET is a multicenter, randomized, double-blind, parallel, placebo-controlled, phase III trial.■  Patients were enrolled from centers in 40 countries in Europe, North and South America, Asia, and Australasia. ■  The final study design comprised 3 parts: –  Part A: primary efficacy analysis at 2 years (July 2014)2‒ Part B: sensitivity analysis of efficacy at 5 years (March 2017)3‒ Part C: analysis of overall survival which is planned after 248 events. ■  ExteNET is registered on Clinicaltrials.gov (identifier, NCT00878709).Patients■  Women with confirmed stage 2–3c (1–3c in original protocol) HER2-positive breast cancer.■  Clinical and radiologic assessments were required to be negative for recurrences or metastatic disease at study entry.■  Patients had received (neo)adjuvant therapy with trastuzumab completed within 1 year (2 years in original protocol) before randomization.Treatment■  Women were randomly assigned to oral neratinib 240 mg once daily continuously or matching placebo for 1 year. ■  Prophylaxis for the prevention of neratinib-associated diarrhea was not mandatory.Assessments■  During years 1 and 2, physical examinations were performed at month 1, every 3 months during year 1, and every 4 months during year 2, mammograms were performed annually where appropriate, and computed tomography or bone scans were performed if clinically indicated. ■  During years 3 to 5, physical examination and mammogram schedules were based on standard of care, and details of recurrent disease events and deaths were obtained from medical records.Outcomes■  The primary study endpoint was iDFS after 2 years of follow-up.■  Secondary endpoints included disease-free survival including ductal carcinoma in situ (DCIS), time to distant recurrence, distant disease-free survival, cumulative incidence of central nervous system (CNS) recurrences, and safety.Statistical analysis■  Exploratory analyses were performed in the subpopulation of patients enrolled from Asian countries (i.e. China, Hong Kong, Japan, Korea, Malaysia, Singapore, and Taiwan).■  Patients of Asian ethnicity enrolled from non-Asian countries (n=44) were not included in the Asian subpopulation. ■  Efficacy analyses were by intention-to-treat and performed at 2 and 5 years post-randomization.■  Kaplan Meier methods were used to analyze time-to-event endpoints, and a unstratified Cox proportional-hazards model was used to estimate HR with 95% CI for neratinib versus placebo.Results■  2840 women were randomly assigned to study treatment and constituted the intention to-treat population (neratinib, n=1420; placebo, n=1420).■  341 women were enrolled from centers in Asia (neratinib, n=165; placebo, n=176) [Figure 1].Figure 1. ExteNET analysis flowchart ■  Patient demographics and characteristics at baseline were generally balanced between treatment groups in the Asian population (Table 1).■  Compared with the intention-to-treat population, Asian patients (neratinib and placebo combined) were more likely to have node-negative disease (28.7% vs 23.6%) and hormone receptor-negative tumors (52.2% vs 42.6%). ■  Asian patients were also less likely to have received trastuzumab concurrently with chemotherapy (41.3% vs 62.3% in the intention-to-treat population),  but more likely to have received an anthracycline plus taxane (81.2% vs 67.9%). Table 1. Baseline characteristics in Asian and intention-to-treat populationsAsian populationIntention-to-treat  populationVariableNeratinib(n=165)Placebo(n=176)Neratinib(n=1420)Placebo(n=1420)Age, years, median (range) 52 (26–81) 53 (27–72) 52 (25–83) 52 (23–82)Body mass index, kg/m2 mean (SD) 22.6 (3.8) 23.1 (3.3) 27.4 (5.8) 27.5 (5.8)Nodal status*Negative 1–3 positive node 4+ positive nodes43 (26.1) 75 (45.5) 47 (28.5)55 (31.3) 74 (42.0) 47 (26.7)335 (23.6) 664 (46.8) 421 (29.6)336 (23.7) 664 (46.8) 420 (29.6)Hormone receptor status*Positive Negative77 (46.7) 88 (53.3)86 (48.9) 90 (51.1)816 (57.5) 604 (42.5)815 (57.4) 605 (42.6)Previous trastuzumab regimen*Concurrent Sequential66 (40.0) 99 (60.0)75 (42.6) 101 (57.4)884 (62.3) 536 (37.7)886 (62.4) 534 (37.6)Menopausal status at diagnosisPremenopausal Postmenopausal90 (54.5) 75 (45.5)83 (47.2) 93 (52.8)663 (46.7) 757 (53.3)664 (46.8) 756 (53.2)Prior (neo)adjuvant therapyTrastuzumab Anthracycline only Anthracycline plus taxane Taxane only Non-anthracycline or taxane165 (100) 17 (10.3) 136 (82.4) 12 (7.3) 0176 (100) 21 (11.9) 141 (80.1) 13 (7.4) 1 (0.6)1420 (100) 136 (9.6) 962 (67.7) 318 (22.4) 4 (0.3)1420 (100) 135 (9.5) 965 (68.0) 316 (22.3) 4 (0.3)Data are presented as n (%), unless otherwise stated. SD, standard deviation. *Stratification factor.Efficacy■  Efficacy findings are summarized in Table 2 and Kaplan-Meier curves for iDFS are presented in Figure 2.■  After 2 years’ follow-up, the iDFS rate in the Asian population was 92.8% in the neratinib group and 90.8% in the placebo group (HR 0.71; 95% CI 0.31–1.57), corresponding with an absolute between-group difference of 2.0%.■  For other secondary endpoints, the trend favoring neratinib treatment was also consistently observed (Table 2). ■  After 5 years’ follow-up, the iDFS rate in the Asian population was 91.9% in the neratinib group and 87.2% in the placebo group (HR 0.54; 95% CI 0.26–1.08), corresponding with an absolute between-group difference of 4.7%.■  The number of CNS recurrences was numerically smaller in the neratinib group than in the placebo group at both time-points (1 vs 4 events, respectively).Table 2. Efficacy findings after 2 and 5 years in the Asian and intention-to-treat populationsParameter Asian populationIntention-to-treat  populationHazard ratio(95% CI)Hazard ratio(95% CI)P value(2-sided)Primary 2-year analysisInvasive disease-free survival Disease-free survival with DCIS Distant disease-free survival Time to distant recurrences0.70 (0.31–1.55) 0.66 (0.29–1.43)  0.59 (0.20–1.54) 0.59 (0.20–1.54)0.66 (0.49–0.90) 0.61 (0.45–0.83) 0.74 (0.52–1.05) 0.73 (0.51–1.04)0.008 0.001 0.094 0.0875-year analysisInvasive disease-free survival Disease-free survival with DCIS Distant disease-free survival Time to distant recurrences0.57 (0.27–1.13) 0.55 (0.26–1.08) 0.50 (0.21–1.07) 0.50 (0.21–1.07)0.73 (0.57–0.92) 0.71 (0.56–0.89) 0.78 (0.60–1.01) 0.79 (0.60–1.03)0.008 0.004 0.065 0.078CNS, central nervous system; CI, confidence intervals; DCIS, ductal carcinoma in situ.Figure 2. iDFS in Asian and intention-to-treat populations at 2 years (A) and  5 years (B) Treatment exposure■  In the Asian population, the median duration of treatment was similar in both treatment arms (neratinib, 11.5 months; placebo, 11.6 months).■  However, Asian patients were more likely to complete study treatment (neratinib, 70.3%; placebo, 85.8%) than patients in the overall study population (62.1% vs 82.9%, respectively).Safety■  In the Asian population, diarrhea was the most common adverse event with neratinib (Table 3); no grade 4 diarrhea occurred in either treatment group.■  All other grade 3 events occurred in single patients only with neratinib.■  Grade 4 events were reported in 1 patient (0.6%) in the neratinib group (anemia) and 3 patients (1.7%) in the placebo group (brain edema, n=1; amylase increased, abnormal hepatic function, cholestatic jaundice, n=1; gastric cancer, n=1). No grade 4 event was considered to be treatment related.■  One grade 5 event (gastric cancer) occurred in the placebo group.Table 3. Treatment-emergent adverse events in the Asian safety population (≥10% incidence)Neratinib(n=165)Placebo(n=176)Adverse event, n (%) Any-grade Grade 3 Any-grade Grade 3Diarrhea Nausea Fatigue Vomiting Abdominal pain Headache Abdominal pain upper Rash Decreased appetite Dizziness Stomatitis Nasopharyngitis Paronychia Influenza-like illness Weight decreased Pyrexia Palmar-plantar erythrodysesthesia162 (98.2) 58 (35.2) 31 (18.8) 51 (30.9) 28 (17.0) 27 (16.4) 27 (16.4) 51 (30.9) 29 (17.6) 15 (9.1) 40 (24.4) 25 (15.2) 24 (14.5) 23 (13.9) 21 (12.7) 17 (10.3) 17 (10.3)76 (46.1) 1 (0.6) 0 1 (0.6) 0 0 1 (0.6) 1 (0.6) 1 (0.6) 1 (0.6) 1 (0.6) 0 1 (0.6) 0 1 (0.6) 0 082 (46.6) 30 (17.0) 19 (10.8) 14 (8.0) 20 (11.4) 27 (15.3) 11 (6.3) 17 (9.7) 7 (4.0) 21 (11.9) 14 (8.0) 54 (30.7) 0 22 (12.5) 2 (1.1) 10 (5.7) 2 (1.1)3 (1.7) 0 0 0 0 0 0 0 0 1 (0.6) 0 0 0 0 0 0 0Note: Adverse events were graded according to National Cancer Institute Common Terminology Criteria, version 3.0.■  With the exception of lower rates of dizziness and nasopharyngitis, Asian patients treated with neratinib experienced higher rates of all-grade adverse events compared with those who received placebo.■  Grade 3 diarrhea was also more common with neratinib in Asian patients (46.1%) compared with the rate seen in the overall safety population (39.8%).Conclusions■  In ExteNET, the benefits of neratinib appeared to be similar among Asian patients than in the intention-to-treat population at both the 2-year and 5-year timepoints.■  Asian patients treated with neratinib experienced a higher rate of most adverse events compared with those receiving placebo, although this did not appear to impact on treatment duration or efficacy outcome. ■  Despite small patient numbers, our analyses suggest that the findings from ExteNET are applicable to Asian patients.References1. Rabindran SK. Cancer Lett 2005;227:9–23. 2.  Chan A, et al. Lancet Oncol 2016;17:367–77.3. Martin M, et al. Lancet Oncol 2017, in press. 4. Bhoo-Pathy N, et al. Eur J Cancer 2013;49:703–9.AcknowledgementsExteNET was sponsored by Wyeth, Pfizer, and Puma Biotechnology Inc.  Puma Biotechnology Inc. also funded the provision of editorial support provided by  Miller Medical Communications.P1-13-11Presented at the 40th Annual San Antonio Breast Cancer Symposium (SABCS), Dec 5–9, 2017 in San Antonio, TXScreened for eligibility(n=3278)Ineligible (n=436)Randomly assigned (n=2842)Excluded (n=2) Assigned twice (n=2)  Intention-to-treat populationAllocated to neratinib (n=1420) Received neratinib (n=1408) Did not receive neratinib (n=12)   Intention-to-treat populationAllocated to placebo (n=1420) Received placebo (n=1408) Did not receive placebo (n=12)  Asian populationNeratinib (n=165) Japan (n=89) China (n=23) Korea (n=22) Hong Kong (n=13) Taiwan (n=11) Malaysia (n=3) Singapore (n=4)  Asian populationPlacebo (n=176) Japan (n=116) China (n=26) Korea (n=15) Hong Kong (n=17) Taiwan (n=1) Malaysia (n=1) Singapore (n=0) 05060708090Invasive disease-free survival (%)100A0 3 6 9 12 15 18 21 24Months after randomization165176Neratinib (Asia)Placebo (Asia)Neratinib (intention-to-treat)Placebo (intention-to-treat)No. at riskAsian populationNeratinibPlacebo1420142015316912881367151163125713231471591227129114314511881242135141115012061351391108116113313710331089108114662704Intention-to-treat populationNeratinibPlacebo0 6 12 18 24 30 36 42 48 54 60165176No. at riskAsian populationNeratinibPlacebo142014201531651316135415115412721298147149122512481371441106114212813297810291281329651011127131949991127129938978126128920958124122885927Intention-to-treat populationNeratinibPlacebo05060708090Invasive disease-free survival (%)100BMonths after randomizationNeratinib (Asia)Placebo (Asia)Neratinib (intention-to-treat)Placebo (intention-to-treat)Copyright 2017 Puma Biotechnology

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

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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

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