Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens

Ming Shen Dai, Yin Hsun Feng, Shang Wen Chen, Norikazu Masuda, Thomas Yau, Shou Tung Chen, Yen Shen Lu, Yoon Sim Yap, Peter C S Ang, Sung Chao Chu, Ava Kwong, Keun Seok Lee, Samuel Ow, Sung Bae Kim, Johnson Lin, Hyun Cheol Chung, Roger Ngan, Victor C Kok, Kun Ming Rau, Takafumi Sangai, Ting Ying Ng, Ling Ming Tseng, Richard Bryce, Judith Bebchuk, Mei Chieh Chen, Ming Feng Hou, Ming Shen Dai, Yin Hsun Feng, Shang Wen Chen, Norikazu Masuda, Thomas Yau, Shou Tung Chen, Yen Shen Lu, Yoon Sim Yap, Peter C S Ang, Sung Chao Chu, Ava Kwong, Keun Seok Lee, Samuel Ow, Sung Bae Kim, Johnson Lin, Hyun Cheol Chung, Roger Ngan, Victor C Kok, Kun Ming Rau, Takafumi Sangai, Ting Ying Ng, Ling Ming Tseng, Richard Bryce, Judith Bebchuk, Mei Chieh Chen, Ming Feng Hou

Abstract

Purpose: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein.

Methods: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety.

Results: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity.

Conclusion: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted.

Clinical trial registration: NCT01808573.

Keywords: Brain metastases; CNS metastases; HER2-positive breast cancer; Lapatinib; Neratinib; Tyrosine kinase inhibitor.

Conflict of interest statement

MSD receives honoraria and consulting fees from CANbridge. NM has received honoraria from Chugai, AstraZeneca, Pfizer, Eli Lilly, Eisai, and Takeda; and research funding from Chugai, AstraZeneca, Kyowa Kirin, Merck Sharp & Dohme, Novartis, Pfizer, Eli Lilly, Eisai, Nippon-Kayaku, and Daiichi Sankyo. STC has received Grants/research support from Roche, AstraZeneca, Pfizer, Novartis, and Eli Lily, and has an advisor/consultant role with Roche, AstraZeneca, Pfizer, Novartis, and Eli Lily. YSL has received grants and speaker fees from Novartis and Merck Sharp & Dohme; speaker fees from Pfizer and Eli Lily; and clinical trial support and speaker fees from Roche. YSY has received honoraria from Novartis, Pfizer, Eli Lily, Eisai, Merck Sharp & Dohme, and AstraZeneca. AK has received institutional funding from AstraZeneca, Novartis, Roche, GSK, Puma, Pfizer, IceCure, and Stryker. KSL has received consulting fees from Roche, Eli Lilly, and Novartis. SO has received honoraria from AstraZeneca, Pfizer, Novartis, and Eli Lily. SBK has received research funding from Novartis, Sanofi-Aventis, Kyowa Kirin, and DongKook Pharm; and has served as a consultant/advisory board member for Novartis, AstraZeneca, Eli Lilly, Enzychem, Dae Hwa Pharm, ISU Abxis, and Daiichi Sankyo. HCC has received Grant/research support from Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Merck-Serono, Bristol Myers Squibb/Ono, Taiho, Amgen, Beigene, Incyte; honoraria from Merck-Serono and Eli Lilly; and consultation fees from Taiho, Celltrion, Merck Sharp & Dohme, Eli Lilly, Bristol Myers Squibb, Merck-Serono, Gloria, Beigene, Amgen, and Zymework. LMT has received grant/research support from Merck Sharp & Dohme, Pfizer, and Novartis; honoraria from AstraZeneca, CANbridge, Amgen, Roche, Novartis, and Pfizer; and consultation fees from CANbridge, Eli Lilly, Amgen, Roche, Novartis, and Pfizer. RB, KK, and JB are employees and stockholders of Puma. MC is an employee of CANbridge. MFH has received grant/research support from Takeda; honoraria from Roche, Novartis, Pfizer, Sanofi, TTY Biopharm, Eli Lilly, GlaxoSmithKline, EnGen Bio, BD, AstraZeneca, Eisai, and Chugai; and consultation fees from Roche, Novartis, AstraZeneca, Sanofi, TTY Biopharm, and Eli Lilly.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Kaplan–Meier curves for centrally assessed PFS and OS in the Asian subgroup. CI confidence interval, L+C lapatinib plus capecitabine, N+C neratinib plus capecitabine, OS overall survival, PFS progression-free survival
Fig. 2
Fig. 2
Cumulative incidence of intervention for CNS disease in the Asian cohort. CI confidence interval, L+C lapatinib plus capecitabine, N+C neratinib plus capecitabine

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