Abstract P2-20-01: Impact of neratinib on development and progression of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC): Findings from the NALA, NEfERT-T, and TBCRC 022 trials
Authors: Awada Ahmad H , Brufsky Adam M , Saura Cristina , Freedman Rachel A , Lin Nancy U , Bebchuk Judith , Xu Feng , Hurvitz Sara 
Published: March 2020

Abstract
Background: The development of metastatic disease in the CNS presents a considerable challenge in the management of patients with MBC as a result of the lack of evidence-based treatment options currently available. Up to 50% of patients with HER2+ MBC develop CNS metastases. A (non-significant) reduction in the cumulative incidence of CNS recurrences was seen in the randomized phase 3 ExteNET trial of neratinib as extended adjuvant treatment of patients with early-stage HER2+ breast cancer following adjuvant trastuzumab-based therapy (Martin et al. Lancet Oncol 2017). Here we review data from the following three trials of neratinib in the metastatic setting: the Phase 3 NALA trial (ClinicalTrials.gov: NCT01808573; Saura et al. ASCO 2019), the Phase 2 NEfERT-T trial (NCT00915018; Awada et al. JAMA Oncol 2016); and the TBCRC 022 trial (NCT01494662; Freedman et al. J Clin Oncol 2019), which suggest activity for neratinib in patients with MBC and CNS metastases. Methods: Patients in NALA (who had received at least 2 lines of HER2-directed therapy for MBC) were randomized 1:1 to neratinib (N; 240 mg qd po) + capecitabine (C; 750 mg/m2 bid po) or lapatinib (L; 1250 mg qd po) + C (1000 mg/m2 bid po). In the NEfERT-T trial, previously untreated patients with recurrent and/or MBC were randomized 1:1 to N (240 mg qd po) or trastuzumab (T; 4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (P; 80 mg/m2 on days 1, 8, and 15 every 28 days). In TBCRC 022, patients with measurable, progressive HER2+ brain metastases received N (240 mg qd po) + C (750 mg/m2 qd po). The co-primary endpoints in NALA were centrally assessed progression-free survival (PFS) and overall survival (OS); time to intervention for symptomatic metastatic CNS disease was a secondary endpoint. PFS was the primary endpoint in NEfERT-T; frequency of and time to symptomatic and/or progressive CNS lesions was a secondary endpoint. The primary endpoint in TBCRC 022 was composite CNS objective response rate (ORR), requiring a reduction of ≥50% in the sum of target CNS lesion volumes without progression of non-target lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression.
Results: CNS outcomes in NALA, NEfERT-T, and TBCRC 022 are summarized in the Table. In NALA, significantly fewer N+C vs L+C-treated patients required intervention for symptomatic CNS metastases. In NEfERT-T, the frequency of symptomatic or progressive CNS recurrences was significantly reduced and the time to onset of CNS progression significantly delayed in the N+P group vs the T+P group. In TBCRC 022, almost half of L-naive patients had a partial response using composite criteria.
Table. Overall/CNS outcomes in NALA, NEfERT-T, and TBCRC 022NALANEfERT-TTBCRC 022N+CL+CN+PT+PL-naive N+CL-treated N+CNo. of patients3073142422373712ORR, %332775781443Composite CNS ORR, %aN/AN/AN/AN/A4933CBR, %45*368885N/AN/APFSHR (p-value)0.76 (0.0059)1.02 (0.89)N/AMedian, months8.8b6.6b12.912.95.53.1OSHR (p-value)0.88 (0.2086)1.05 (0.77)N/AMedian, months24.0b22.2bNENE13.315.1Intervention for CNS disease, overall cumulative incidence, %22.8*29.2N/AN/AN/AN/AProgressive CNS disease, cumulative incidence, %c11.213.910.1**20.2N/AN/A*p&lt;0.05 for N+C vs L+C. **p=0.002 for N+P vs T+P. aDefined as a reduction of ≥50% in the sum of target CNS lesion volumes without progression of non-target lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. bRestricted mean values. cOverall cumulative index in NALA; 2-year cumulative index in NEfERT-T. CBR = clinical benefit rate; N/A = not applicable. NE = not estimable.Conclusions: Neratinib has demonstrated activity against CNS brain metastasis in the setting of advanced and metastatic breast cancer and may also limit the development of new CNS metastases in the adjuvant setting. A pooled analysis of data from NALA and NEfERT-T, which will enable subgroup analyses to be performed, is underway and will be presented at the meeting.
Citation Format: Ahmad H Awada, Adam M Brufsky, Cristina Saura, Rachel A Freedman, Nancy U Lin, Judith Bebchuk, Feng Xu, Sara Hurvitz. Impact of neratinib on development and progression of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC): Findings from the NALA, NEfERT-T, and TBCRC 022 trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-01.