Abstract PD13-09: Impact of neratinib on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial

Abstract

Background: The development of central nervous system (CNS) metastases presents a considerable challenge in metastatic breast cancer (MBC) due to the limited availability of evidence-based treatments. Up to 50% of patients with HER2-positive (HER2+) MBC develop CNS metastases during the course of their disease. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated activity against CNS metastases in HER2+ MBC in two phase 2 studies (NEfERT-T, TBCRC 022) and one phase 3 study (NALA); significant benefits for predefined CNS endpoints were reported in NEfERT-T and confirmed in NALA. Here we present an exploratory analysis of patients from NALA with CNS involvement at enrollment. Methods: NALA was an international, randomized, open-label, active-controlled, phase 3 study in patients with HER2+ MBC who had received ≥2 lines of HER2-directed therapy in the metastatic setting (ClinicalTrials.gov: NCT01808573). Patients with asymptomatic metastatic brain disease managed with stable doses of corticosteroids for ≥14 days prior to randomization were eligible, whereas patients with symptomatic or unstable brain metastases were excluded. Patients were randomized (1:1 ratio) 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). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Intervention for symptomatic metastatic CNS disease was a secondary endpoint. CNS disease at baseline was defined as patients with treated or untreated disease in the ‘brain’ assessed by investigator at enrollment. CNS imaging was not mandatory at screening. Results: Of the 621 patients enrolled in NALA, 101 (16%) had documented baseline CNS disease and 520 (74%) had no CNS disease at baseline. Patients with CNS disease had a lower performance status and were more likely to have hormone receptor-negative disease than those with no CNS disease; no major imbalances of baseline characteristics were noted between treatment arms. Overall, 78 (77%) patients had previously received CNS radiation [whole brain, n=59 (58%); stereotactic, n=17 (17%); unknown, n=2 (2%)], and 5 (5%) patients had undergone CNS surgery. Median treatment duration was 5.7 (IQR 2.8-8.5) months for N, and 3.5 (IQR 2.1-6.9) months for L. PFS, OS, and cumulative incidence of interventions for symptomatic CNS disease are summarized in the table. No new safety signals were detected. Conclusions: Regardless of the status of CNS metastases at baseline, patients appeared to have better outcomes in the N+C arm compared with the L+C arm. Table. Efficacy outcomes in patients with and without CNS disease at baselineIntention-to-treat (n=621)CNS metastases at baseline – Yes (n=101)CNS metastases at baseline – No (n=520)N+C (n=307)L+C (n=314)N+C (n=51)L+C (n=50)N+C (n=256)L+C (n=264)PFSaHazard ratio (95% CI)0.76 (0.63–0.93)0.66 (0.41–1.05)0.76 (0.62–0.94)P-value0.00590.07410.0099Restricted mean PFSb, months8.86.67.85.59.06.9Difference, months2.22.32.1OSHazard ratio (95% CI)0.88 (0.72–1.07)0.90 (0.59–1.38)0.85 (0.68–1.06)P-value0.20860.63520.1517Restricted mean OSb, months24.022.216.415.425.623.6Difference, months1.71.02.0Incidence of CNS interventionOverall cumulative incidencec, %22.7629.1940.1347.7919.1624.65P-value0.0430.4300.067aCentrally confirmed; bRestriction prespecified as 24 months for PFS, and 48 months for OS; c % requiring intervention for CNS disease (competing risk model) Citation Format: Cristina Saura, Larisa Ryvo, Sara Hurvitz, William Gradishar, Beverly Moy, Suzette Delaloge, Sung-Bae Kim, Mafalda Oliveira, Maureen Trudeau, Ming-Shen Dai, Barbara Haley, Ron Bose, Luciana Landeiro, Judith Bebchuk, Aimee Frazier, Kiana Keyvanjah, Richard Bryce, Adam Brufsky. Impact of neratinib on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA 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 PD13-09.

Management of Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases: ASCO Guideline Update

“…20 The Panel is also aware of a San Antonio Breast Cancer 2020 presentation on the neratinib plus capecitabine versus lapatinib plus capecitabine regimen; however, abstracts are excluded as evidence. 10 The evidence is insufficient to make a recommendation in second-line and the Expert Panel will await a full publication and publications on other studies of this regimen.In addition to compounds previously discussed, a subgroup of patients receiving trastuzumab deruxtecan who have stable metastases, in the DESTINY 0-1 study, showed sustained response of 18.1 versus 16.4 months, regardless of CNS metastases. Because investigators presented this in an ASCO abstract that is not yet published, additional study is warranted.…”

“…The Panel is also aware of a San Antonio Breast Cancer 2020 presentation on the neratinib plus capecitabine versus lapatinib plus capecitabine regimen; however, abstracts are excluded as evidence. 10 The evidence is insufficient to make a recommendation in second-line and the Expert Panel will await a full publication and publications on other studies of this regimen.…”

“…In addition, several of these studies were conducted in the pre–HER2-targeted therapy era. Approximately 5% of patients with advanced HER2-positive breast cancer and brain metastases have leptomeningeal metastases 10 (see https://www.cancer.net/cancer-types/brain-tumor/statistics), but this guideline does not comprehensively review treatment of patients with leptomeningeal metastases.…”

Clinicopathologic and Genomic Landscape of Breast Carcinoma Brain Metastases

“…However, limited evidence of potential central nervous system activity of targeted agents, including alpelisib and olaparib, is available from case reports [17,18]. Additionally, in the NALA trial, neratinib in combination with capecitabine showed good efficacy in patients with HER2-positive BCBM [19]. Studies have previously examined the genomic landscape of BCBM and reported genomically distinct features from primary breast cancer as well as extracranial metastasis [20].…”