University of California Los Angeles/Jonsson Comprehensive Cancer Center, Los Angeles, California, USA.
Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, SOLTI Breast Cancer Cooperative Group, Barcelona, Spain.
Oncologist. 2021 Aug;26(8):e1327-e1338. doi: 10.1002/onco.13830. Epub 2021 Jun 7.
Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C).
NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered.
Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed.
These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC.
In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.
奈拉替尼在曲妥珠单抗治疗后出现中枢神经系统（CNS）转移的 HER2 阳性转移性乳腺癌（MBC）患者中具有疗效。我们报告了 III 期 NALA 试验中基线时存在 CNS 转移的患者的结果，该试验比较了奈拉替尼联合卡培他滨（N+C）与拉帕替尼联合卡培他滨（L+C）的疗效。
NALA 是一项针对 HER2 阳性 MBC 患者的随机、阳性对照试验，这些患者之前接受过两种或更多种 HER2 靶向治疗方案。有症状/稳定脑转移（已治疗或未治疗）的患者符合入组条件。患者被分配至 N+C（奈拉替尼 240 mg 每天一次，卡培他滨 750 mg/m²每天两次）或 L+C（拉帕替尼 1250 mg 每天一次，卡培他滨 1000 mg/m²每天两次）。独立评估无进展生存期（PFS）、总生存期（OS）和 CNS 终点。
在 621 名入组患者中，有 101 名（16.3%）基线时已知存在 CNS 转移（N+C 组，n=51；L+C 组，n=50）；81 名患者既往接受过 CNS 定向放疗和/或手术。在 CNS 亚组中，N+C 组的 24 个月时中位 PFS 为 7.8 个月，L+C 组为 5.5 个月（风险比 [HR]，0.66；95%置信区间 [CI]，0.41-1.05），N+C 组的 48 个月时中位 OS 为 16.4 个月，L+C 组为 15.4 个月（HR，0.90；95%CI，0.59-1.38）。在基线时存在可测量 CNS 病变的患者中（n=32），N+C 组和 L+C 组的 CNS 疾病干预的 12 个月累积发生率分别为 25.5%和 36.0%，CNS 疾病进展的累积发生率分别为 26.2%和 41.6%。
这些分析表明，与 L+C 相比，N+C 可改善 HER2 阳性 MBC 患者伴 CNS 转移患者的 PFS 和 CNS 结局。
在先前接受过两种或更多种 HER2 靶向治疗方案的 HER2 阳性乳腺癌伴 CNS 转移的患者亚组中，与拉帕替尼联合卡培他滨相比，奈拉替尼联合卡培他滨治疗可改善无进展生存期和 CNS 结局。这些发现建立在先前描述奈拉替尼在预防和治疗 CNS 转移方面疗效的 II 期和 III 期研究的基础上，支持奈拉替尼作为曲妥珠单抗靶向治疗后出现 HER2 阳性脑转移患者的一种全身性治疗选择。
