NALA Phase 3 Trial Outcomes in Patients Treated with Neratinib or Lapatinib

Conference Correspondent 

Central nervous system (CNS) metastases pose a significant challenge in metastatic breast cancer management due to the lack of available of evidence-based treatments. By studying the natural history and progression of the disease, we now recognize that up to half of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer have CNS metastases. Neratinib (Nerlynx) is an irreversible pan-HER tyrosine kinase inhibitor that has proven activity against CNS metastases in HER2-positive metastatic breast cancer. Demonstrated activity has been shown in 2 phase 2 studies called the NEfERT-T and TBCRC 022 studies, as well as one phase 3 study, NALA. For predefined CNS end points, significant improvements were reported in NEfERT-T and verified in NALA.

Cristina Saura, MD, Department Head, Breast Cancer Program, and Principal Investigator, Breast Cancer & Melanoma Group, Vall d’Hebron University Hospital, Barcelona, Spain, and colleagues reported findings from an exploratory analysis of patients from the NALA study with CNS involvement at the time of enrollment.

NALA is an international, randomized, active-controlled, open-label, phase 3 study assessing patients with HER2-positive metastatic breast cancer who had been treated with ≥2 lines of HER2-directed therapy in the metastatic setting.

Patients were eligible for participation in the study if they had asymptomatic metastatic brain disease managed with stable doses of corticosteroids for ≥14 days before randomization. Patients with symptomatic or unstable brain metastases were excluded from participation in the study. Patients were randomized 1:1 to receive neratinib (240 mg orally once daily) plus capecitabine (Xeloda; 750 mg/m2 orally twice daily) or lapatinib (Tykerb; 1250 mg orally once daily) plus capecitabine (1000 mg/m2 orally twice daily).

Centrally assessed progression-free survival and overall survival were the co-primary end points. A secondary end point was intervention for symptomatic metastatic CNS disease.

At baseline, CNS disease was defined as patients with treated or untreated disease in the brain that was assessed by the investigator at the time of enrollment. At screening, CNS imaging was not mandatory.

At baseline, 16% of the total 621 patients enrolled in NALA had documented CNS disease and 74% had no CNS disease. Between the treatment arms, baseline characteristics were considered well-balanced. A lower performance status was observed among patients with CNS disease, and they were more likely to have hormone receptor–negative disease than those without CNS disease. CNS radiation had been administered to 77% of the patients (N = 78), with 58% receiving whole brain treatment, 17% receiving stereotactic, 5% in the realm of undergoing CNS surgery, with the remainder 2% of unknown origin.

The median treatment duration was 3.5 months for lapatinib compared with 5.7 months for neratinib.

Patients treated with neratinib plus capecitabine compared with lapatinib plus capecitabine had significantly lower progression-free survival (8.8 vs 6.6 months; P = .0059), numerically higher but not statistically significant overall survival (24.0 vs 22.2 months; P = .2086), and lower incidence of CNS intervention (22.76% vs 29.19%; P = .043) regardless of the presence or absence of CNS metastases at baseline. New safety signals were undetected.

Irrespective of the baseline status of CNS metastases, patients had better outcomes in the neratinib plus capecitabine arm compared with the lapatinib plus capecitabine arm.

Source: Saura C, Ryvo L, Hurvitz S, et al. 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. Presented at: San Antonio Breast Cancer Symposium, December 8-11, 2020. Abstract PD13-09.

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