As reported in the Journal of Clinical Oncology by Cristina Saura, MD, and colleagues, the phase III NALA trial has shown significantly prolonged progression-free survival with neratinib/capecitabine vs lapatinib/capecitabine in patients with HER2-positive metastatic breast cancer who had received two or more prior HER2-directed regimens.

The trial supported the February 2020 U.S. Food and Drug Administration approval of neratinib in combination with capecitabine for treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti–HER2-based regimens in the metastatic setting.

Cristina Saura, MD

Study Details

In the open-label trial, 621 patients (including 3 men) from 28 countries in Europe, North and South America, Asia, and Australia were randomly assigned between May 2013 and July 2017 to receive neratinib plus capecitabine (n = 307) or lapatinib plus capecitabine (n = 314). Patients with stable, asymptomatic central nervous system disease were eligible for the study.

The neratinib group received neratinib at 240 mg once daily plus capecitabine at 750 mg/m² twice daily on days 1 to 14 of 21-day cycles, with mandated loperamide antidiarrheal prophylaxis during cycle 1. The lapatinib group received lapatinib at 1,250 mg once daily plus capecitabine at 1,000 mg/m² twice daily on 14 of 21 days. Treatment was continued until disease progression or unacceptable toxicity.

The coprimary endpoints were progression-free survival on blinded central review and overall survival. The trial was considered positive if either primary endpoint was met. Secondary endpoints included time to central nervous system disease intervention, objective response rate, duration of response, and clinical benefit rate (complete or partial response and stable disease for ≥ 24 weeks).

Efficacy Outcomes

Median follow-up was 29.9 months (interquartile range = 21.9–40.6 months). Patients in the neratinib group had significantly prolonged progression-free survival vs the lapatinib group (hazard ratio [HR] = 0.76, 95% confidence interval [CI] = 0.63–0.93, P = .0059). Median progression-free survival was 5.6 months (95% CI = 4.9–6.9 months) vs 5.5 months (95% CI = 4.3–5.6 months). The Kaplan-Meier curves for progression-free survival overlapped during the first 24 weeks of treatment, and thereafter showed clear separation; the shape of the curve indicated violation of the proportional hazards assumption, which was confirmed by statistical testing.

A restricted means analysis supported the primary analysis, showing mean progression-free survival of 8.8 months (95% CI = 7.8–9.8 months) vs 6.6 months (95% CI = 5.9–7.4; P = .0003), with a mean difference of 2.2 months. Kaplan-Meier estimates of progression-free survival at 6, 12, and 18 months were 47.2% vs 37.8%, 28.8% vs 14.8%, and 16.3% vs 7.4%, respectively.

A numeric benefit in overall survival was observed with neratinib/capecitabine (192 vs 218 deaths), but did not achieve statistical significance (HR = 0.88, 95% CI = 0.72–1.07, P = .2086). Mean overall survival was 24.0 months (95% CI = 22.1–25.9 months) vs 22.2 months (95% CI = 20.4–24.0 months).

The overall cumulative incidence of intervention for central nervous system disease was 22.8% vs 29.2% (P = .043). Objective response was observed in 32.8% of 256 patients in the neratinib group vs 26.7% of 270 in the lapatinib group with measurable disease at baseline (P = .120), including complete response in 4 patients (1.6%) vs 1 patient (0.4%). Median duration of response was 8.5 months vs 5.6 months (HR = 0.50, P = .0004). The proportion of patients with responses lasting ≥ 12 months was 36.9% vs 16.8%. The clinical benefit rate was 44.5% vs 35.6% (P = .0328).

Adverse Events

The most common adverse events of any grade in the neratinib group were diarrhea (83% vs 66% in lapatinib group), nausea (53% vs 42%), palmar-plantar erythrodysesthesia (45.9% vs 56.3%), and vomiting (45.5% vs 31.2%). Grade 3 or 4 adverse events occurred in 58% vs 57% of patients, with the most common in the neratinib group including diarrhea (24.4% vs 12.5%; all grade 3), palmar-plantar erythrodysesthesia (9.6% vs 11.3%), hypokalemia (4.6% vs 6.4%), nausea (4.3% vs 2.9%), and vomiting (4.0% vs 1.9%). Grade 3 diarrhea was most common during the first treatment cycle (16% vs 5%).

Serious adverse events occurred in 34.0% vs 29.9% of patients. Adverse events led to discontinuation of any study drug in 13.9% vs 18.0%. Adverse events led to death in 8 patients in the neratinib group and 10 patients in the lapatinib group; only fulminant hepatitis leading to death in a patient in the lapatinib group was considered treatment-related.

No new safety concerns regarding cardiac events were identified; cardiac arrhythmia occurred in 3.3% vs 3.5% of patients, ischemic heart disease in 0.7% vs 0.6%, QT prolongation in 2.3% vs 3.9%, and left ventricular ejection fraction decrease in 4.3% vs 2.3%.

The investigators concluded, “NALA is the first study to demonstrate superiority of one HER2-directed tyrosine kinase inhibitor over another in metastatic breast cancer and provides evidence for the efficacy and tolerability of neratinib plus capecitabine in this setting. The primary endpoint of centrally assessed progression-free survival was significantly improved with neratinib plus capecitabine vs lapatinib vs capecitabine, and there were favorable outcomes across secondary endpoints, including duration of response and time to intervention for central nervous system disease. Neratinib plus capecitabine is an appropriate treatment option for patients with HER2-positive metastatic disease progressing after two or more lines of HER2-directed treatment.”

Dr. Saura, of the Breast Cancer Unit, Vall d’Hebron University, Barcelona, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Puma Biotechnology. For full disclosures of the study authors, visit ascopubs.org.