Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial

Abstract

Background.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). Materials and Methods. NALA was a randomized, activecontrolled 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 2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m 2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. Results. 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. Conclusion. These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC. The Oncologist ;9999:• • Implications for Practice: 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,

Neratinib and Capecitabine for the Treatment of Leptomeningeal Metastases from HER2-Positive Breast Cancer: A Series in the Setting of a Compassionate Program

“…Further insights were provided by the randomized phase 3 NALA trial that has confirmed that intracranial objective response rate, PFS and OS were higher in patients with BM treated with neratinib plus capecitabine (26.3%; 7.8 months; 16.4 months) as compared with patients who received lapatinib plus capecitabine (15.4%; 5.5 months; 15.4 months) [ 9 ]. Furthermore, neratinib plus capecitabine as compared with lapatinib and capecitabine was also associated with a longer PFS (12.4 months vs. 8.3 months), and lower cumulative incidence of interventions for CNS disease (25.5% vs. 36.0%), and progressive CNS disease (26.2% vs. 41.6%), suggesting that such a combined treatment could be a valuable option in patients with CNS involvement from HER2-positive metastatic BC [ 10 ].…”

Efficacy of tyrosine kinase inhibitors for the treatment of patients with HER2-positive breast cancer with brain metastases: a systematic review and meta-analysis

“… 6 Patients in the neratinib arm experienced improved PFS and CNS outcomes, but similar OS when compared with those treated with lapatinib. 26 Finally, in addition to their use as a treatment for established BM, there is growing interest in the use of TKIs such as neratinib as a means of preventing or delaying the occurrence of BM in patients with early 27 or metastatic 15 BC.…”

Intracranial Metastatic Disease: Present Challenges, Future Opportunities

“…Among these two patient cohorts, median PFS was 5.5 and 3.1 months, respectively, and median OS was 13.3 and 15.1 months, respectively, though no direct comparisons between groups were reported ( 109 ). When compared head-to-head with lapatinib and capecitabine (L+C) in a recent RCT, neratinib and capecitabine (N+C) showed a substantial though not statistically significant effect on OS (13.9 vs. 2.4 months, HR 0.90, p=0.635) and PFS (5.6 vs. 4.3 months, HR 0.66, p=0.074) in HER2-positive breast cancer patients with IMD who have previously failed at least two anti-HER2 therapies ( 110 ). The lack of statistical significance may have been due to small sample sizes.…”