Neratinib plus capecitabine improved progression-free survival and time to intervention for central nervous system disease in patients with previously treated HER2-positive metastatic breast cancer compared with lapatinib plus capecitabine, results from the phase 3 NALA trial show.
The combination of neratinib (Nerlynx) and capecitabine (Xeloda) improved progression-free survival (PFS) and time to intervention for central nervous system (CNS) disease in patients with previously treated HER2-positive metastatic breast cancer compared with lapatinib (Tykerb) plus capecitabine, results from the phase 3 NALA trial show.
Neratinib plus capecitabine was approved by the FDA as an extended adjuvant treatment of patients with early-stage disease based on results from the phase 2 ExteNET trial (NCT00878709). Other studies, like the NEfERT-T trial (NCT00915018) and the CONTROL trial (NCT02400476), also showed efficacy improvement and addressed the revealed safety concerns with the agent. Studies showed neratinib’s ability to induce CNS responses in patients with HER2-positive breast cancer, including NEfERT-T and the phase 2 TBCRC 022 trial (NCT01494662).
Lapatinib has also been efficacious as treatment of patients with HER2-positive breast cancer and CNS involvement. In the phase 2 LANDSCAPE trial (NCT00967031), the agent led to a CNS response rate of 66%.
It was based on these earlier studies of neratinib and lapatinib that the NALA trial was designed to compare the efficacy of neratinib/chemotherapy versus lapatinib/chemotherapy in 621 patients from 28 countries who were treated at 203 sites in Europe, North and South America, Asia, and Australia. Patients were randomized 1:1 to either arm. Neratinib was administered at a dose of 240 mg once daily with capecitabine 750 mg/m2 twice daily. Lapatinib was administered at 1250 mg once daily plus capecitabine 1000 mg/m2.
A total of 307 patients were enrolled in the neratinib arm and 314 into the lapatinib arm, and patients were followed for a median of 29.9 months (interquartile range [IQR], 21.9-40.6 months). The median PFS observed with neratinib was 8.8 months compared with 6.6 months with lapatinib, which was a significant improvement in PFS (HR, 0.76; 95% CI, 0.63-0.93; stratified log-rank P = .0059). Notably, a Kaplan-Meier plot showed the PFS curves were overlapping over the first 24 weeks, then separated. Kaplan-Meier PFS estimates were provided for 6 months, 12 months, and 18 months. The estimated 6-month PFS rate was 47.2% (95% CI, 41.1%-53.1%). The 12-month PFS rate estimate was 28.8 months (23.1-34.8 months), and the 18-month PFS rate was estimated to be 16.3 months (11.3-22.1 months).
Among the subgroup populations in the study, neratinib showed superiority over lapatinib in terms of PFS, with the exception of patients with hormone receptor-negative disease.
The locally assessed median OS was 24.0 months in the neratinib group versus 22.2 months in the lapatinib group, a difference that was not statistically significant (HR, 0.88; 95% CI, 0.72-1.07; stratified log-rank P =.2086).
The objective response rate (ORR) was 32.8% (95% CI, 27.1%-38.9%) in the neratinib arm compared with 26.7% (95% CI, 21.5%-32.4%) in the lapatinib arm (P = .1201). The best responses were complete response observed in 1.6% of patients (n = 4) in the neratinib arm and 0.4% of patients (n = 1) in the lapatinib arm. Additionally, 39.1% of the neratinib arm (n = 100) achieved partial responses, and 33.7% of patients in the lapatinib arm (n = 91) achieved partial responses. Stable disease was observed in 35.2% of the neratinib group (n = 90) compared with 44.1% (n = 119) of the lapatinib group. Over 18% of the neratinib arm (n = 47) had progressive disease, as did 5.9% (n = 16) of the lapatinib arm.
The median duration of response (DOR) was 8.5 months (95% CI, 5.6-11.2) among patients who received neratinib compared with 5.6 months (95% CI, 4.2-6.4) for patients who received lapatinib (HR, 0.50; 95% CI, 0.33-0.74; P =.0004).
The clinical benefit rate (CBR) of neratinib plus capecitabine was 44.5% (95% CI, 38.3%-50.8%) versus 35.6% (95% CI, 29.8%-41.6%) with lapatinib plus capecitabine (P =.0328).
For the safety analysis, 303 patients from the neratinib arm and 311 patients from the lapatinib arm were evaluable. The median treatment duration was 5.7 months (IQR, 2.7-10.4 months) for neratinib/capecitabine and 4.4 months (IQR, 2.3-7.1 months) for lapatinib/capecitabine. Treatment-emergent adverse events (AEs) were observed in 611 patients, and 196 patients experienced serious treatment-emergent AEs. Of the patients with a serious treatment-emergent AE, 103 had received neratinib, and 93 received lapatinib. In addition, treatment-related AEs were observed in 588 patients, 289 of whom were in the neratinib combination group and 299 of whom received the lapatinib combination.
The most common treatment-emergent AEs included any-grade diarrhea (83.2%), nausea (53.1%), palmar-plantar erythrodysesthesia syndrome (45.9%), and vomiting (45.5%). Grade 3 diarrhea was notable in 24.4% of patients in the neratinib arm and 12.5% of the lapatinib. Most patients experienced grade 3 diarrhea during the first cycle of treatment.
In terms of dose reductions and discontinuations, 5.3% of patients from the neratinib arm and 4.2% of patients from the lapatinib arm required dose reductions due to diarrhea. Two hundred ninety-eight patients received antidiarrheals to address the toxicity. None of the cardiac events were of concern in this study.
The study also included a health-related quality of life analysis which showed a similar mean QLQ-C30 summary score and Global Health Status/QoL subscale score between the arms.
Overall neratinib plus capecitabine was effaceable and safe for use in pretreated patients with HER2-positive breast cancer who has CNS involvement. No new safety signals were observed with the neratinib combination in this study.
The patient population was compiled of individuals aged 18 years or older with an ECOG performance status of 1 or lower, a confirmed diagnosis of HER2-positive breast cancer with CNS metastasis, and at least 2 prior lines of HER2-directed therapies.
Baseline assessment showed the median age of patients in the neratinib arm was 55 years (range, 47-63), and for the lapatinib arm was 54 years (range, 47-62). All patients in the neratinib arm were female, and the majority of the lapatinib arm was female. Three patients in the lapatinib arm were male, however. ECOG performance status at the time of enrollment was 0 for 174 patients (56.7%) in the neratinib arm and 164 patients (52.2%) in the lapatinib arm. The remaining patients had an ECOG performance status of 1. Most patients were hormone receptor-positive including 181 patients (59.0%) in the neratinib arm and 186 patients (59.2%) in the lapatinib arm.
The majority of patients had visceral-only disease locations including 259 patients (84.4%) in the neratinib arm and 270 (86.0%) in the lapatinib arm. Bone was the disease location that impacted the least patients in this study which was 21 patients (6.8%) in the neratinib group and also 21 patients in the lapatinib group (6.7%).
Most patients, including 215 patients (70.0%) of the neratinib arm and 215 patients (68.5%) in the lapatinib arm, received only 2 prior HER2-directed therapies as required in the study protocol, but there were also 92 patients (30.0%) who received neratinib and 99 patients (31.5%) who received lapatinib that had 3 prior HER2-directed therapies. Trastuzumab (Herceptin) was the most common prior HER2-directed therapy, having been received by 124 patients (40.4%) in the neratinib group and 113 patients (36.0%) in the lapatinib group. The combination of trastuzumab and pertuzumab (Perjeta) was the least common prior HER-2 directed treatment, which was received by only 24 patients (7.8%) in the neratinib arm and 23 patients (7.3%) in the lapatinib arm.
NALA is a randomized, multicenter, open-label, active-controlled parallel design study that accessed the co-primary end point of PFS and OS. The secondary end points of the study included intervention for symptomatic metastatic central nervous system disease, ORR, CBR, DOR, and the percentage of patients with treatment-emergent AEs.
Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase iii NALA trial. J Clin Oncol. Published online July 17, 2020. doi: 10.1200/JCO.20.00147