Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial

Abstract

Purpose: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.

Methods: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m² twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m² twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).

Results: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups.

Conclusion: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

FIG 1.

NALA trial profile. Screening failures were as follows: 251 patients did not meet the inclusion criteria, 118 of whom did not have centrally assessed HER2 overexpression of gene-amplified tumor; 152 patients were ineligible on the basis of the exclusion criteria; 11 patients were ineligible on the basis of both inclusion and exclusion criteria; and the reason for screen failure was not given for 2 patients. There could have been > 1 reason for each patient to have failed screening. (*) No previous treatment with capecitabine, neratinib, lapatinib, or other HER2-directed TKI was permitted. Patients were excluded if they had received previous treatment resulting in an anthracycline dose equivalent to a cumulative doxorubicin dose > 450 mg/m². Patients with symptomatic or unstable CNS metastatic disease were not eligible; patients with asymptomatic CNS metastases (treated or untreated) were eligible. Patients undergoing treatment for asymptomatic CNS metastases had to be on a stable dose of corticosteroids for ≥ 14 days before randomization. Patients with diarrhea as a major symptom of a significant chronic GI disorder were excluded.

FIG 2.

Kaplan-Meier curves for (A) centrally assessed progression-free survival (PFS), and (B) overall survival (OS) in the intention-to-treat population.

FIG 3.

Intervention for CNS disease.

FIG 4.

Changes over time in European Organization for Research and Treatment of Cancer (A) Quality of Life Questionnaire core module (QLQ-C30) summary score, and (B) QLQ-C30 Global Health Status score. Higher scores represent higher quality of life/levels of functioning. CxDy, cycle x day y.

FIG A1.

Subgroup analyses of (A) centrally assessed progression-free survival, and (B) overall survival in the intention-to-treat population. C, capecitabine; HR, hazard ratio; L, lapatinib; N, neratinib.

FIG A2.

Kaplan-Meier analysis of progression-free survival (PFS) according to hormone receptor status: patients with (A) hormone receptor–negative and (B) hormone receptor–positive disease. HR, hazard ratio.

FIG A3.

Kaplan-Meier analysis of progression-free survival (PFS) according to disease location: (A) visceral disease, and (B) nonvisceral disease. HR, hazard ratio.

FIG A4.

Kaplan-Meier analysis of overall survival (OS) according to hormone receptor status: patients with (A) hormone receptor–negative, and (B) hormone receptor–positive disease. HR, hazard ratio.

FIG A5.

Kaplan-Meier analysis of overall survival (OS) according to disease location: (A) visceral disease, and (B) nonvisceral disease. HR, hazard ratio; NE, not estimable.

FIG A6.

Kaplan-Meier analysis of response duration. HR, hazard ratio.