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 = .004). 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.

Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial

“…Benefits of neratinib in the prevention 22,23 and treatment 24 of CNS metastases in HER2+ breast cancer have been reported in other phase II and III studies, supporting a recommendation in current J o u r n a l P r e -p r o o f treatment guidelines for the use of neratinib-based therapy in brain metastases. 25 In the randomized NEfERT-T trial of patients with metastatic HER2-positive breast cancer treated in the first-line setting, the incidence of symptomatic or progressive CNS events was significantly reduced with neratinib plus paclitaxel versus trastuzumab plus paclitaxel (p=0.002).…”

“…22 Further support for the role of neratinib in CNS disease was shown in the phase III NALA trial. 23 In this trial of 621 patients, neratinib plus capecitabine significantly reduced the cumulative incidence of therapeutic interventions for CNS disease compared with lapatinib plus capecitabine after 2 or more HER2directed therapies for metastatic disease (p=0.043). 23 In the HR+/≤1-year population, adverse events associated with neratinib were generally transient and manageable with dose modifications and/or conventional treatment, as has been reported for the ITT population.…”

“…23 In this trial of 621 patients, neratinib plus capecitabine significantly reduced the cumulative incidence of therapeutic interventions for CNS disease compared with lapatinib plus capecitabine after 2 or more HER2directed therapies for metastatic disease (p=0.043). 23 In the HR+/≤1-year population, adverse events associated with neratinib were generally transient and manageable with dose modifications and/or conventional treatment, as has been reported for the ITT population. Diarrhea, a known class effect of tyrosine kinase inhibitors, 26 was common with neratinib in the absence of proactive antidiarrheal prophylaxis (grade 3, 39%), although most grade 3…”

Treatment Landscape and Prognosis After Treatment with Trastuzumab Emtansine

“…With novel anti-HER2 therapies that at least in part address several resistance mechanisms, there is an even greater chance that the continuation of an anti-HER2 treatment after progression results in a clinically relevant therapy efficacy. For example, Neratinib, another tyrosine kinase inhibitor, has been approved for the adjuvant treatment of patients with HER2-positive early BC for an extended adjuvant therapy and has also been approved in the U. S. for metastatic BC 28 , 29 . Afatinib, however, did not show any improvement in the outcomes for patients with metastatic BC compared to trastuzumab 30 .…”

Progression-Free Survival and Overall Survival in Patients with Advanced HER2-Positive Breast Cancer Treated with Trastuzumab Emtansine (T-DM1) after Previous Treatment with Pertuzumab

“…In addition, other novel substances are being developed for the treatment of HER2-positive BC patients. Neratinib, a tyrosine kinase inhibitor, has recently been approved for the extended adjuvant treatment of patients with HER2-positive early BC, due to its significant improvement of five-year disease-free survival (DFS) [ 22 ]; it was approved in the United States for the treatment of metastastic breast cancer as well, based on an improvement of PFS and time to intervention for the involvement of the central nervous system [ 23 ]. Margetuximab, a novel HER2 antibody, appears to enhance antibody-dependent, cell-mediated cytotoxicity (ADCC), while being well-tolerated [ 24 ].…”