Drug combo reduces frequency of central nervous system metastases

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While neratinib plus paclitaxel was not superior to trastuzumab plus paclitaxel as first-line treatment for ERBB2-positive metastatic breast cancer in terms of progression-free survival, the combination was associated with delayed onset and reduced frequency of central nervous system metastases, a finding that requires a larger study to confirm.

Metastatic ERBB2-positive breast cancer has a characteristic spread with most patients developing liver metastases and about half having poor prognosis with central nervous system involvement.

Dr Ahmad Awada, of the Jules Bordet Institute, Brussels, and co-authors conducted a randomised clinical trial to examine progression-free survival in women with recurrent or metastatic ERBB2-positive breast cancer. They also examined secondary outcomes that included time to symptomatic or progressive central nervous system lesions and safety.

The NEfERT-T trial was conducted from 2009 through 2014 at 188 centres in 34 counties with 479 women, who were eligible if they had asymptomatic central nervous system lesions. The women were divided into two groups: 242 who received neratinib with paclitaxel and 237 who received trastuzumab plus paclitaxel.

Median progression-free survival was 12.9 months in both groups. However, the incidence of central nervous system recurrences was lower and the time to central nervous system metastases was delayed with neratinib plus paclitaxel, according to the results.

Diarrhoea and gastrointestinal effects, such as nausea and vomiting, were the main adverse events associated with neratinib plus paclitaxel, which was consistent with the safety profile previously documented for this combination, the authors report.

The authors note the study protocol did not include screening for central nervous system metastases but rather identified them on the presentation of symptoms, which means it is likely that central nervous system events were underestimated. The accrual goal of the study also was reduced from 1,200 to 480 patients, which the authors note was a limitation with regard to efficacy, along with the exclusion of patients with progressive or symptomatic central nervous system disease.

“Neratinib in combination with paclitaxel was not superior in terms of PFS (progression-free survival) compared with trastuzumab-paclitaxel in the first-line treatment of women with ERBB2-positive metastatic breast cancer but showed similar efficacy and may delay the onset and reduce the frequency of CNS (central nervous system) metastases,” the authors conclude.

“The results presented herein by Awada et al are of sufficient interest to merit further investigation, preferably prospectively (with antidiarrheal prophylaxis), and in principle coupled with an extensive companion biomarker campaign designed to further characterize and classify those patients at highest risk for development of metastasis,” writes Dr Mark D Pegram, of the Stanford School of Medicine, California, in a related editorial.

Importance: Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed.
Objective: To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer.
Design, Setting, and Participants: In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region.
Interventions: Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory.
Main Outcome and Measures: The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety.
Results: The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower (relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004). Common grade 3 to 4 adverse events were diarrhea (73 of 240 patients [30.4%] with neratinib-paclitaxel and 9 of 234 patients [3.8%] with trastuzumab-paclitaxel), neutropenia (31 patients [12.9%] vs 34 patients [14.5%]) and leukopenia (19 patients [7.9%] vs 25 patients [10.7%]); no grade 4 diarrhea was observed.
Conclusions and Relevance: In first-line ERBB2-positive metastatic breast cancer, neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of progression-free survival. In spite of similar overall efficacy, neratinib-paclitaxel may delay the onset and reduce the frequency of central nervous system progression, a finding that requires a larger study to confirm.

JAMA material
JAMA Oncology abstract
JAMA Oncology editorial

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