Neratinib Plus Capecitabine Shows Activity in HER2-Positive Metastatic Breast Cancer
Neratinib is an irreversible pan-tyrosine kinase inhibitor with activity against HER1, HER2, and HER4. In a phase I/II trial reported in the Journal of Clinical Oncology, Saura et al found that the combination of neratinib and capecitabine exhibited high activity in patients with trastuzumab (Herceptin)- and taxane-pretreated HER2-positive metastatic breast cancer, including those with prior treatment with the dual HER1/HER2 kinase inhibitor lapatinib (Tykerb).
Phase I
In the phase I dose-escalation phase in 33 patients, the maximum tolerated dose of the combined regimen was found to be neratinib at 240 mg once a day continuously and capecitabine at 1,500 mg/m2 twice a day on days 1 and 14 every 21 days. No dose-limiting toxicity was observed at this level; dose-limiting toxicities at higher doses of neratinib or capecitabine included diarrhea, increased liver enzymes, and asthenia.
Phase II
In the phase II portion, 72 patients, including 7 with prior lapatinib treatment, received the maximum tolerated dose of the combination. The overall response rate in 65 patients with no prior lapatinib was 64% (95% confidence interval [CI] = 51%–76%), including complete response in 12%. In the 7 patients with prior lapatinib treatment, the response rate was 57% (95% CI = 18%–90%), including complete response in 1 patient (14%).
Stable disease ≥ 24 weeks was achieved in an additional 8% and 14% of patients. Median progression-free survival was 40.3 weeks (95% CI = 30.3–66.0 weeks) and 35.9 weeks (95% CI = 18.9–60.1 weeks).
Adverse Events
In phase I and II combined, the most common drug-related adverse events of any grade were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In the phase II portion, treatment-related grade 3 or 4 adverse events occurred in 60% of patients (60% of those with no prior lapatinib, 57% of those with prior lapatinib), with the most common being diarrhea (26%; 26% and 29%) and palmar-plantar erythrodysesthesia (14%; 15% and 10%). Grade 3 or 4 hypokalemia occurred in three patients (43%) with prior lapatinib treatment (6% overall, 2% of those with no prior lapatinib).
A phase III registration trial (NALA; EUDRACT No. 2012-004492-38) has been initiated to compare the activity of neratinib plus capecitabine vs lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer who have received two HER2-directed regimens for metastatic disease.
The investigators concluded: “Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib.”
Cristina Saura, MD, of Vall d’Hebron Institute of Oncology, Barcelona, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by Pfizer and Wyeth. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
