The combination of neratinib and capecitabine showed positive efficacy outcomes, but also a high degree of toxicity, in patients with progressive HER2-positive breast cancer and brain metastases, according to results from a phase 2 study.
“Neratinib [is] an irreversible pan-HER tyrosine kinase inhibitor that inhibits signal transduction,” wrote Rachel A Freedman, MD, MPH, of the Dana-Farber Cancer Institute in Boston, and her colleagues. Their report is in the. The researchers grouped patients into two cohorts, those without previous lapatinib (n = 37) and those with previous lapatinib exposure (n = 12), which were termed cohort 3A and 3B, respectively. All study participants were given neratinib 240 mg once daily in combination with capecitabine 750 mg/m2 twice daily for a total of 14 days, followed by 7 days without capecitabine.
The primary outcome measured was the composite central nervous system (CNS) objective response rate (ORR) of each individual cohort, which was defined as a decrease of at least 50% in the total target CNS lesion volumes, in the absence of other markers of further progression.
After analysis, Dr. Freedman and her colleagues found that the CNS ORR was 49% (95% confidence interval, 32%-66%) and 33% (95% CI, 10%-65%) in cohorts 3A and 3B, respectively. In addition, the team reported that the median progression-free survival was 5.5 and 3.1 months in the same respective cohorts.
With respect to safety, the most frequently seen adverse event was diarrhea, with 29% of study participants having grade 3 toxicity. The researchers reported that no grade 4 adverse events were seen.
“It is possible that selection bias affected toxicity events, because no patients in cohort 3B stopped treatment [due to] toxicity,” they said.
A key limitation of the study was the lack of a comparison group, which could be added in future trials.
“Future studies could examine local therapy versus systemic therapy in CNS disease and additionally explore the role of other neratinib-based combination regimens,” they concluded.
The study was supported by grant funding from Puma Biotechnology, the Translational Breast Cancer Research Consortium’s foundation partners, the American Cancer Society, Susan G. Komen for the Cure, the Breast Cancer Research Foundation, and the Dana-Farber/Harvard Cancer Center. The authors reported financial affiliations with Puma Biotechnology, Genentech, Eli Lilly, Novartis, Pfizer, and others.
SOURCE: Freedman RA et al. J Clin Oncol. 2019 Mar 12. .