Findings hint at CNS benefit for neratinib

By Peggy Peck, Editor-in-Chief, BreakingMED

CHICAGO —A phase III trial comparing neratinib plus capecitabine to lapatinib plus capecitabine as third-line therapy in HER2+ positive metastatic breast cancer found the neratinib combo superior.

The results of the NALA III trial were reported during an oral abstract session at the American Society of Clinical Oncology meeting here.

Of note, Adam M. Brufsky, MD, PhD, professor of medicine and co-director of the Comprehensive Breast Cancer Center, Magee Women’s Hospital of the University of Pittsburgh Medical Center, who presented the findings, said that fewer patients in the neratinib arm were treated for symptomatic brain metastases, suggesting that the neratinib/capecitabine combination may delay central nervous system progression.

The trial randomized 303 patients to the neratinib arm and 311 to the lapatinib arm.

NALA III discussant Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, said the CNS findings were a strength of the NALA III trial since extending survival in metastatic breast cancer also increases the risk for CNS involvement in the disease. But he noted that diarrhea was still a concern for 25% of the patients treated with neratinib, even though loperamide was offered to patients. Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center, who presented study findings at the same session, noted that many patients stop taking loperamide due to constipation.

Overall, Barrios said the neratinib combination offered modest benefit, but he questioned if it would be superior to the antibody drug conjugate trastuzumab emtansine (TDM-1) in a second-line setting.

“For the primary analysis of centrally confirmed PFS, treatment with neratinib plus capecitabine resulted in a statistically significant improvement in centrally confirmed PFS (hazard ratio=0.76, P=0.0059) compared to treatment with lapatinib plus capecitabine. Because the proportional hazard assumption did not hold, the statistical analysis plan for the NALA trial prespecified that a restricted means survival analysis at 24 months would be performed. In this prespecified analysis, the mean PFS for the patients treated with neratinib plus capecitabine was 8.8 months and the mean PFS for the patients treated with lapatinib plus capecitabine was 6.6 months,” according to a statement issued by Puma Biotechnology, which funded the trial.


The NALA 3 trial was supported by Puma Biotechnology.

Brufsky reported consulting or advisory roles with Myriad Pharmaceuticals, Merck, Bioarray Therapeutics, Puma Biotechnology, Genomic Health, NanoString Technologies, BioTherapeutics, Lilly, Bayer, Novartis, Celgene, Adendia, Genentech/Roche, and Pfizer.


Brufsky, A “Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial” ASCO 2019; Breast Cancer – Metastatic, Oral Abstract Session, June 4, Abstract 1002.

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