ERBB2/HER2 Mutations Might Be ‘Targetable Drivers’ in Some Lung Cancers

ERBB2/HER2 mutations appear to be rare but targetable oncogenic drivers in non-small cell lung cancer (NSCLC), according to findings from a small retrospective cohort records analysis published in the Journal of Thoracic Oncology.

“Four of the nine patients had response to targeted therapies, with durations of response ranging from three to 10 months,” noted lead study author Jody C. Chuang, MD, PhD, of the Stanford Hospital & Clinics in Stanford, Calif., and colleagues. “We also explored potential resistance mechanisms upon progression on targeted therapies in a subset of patients, and identified a de novo PIK3CA mutation and ERBB2 copy-number gain as potential resistance mechanisms.”

The receptor tyrosine protein kinase ERBB2/HER2 (HER2/neu) is a tumor driver and amplification of ERBB2 is associated with tumor sensitivity to ERBB2-directed agents in some breast and gastroesophageal tumors. Acquired ERBB2 tumor mutations occur in a small number-perhaps 2%-of people diagnosed with NSCLC, the authors noted.

The researchers identified nine patients with metastatic NSCLC whose tumors harbored ERBB2 exon 20 insertion mutations that had undergone treatment with ERBB2/HER2-targeted agents such as trastuzumab, ado-trastuzumab, or afatinib. Seven of the patients were treated at Stanford University in California and two others were treated at the Sun-Yat-sen University Cancer Center in China. Responses were assessed using RECIST v1.1 criteria.

Four female patients experienced responses to ERBB2-targeted therapies, for a response rate of 44%. These patients had been administered trastuzumab plus chemotherapy; two of them had received also afatinib.

Five patients, three of whom were male, did not experience responses.

Patients with ERBB2 mutations “tend to be younger with little or no smoking history,” the authors noted. One patient had a novel PIK3CA mutation (R425L) that might have conveyed trastuzumab resistance.

Tolerability was a “challenge” for the patients, including dose-limiting afatinib toxicities (diarrhea and mucositis).

Additional research is needed and although one of the patients failed to respond to nivolumab, immunotherapies are nevertheless also “worth considering” for ERBB2 mutation-harboring NSCLC, the authors believe.

Coauthors disclosed payments from ACEA, Celgene, Clovis, Gilead, Nektar, Peregrine, Pfizer, and Roche.