HER2 inhibition shows promise in HER2-positive non-small cell lung cancer

Human epidermal growth factor receptor 2 (HER2) mutations may offer an important treatment target in a subset of patients with non-small cell lung cancer, according to data from a phase II randomized trial of neratinib and temsirolimus, presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, Spain.

HER2-mutated non-small cell lung cancer (NSCLC) is a small subset of NSCLC cases—approximately 1% to 2% cases—but inhibiting HER2 for these patients seems important, explained lead author Benjamin Besse, MD, PhD, head of the thoracic cancer unit at Gustave Roussy, Paris, France.

Neratinib inhibits the HER2 receptor while temsirolimus inhibits mTOR, a protein that belongs to the signaling cascade of HER2, Besse explained.

In a randomized, two-stage study, 27 patients with advanced, metastatic NSCLC whose tumors tested positive for HER2 somatic mutations were randomized either to treatment with oral neratinib (240 mg od continuously) alone, or in combination with intravenous temsirolimus (8 mg/week, dose escalation to 15 mg/week after one 3-week cycle if tolerated, at the investigator's discretion).

Preliminary results from stage one of the ongoing study show the combination of neratinib and temsirolimus had a 21% overall response rate in 14 patients, with a median progression-free survival of 4 months.

Researchers did observe more gastrointestinal effects such as diarrhea from combination therapy compared to neratinib alone, but it was not a limiting toxicity and the side effect was managed up front with prophylactic loperamide.

"HER2 mutated non-small cell lung cancer represents a very small number of patients, but it reflects the new face of NSCLC. It is not a single homogeneous disease, but a lot of different molecularly defined subsets of patients with potential 'drugable targets', for which specific strategies should be addressed," summarized Besse.

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