While it is best known as a biomarker in breast cancer, HER2 has also been identified as a driver of other cancers, including lung cancer. Assays are available to identify aberrations in the HER2-gene allowing the identification of patients who could benefit from targeted therapy. For example, dacomitinib has shown activity in lung cancer cell lines and its effectiveness in patients is investigated for the first time in this study.
The context
Both mutations in the HER2 gene and the presence of multiple copies of the gene can drive the develoment of cancer. In lung cancer, HER2 mutations are present in 1 – 4% of patients and amplifications in 2 – 5%. New assays lead to an increased identification of patients who can be treated by targeting this mechanism.
Dacomitinib is an inhibitor which anchors to HER2 and similar receptors, and inhibits their function. The compound’s effect was previously investigated in patients with EGFR mutations. In this study, its value for HER2+ patients was investigated.
The nuts and bolts
The study included 30 stage IIIb and IV lung adenocarcinoma patients, who had their HER2 status confirmed by microscopy and/or determining the genetic sequence. They were treated with 45 mg dacomitinib once-a-day in 28 day cycles. This was continued until disease progression or unacceptable toxicity. Tumor assessments were done at 4 weeks, 8 weeks and then every 8 weeks, while toxicity was monitored continuously.
After dacomitinib treatment, a small positive effect was seen in 12% of the patients with HER2 mutations. Patients with HER2 amplifications experienced no benefit from dacomitinib treatment. As most patients didn’t respond to the treatment, this indicates that the term “HER2 positive” is not specific enough to describe these cancers. To correctly identify patients that benefit from HER2-targeted drugs, more in-depth characterization of the HER2 gene is needed.
The study also reveals the complexity of finding mutations that can be used as targets for treatment. Enough patients with each mutation should be available to make it possible to study their effect. Also drug development is challenging, as it is difficult to identify small patient groups with a certain molecular background in which the drug will have effect. Sharing information such as precise molecular profiles of tumors will be essential to accelerate cancer drug development. A searchable database where these results are collected could go a long way in unraveling complexities of various cancers.
How will this help me?
The results of this study show that targeted therapies for HER2 aberrations show promise and can lead to meaningful responses for patients with selected genetic profile. More elaborate studies are required to validate the effects of dacomitinib in lung cancer and identify the mutations that can be targeted.
Source
Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors – Annals of Oncology (2015)