Where are we today regarding the clinical evaluation of NRG1-directed therapies?
NRG1 fusions are oncogenic events, i.e., transforming events that occur in all tumor types, although in fairly low frequencies. Their prevalence is less than 1 % throughout all tumor types. Some reports have estimated the NRG1 fusion prevalence at approximately 0.2 % . Although NRG1 fusions are not a common event, they represent an important actionable driver. On the cell level, what happens is that the NRG1 fusion partner provides a transmembrane anchor for the EGF-like domain of NRG1. This EGF domain then serves as a ligand that interacts with HER3 or HER4, which will heterodimerize and induce signaling through phosphorylation via the MAPK/PI3K pathways.
At ESMO 2019, we saw some early signs of drug activity in NRG1-positive lung cancer with updates on several prospective trials in progress or in the planning stages. With the pan-ErbB TKI afatinib, clear responses have been observed in previous case reports, reinforced by an updated case series presented at ESMO 2019 . Of course, given the nature of these reports, this does not actually inform us with respect to the response rate, but what it does tell us is that NRG1 fusions are actionable drivers, and it demonstrates the major characteristics that we are looking for in viable therapeutic targets: rapid responses, potentially durable responses, and dramatic responses. This is a clear target, and when we identify it, we should act upon it. Several trials are in development, and hopefully in the years to come we will see the results obtained in patients with these rare but important events.
Will there be any novel molecular targets for lung cancer treatment in the foreseeable future?
The molecular targets established in the treatment of NSCLC do indeed guide our initial therapy. Approved agents are available for EGFR-, ALK-, ROS1-, BRAF– and NTRK-positive disease. What we have recently seen is the emergence of RET fusions as a clear actionable driver. Hopefully, highly selective RET kinase inhibitors such as selpercatinib and pralsetinib (BLU-667) will reach approval for the treatment of RET-positive tumors soon. MET exon 14 skipping mutations, EGFR exon 20 mutations and HER2 insertions are clearly actionable drivers. We do not have FDA-approved drugs for these targets yet, but we certainly will in the near future. For the treatment of lung cancer with NRG1 fusions, prospective studies that show efficacy of targeted agents are still lacking, but they will come.
We can assume that there are more oncogenic driver aberrations out there, although they will be harder to find, as they will probably be less common than those we already have. However, it is important to identify these drivers, because they affect the tumor biology and will help select for targeted therapy and, importantly, potentially de-select for immunotherapy.
- Jonna S et al., Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res 2019; 25(16): 4966-4972
- Liu SV et al., Targeting NRG1 fusions in multiple tumour types: afatinib as a novel potential treatment option. ESMO 2019, abstract 1969P
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