EGFR Mutations Help Match Individuals With NSCLC to Treatment

Grouping epidermal growth factor receptor (EGFR) mutations’ function and structure provides the framework to match individuals with non-small cell lung cancer (NSCLC) to the right treatment, the results of a study conducted by investigators at the University of Texas MD Anderson Cancer Center show.

“More than 70 different EGFR mutations have been identified in patients, but drugs have only been approved for a handful of them. One of the immediate implications of our research is the discovery that therapies we already have may work for many of these mutations,” John Heymach, MD, PhD, chair of thoracic/head and neck medical oncology, said in a statement.

“For some mutations, older drugs may actually work better, and for other mutations, newer drugs work better,” he said.

There are 4 EGFR-mutant NSCLC subgroups: classical-like; Exon 20 loop insertion; P-loop aC-helix compression; and T790M-like. Classical-like groups have little or no impact on drug binding. Exon 20 loop insertion has insertions of additional amino acids in the loop after the C-terminal end of the aC-helix. P-loop aC-helix compression contains mutation on the interior surface of the ATP binding pocket, or C-terminal end of the aC-helix. T790M-like groups contain at least 1 mutation in hydrophobic cleft and are often resistant to first-generation therapy.

“Right now, in the absence of guidance, clinicians often use the newest treatment for all EGFR mutations. This model can help us pick better therapies for patients immediately and hopefully develop better drugs for specific subgroups of mutations,” Heymach said.

Classical-like mutations were sensitive to tyrosine kinase inhibitors (TKI)s but particularly third-generation ones. Exon 20 loop insertions responded best to second-generation TKIs. P-loop aC-helix compression mutations were the most sensitive to second-generation TKIs. T790M-like mutations were sensitive to ALK and protein kinase C inhibitors, with some sensitivity to third-generation TKIs.

First-, second-, and third-generation TKIs target different EGFR proteins. The current approach is to test new drugs based on exon number, which indicates where the mutation occurred on the DNA.

In the study, investigators analyzed data from 16,175 individuals with EGFR-mutant NSCLC from 5 patient databases. Investigators looked at the time to treatment failure, which is the indication of how quickly the cancer became resistant to therapy.

Lower overall survival rates and shorter time to treatment failure were associated with atypical mutations, regardless of treatment.

Classical mutations treated with first and third TKIs had a longer time to treatment failure.

The investigators found that screening cell lines against 18 EGFR inhibitors to show the found distinct subgroups showed structure was more predictive than exon-based groups.

The study results also showed the importance of biomarker testing for individuals with new NSCLC or a reoccurrence. This can detect oncogenic driver EGRF mutations, which fall into these subgroups.

The investigators say this is important for rare mutations because they are harder to identify with traditional methods.

Reference

Classifying EGFR mutations by structure and function offers better way to match non-small cell lung cancer patients to treatments. EurekAlert. News release. September 15, 2021. Accessed September 17, 2021. https://www.eurekalert.org/news-releases/928439