Rare, complex EGFR mutations adversely affect EGFR–TKI treatment outcomes

By Shreeya Nanda, Senior medwireNews Reporter

Individuals with advanced non-small-cell lung cancer (NSCLC) who have rare or complex epidermal growth factor receptor (EGFR) mutations have inferior outcomes in response to EGFR–tyrosine kinase inhibitor (TKI) treatment compared with those with common mutations, research indicates.

Additionally, the study population was composed of heterogeneous groups, each of which showed different responses to EGFR–TKIs and had different rates of survival, Young Joo Min (University of Ulsan College of Medicine, Republic of Korea) and co-workers report in Lung Cancer.

The researchers explain that EGFR mutations, of which the exon 19 deletion (del-19) and the L858R substitution in exon 21 are the most common, are known to confer sensitivity to EGFR–TKIs such as gefitinib and erlotinib. But the efficacy of this class of drugs in NSCLC patients with rare or complex mutations remains to be elucidated.

Of the 1738 patients with advanced NSCLC seen at four Korean centres for whom EGFR genotyping data were available, 88 (5.1%) had rare or complex mutations, defined respectively as a mutation other than del-19 or L858R, and two or more distinct mutations co-occurring in the same tumour. And 54 of these patients, 33 with rare and 21 with complex mutations, had received EGFR–TKI therapy.

The overall response rate (ORR) was 20.4%, with no and 11 participants achieving a complete and partial response, respectively. In addition, 20 patients had stable disease, giving a disease control rate of 57.4%.

After a median follow-up of 381 days, median progression-free survival (PFS) was 2.6 months. And overall survival (OS) was 12.7 months.

When the study population was stratified by mutation, patients with single rare mutations in exon 18 (group 1; n=7) and in exon 20 (group 2; n=24) had a significantly poorer response to EGFR–TKIs than individuals with complex mutations with del-19 or L858R (group 3; n=12) and those with other single rare or complex mutations (group 4; n=11). The ORRs for groups 1, 2, 3 and 4 were 0.0%, 8.3%, 33.3% and 45.5%, respectively.

Median PFS was 1.3 months for individuals in group 1 and 2.6 months for those in group 2 – this was significantly shorter than the median PFS of 7.4 and 5.1 months for groups 3 and 4, respectively. Groups 1 and 2 also fared worse in terms of OS, but the difference was not statistically significant.

“These rare or complex mutations are not so infrequent that the efficacy of EGFR-TKIs for patients with these mutations should [not] be elucidated”, say Min et al.

They conclude: “Further studies with larger numbers of patients will be needed to sub-classify these rare or complex mutations and develop optimal treatment strategies.”

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