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Very Rare EGFR Mutations Respond Heterogeneously to TKIs
Patients with non-small cell lung cancer (NSCLC) with very rare EGFR mutations, TP53 co-mutations, and exon 20 insertions may experience worse outcomes when treated with tyrosine kinase inhibitors (TKIs), according to a German study said to be the largest real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments reported yet.
“Atypical EGFR mutations occur in 10% to 30% of NSCLC patients with EGFR mutations and their sensitivity to classical EGFR-tyrosine kinase inhibitors (TKI) is highly heterogeneous. We propose a novel National Network Genomic Medicine (nNGM) classification for rare EGFR mutations,” wrote lead author Melanie Janning, MD, DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Germany, and colleagues.
Very rare single and complex mutations, comprising 40% of atypical mutations, show a high heterogeneity of TKI sensitivity. Patients harboring 1 group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKIs, while exon 20 insertions are mostly insensitive to EGFR-TKIs but display sensitivity to exon 20 inhibitors.
Researchers conducted a retrospective, multi-center study of 856 patients NSCLC with atypical EGFR mutations from 12 centers. Clinical follow-up data were available from 260 patients.
Researchers analyzed the data in 3 groups: uncommon mutations (G719X, S7681, L861Q and combinations), exon 20 insertions, and very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions).
“We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous,” concluded Dr Janning, et al.
