medwireNews: Individuals with non-small-cell lung cancer (NSCLC) harboring uncommon or very rare EGFR mutations benefit from treatment with EGFR–tyrosine kinase inhibitors (TKIs), but those with exon 20 insertions do not, German research suggests.
Sonja Loges (University of Heidelberg, Mannheim) and co-investigators say that although atypical EGFR mutations occur in 10–30% of EGFR-mutated NSCLC, real-world outcome data are needed for clinical decision-making in these patients.
To address this, Loges and team retrospectively reviewed data from the multicenter study of the national Network Genomic Medicine (nNGM) in Germany, which included treatment and outcome information for 260 patients with nonresectable NSCLC and atypical EGFR mutations in exons 18–21, including compound mutations with classical or other atypical EGFR mutations.
Of these, 87 (33.5%) had what the researchers classed as “more frequent uncommon” EGFR mutations including G719X, S768I, E709X, L861Q, and combinations of these with classical EGFR mutations such as L858R and exon 19 deletions.
A second group included 71 (27.3%) patients with exon 20 insertions and a third group, of 102 (39.2%) patients, had very rare point mutations, exon 18 deletions, exon 19 insertions, and very rare mutations in combination with other mutations.
The researchers report in the Annals of Oncology that patients with more frequent uncommon EGFR mutations had significantly longer median progression-free survival (PFS) when treated with an EGFR–TKI relative to chemotherapy, at 6.6 versus 5.0 months and a hazard ratio (HR) of 0.54.
Afatinib was the most commonly used EGFR–TKI in this group (46% of 79 treatments), followed by erlotinib (28%), gefitinib (16%), and osimertinib (10%), and median PFS differed significantly by treatment. Specifically, median PFS was longest with afatinib, at 12.0 months, and shortest with erlotinib, at 3.8 months.
Median PFS among the patients with exon 20 insertions was 3.3 months for those given an EGFR–TKI versus 5.0 months with chemotherapy, indicating no overall benefit with EGFR–TKIs in this group.
However, the investigators note that there were some “remarkable” exceptions to this trend, including one patient with a 773_774HVinsAH insertion who had a PFS of 25.4 months with first-line afatinib and another with a 773_774HVinsGHPH insertion who had a PFS of at least 10.0 months with afatinib after progressing during first-line chemotherapy.
In spite of this, Loges et al point out that “exon 20 insertions are very heterogeneous and despite the recent approval of two new drugs specifically for this cohort, additional investigation is warranted in order to identify which type of insertion may respond to specific TKI or drugs.”
In the last group, the patients with very rare EGFR mutations had significantly longer median PFS when receiving an EGFR–TKI versus chemotherapy (6.0 vs 3.5 months; HR=0.67).
The longest PFS among this group occurred with gefitinib treatment, at 16.0 months, while the shortest was with erlotinib (3.1 months), but the small numbers of patients in each group meant the differences did not reach statistical significance.
Indeed, Loges and co-authors stress that “the heterogeneous nature and singular occurrence of many mutations in this group” mean that “further preclinical characterization is warranted in order to determine the functional impact of very rare EGFR mutations.”
Nonetheless, they say that “[i]n the absence of other clinical information, information from one patient with a given very rare alteration who has responded to an EGFR-TKI is valuable to guide treatment decisions, although with a low level of evidence.”
The researchers also looked at immune checkpoint inhibitor use in all three groups, but patient numbers were too small to draw any firm conclusions.
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