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Is There a Unicorn Among the Uncommon EGFR Mutations?

*November 2022*

The uncommon EGFR mutations remain a perennial challenge to treat. They constitute a heterogenous group of molecular alterations within exons 18 to 21, which include substitution mutations of G719X, L861Q, and S768I, and exon 20 insertions, with prevalence of approximately 10% to 20% of EGFR mutation-positive NSCLC. EGFR mutations are highly prevalent in East Asian populations (frequency >50%) compared with Western populations, and most data stem from studies with Asian patients. One of the major challenges in treating uncommon mutations is they are highly heterogenous with low frequencies and often missed by older assays using hotspot detection of specific exons. Nevertheless, with increased utilization of more sensitive molecular profiling assays such as next-generation sequencing (including plasma-based) and multiplex polymerase chain reaction tests in routine clinical practice, their detection rates have increased, providing opportunity for targeted treatment strategies for these patients.

Unlike the “classical” mutations comprising EGFR exon 19 deletions and exon 21 L858R substitution mutations which are well studied in landmark trials, the optimal treatment strategy for these uncommon mutations remains uncertain. Preclinical and clinical data have found greater sensitivity to second- and third-generation tyrosine kinase inhibitors (TKIs) compared with first-generation, and afatinib or osimertinib has been proposed as reasonable first-line option in this setting. Early studies with first-generation EGFR TKIs revealed variable responses and inferior outcomes, but data with afatinib reported more promising results, including a post hoc analysis from the LUX-Lung trials revealing objective response rate (ORR) of 71.1% and median progression-free survival (mPFS) of 10.7 months in the subgroup of 38 patients with major uncommon mutations (such as G719X, L861Q, and S768I). A recent pooled analysis from a large patient database from clinical trials and expanded access programs also revealed activity of afatinib against the uncommon mutations and compound mutations. On the basis of this, the Food and Drug Administration approved the use of afatinib for these rare mutations – being the sole TKI approved for this indication to date. Read more.