Dr Franke on Treatment Options for NSCLC Expressing Uncommon EGFR Mutations

Aaron J. Franke, MD, MS, assistant professor of medicine, Division of Hematology and Oncology, the University of Florida (UF) College of Medicine, associate research leader, Thoracic Cancers Disease Site Group, UF Health Cancer Center, discusses treatment options for patients with uncommon EGFR mutations in non–small cell lung cancer (NSCLC).

About 10% of patients with NSCLC will express uncommon EGFR mutations, or mutations other than exon 19 deletions or exon 21 L858R point mutations, Franke begins. The most frequent uncommon EGFR point mutations are in G719X of exon 18, L861Q in exon 21, S768I in exon 20, and both de novo and acquired exon 20 insertions, Franke states. Approaches to the treatment of these rare EGFR mutations are accordingly grouped as either exon 20 insertion mutations or non–exon 20 mutations, Franke explains. Patients with these substitution mutations may benefit from EGFR TKIs.

The retrospective UNICORN/TCOG1901 study (NCT05421936) evaluated real-world outcomes with the third-generation TKI osimertinib (Tagrisso) as a first-line treatment for NSCLC with uncommon EGFR mutations. Results from this study were recently published in the Journal of Thoracic Oncology, and showed that the agent elicited an overall response rate of 61% and a median duration of response of 17.4 months in all cohorts, Franke reports. Further analysis of patients according to mutational status showed that patients with G719X, L861Q, and de novoT790M mutations all responded well to osimertinib. Moreover, patients with compound EGFRmutations that included both a common and atypical mutation, had better outcomes with osimertinib compared with patients who only expressed uncommon EGFR mutations, Franke adds.

Previous data from the phase 2 LUX-Lung 2 (NCT00525148) and phase 3 LUX-Lung 3 (NCT00949650), and LUX-Lung 6 (NCT01121393) trials led to the expanded FDA approval of afatinib (Gilotrif) as a first-line treatment for patients with metastatic NSCLC expressing non-resistant EGFR mutations. Afatinib is currently the only drug approved for atypical EGFRmutations, Franke notes.

In comparison with these data, findings from the UNICORN trial indicate that osimertinib may bean effective, and potentially more tolerable, addition to the armamentarium, Franke explains. These data also highlight other resistance mutations to target in future therapeutic development, Franke concludes.