Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Epidermal Growth Factor Receptor (EGFR) mutations are key drivers in a subset of non-small cell lung cancer (NSCLC).
• While osimertinib, a third-generation tyrosine kinase inhibitor, is effective against common EGFR mutations (exon 19 deletion, L858R), its impact on atypical EGFR mutations remains less understood.
• Atypical EGFR mutations represent a diverse group of genetic alterations in NSCLC that may influence treatment response.

Purpose of the Study:

• To evaluate the efficacy of osimertinib in patients with NSCLC harboring atypical EGFR mutations.
• To assess the time to treatment discontinuation (TTD) and objective response rate (ORR) of osimertinib in this patient population.
• To explore potential differences in osimertinib activity based on the specific type of atypical EGFR mutation.

Main Methods:

• A multicenter retrospective study included 50 patients with metastatic NSCLC and at least one atypical EGFR mutation (excluding common mutations and T790M).
• Data were collected from six U.S. academic cancer centers.
• Primary endpoint was time to treatment discontinuation (TTD); objective response rate (ORR) was also assessed using RECIST v1.1 criteria.

Main Results:

• The most common atypical EGFR mutations identified were L861Q (40%), G719X (28%), and exon 20 insertion (14%).
• The overall median TTD for osimertinib was 9.7 months, with an ORR of 31.7%.
• Median TTD varied significantly by mutation: 17.2 months for L861Q, 7.8 months for G719X, and 1.5 months for exon 20 insertion.

Conclusions:

• Osimertinib demonstrates clinical activity in patients with NSCLC harboring atypical EGFR mutations.
• The efficacy of osimertinib is dependent on the specific type of atypical EGFR-activating mutation.
• These findings underscore the importance of molecular profiling to guide treatment decisions in NSCLC.