Co-occurrence of EGFR sensitising and resistance mutations at diagnosis in NSCLC

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• De novo epidermal growth factor receptor (EGFR) resistance mutations are infrequently detected in tyrosine kinase inhibitor-naïve patients using standard genotyping.
• The study focuses on synchronous EGFR mutations in non-small cell lung carcinoma (NSCLC).

Purpose of the Study:

• To investigate the incidence and clinical characteristics of de novo EGFR resistance mutations in NSCLC patients.
• To evaluate the efficacy of EGFR tyrosine kinase inhibitors (TKIs) and chemotherapy in this patient cohort.

Main Methods:

• Patients with EGFR mutations were identified using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing.
• Retrospective analysis of patient data from 2008 to 2015.

Main Results:

• De novo EGFR resistance mutations were observed in 12.8 patients treated with an EGFR TKI, showing a 25% overall response rate, 24-month median progression-free survival (PFS), and 34-month median overall survival (OS).
• Erlotinib demonstrated activity in the first-line setting (60% disease control rate, 6-month median duration of response).
• Cytotoxic chemotherapy showed a 67% disease control rate with an 11-month median duration of response.
• Patients with de novo EGFR T790M mutations had 50% stable disease, with one patient showing a prolonged response to erlotinib (>96 months).
• Patients with de novo EGFR S768I mutations receiving erlotinib had 50% ongoing partial responses.

Conclusions:

• The incidence of co-occurring EGFR mutations in NSCLC is approximately 1% on routine assays.
• Erlotinib exhibits therapeutic activity in patients with de novo EGFR mutations, both in first- and second-line settings.
• De novo T790M and S768I mutations represent distinct clinical entities, suggesting chemotherapy as a first-line option for T790M and erlotinib for S768I mutations.