C. Dooms MD, PhD, B. Colinet MD, I. Demedts , N. D’Haene MD, PhD, V. Ninane MD, PhD, T. Pieters MD, PhD, J. Vansteenkiste MD, PhD, B. Weynand MD, PhD, P. Pauwels MD, PhD
Somatic sensitising mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are detected in approximately 10% of patients with advanced non-squamous non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment option for patients with an actionable EGFR mutation. Despite initial responses, the majority of patients progress within one to two years after EGFR-TKIs treatment initiation.
The most common mechanism of resistance is the development of an additional EGFR-T790M mutation in exon 20, found in 50–60% of EGFR-mutant NSCLC patients who were rebiopsied on EGFR-TKI treatment. Phase II and III trials with osimertinib, a third-generation EGFR-TKI, demonstrated an objective response rate (ORR) of 60–70% and median progression-free survival (mPFS) of 10–11 months in EGFR-T790M-positive tumours.
A tissue biopsy of a progressing lesion for confirmation of histology and molecular characterisation is a critical consideration. However, a repeat tissue biopsy is not possible for every patient. Therefore, a liquid biopsy can be considered for EGFR-T790M mutation testing. Indeed, clinical trials testing osimertinib have shown similar clinical outcomes (ORR and mPFS on osimertinib) in patients with T790M-positive plasma versus T790M-positive tumour tissue.
Osimertinib clearly expands relapse treatment options for advanced stage EGFR-mutant NSCLC. Testing for EGFR-T790M at acquired resistance should become a standard component of patient care in EGFR-mutant tumours. In this manuscript, we propose and discuss two possible clinical diagnostic algorithms that could be used for the therapy-orienting testing of EGFR-TKI-resistant NSCLC patients. Tissue and liquid biopsies involve challenges in terms of specific clinical role, safety, logistics, and cost.