Thr790Leu as a Potential Resistance Mechanism to First-Generation EGFR Tyrosine Kinase Inhibitor May Respond to Osimertinib in Patients With Lung Adenocarcinoma.

Introduction: It has been well established that Thr790Met is one of the major resistance mechanisms to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). Nevertheless, whether Thr790Leu (T790L), which shares the mutation site of Thr790 with Thr790Met, mediates resistance to EGFR TKIs remains elusive. The treatment options for patients harboring this rare mutation have not been reported.

Methods: Capture-based targeted ultradeep sequencing was performed on tumor and plasma samples collected at various treatment milestones from three patients with advanced lung adenocarcinoma undergoing targeted therapy.

Results: Needle biopsy of lymph node metastasis from patient 1 revealed T790L at disease progression on first-line treatment of gefitinib. Patient 2 had T790L identified from needle biopsy of lung tissue at disease progression on icotinib treatment. This patient was subsequently treated with osimertinib and achieved stable disease with a progression-free survival of 9 months. For patient 3, at disease recurrence after surgery, resected lung tumor tissue was retrieved for molecular profiling and revealed exon 19 deletion and T790L. The patient subsequently received osimertinib treatment and continued to benefit for 16 months and counting. She has maintained stable disease at the time of submission of this manuscript.

Conclusions: We revealed for the first time that T790L may serve as a potential resistance mechanism to first-generation EGFR TKIs. We also report the first clinical evidence of efficacy generated by osimertinib in patients with lung adenocarcinoma harboring primary or acquired T790L, shedding light on treatment options for this subset of patients.