Real world efficacy of osimertinib in second line/beyond in patients with metastatic EGFR+ non-small cell lung cancer and role of paired tumour-plasma T790M testing at tyrosine kinase inhibitor resistance

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) approved for use in EGFR-mutant lung cancer. We examined its performance in the second/subsequent line after resistance to first- and second-generation (1/2G) EGFR-TKI. Methods: We reviewed electronic records of 202 patients who received osimertinib from July 2015 to January 2019 in the second/subsequent line after progression on prior EGFR-TKI. Of these, complete data from 193 patients were available. Clinical data including patient characteristics, primary EGFR mutation, T790M mutation status, presence of baseline brain metastases (BM), first-line EGFR-TKI use, and survival outcomes were extracted, and results retrospectively analyzed. Results: . 3.1 months respectively (HR 0.52, P=0.01). Tumour T790M+ was significantly associated with longer PFS (P=0.007) and OS (P=0.01) compared to tumour T790M- patients, however this association was not seen with plasma T790M+. Of the 22 patients with paired tumor/plasma T790M testing, response rate (RR) to osimertinib was 30% for those plasma T790M+/tumour T790M-, compared to 63% and 67% for those who were plasma T790M+/tumour T790M+ and plasma T790M-/tumour T790M+, respectively. By multivariable analysis (MVA), Eastern Cooperative Oncology Group (ECOG) performance status ≥2 was associated with shorter OS (HR 2.53, P<0.001) and PFS (HR 2.10, P<0.001), whereas presence of T790M+ was associated with longer OS (HR 0.50, P=0.008) and PFS (HR 0.57, P=0.027). Conclusions: This cohort demonstrated the efficacy of osimertinib in second line/beyond for EGFR+ (EGFR mutation-positive) non-small cell lung cancer (NSCLC). Tissue T790M result appeared more predictive of osimertinib efficacy compared to plasma, highlighting potential T790M heterogeneity and the advantage with paired tumor-plasma T790M testing at TKI resistance. T790M- disease at resistance remains an unmet treatment need.