The role of comprehensive analysis with circulating tumor DNA in advanced non-small cell lung cancer patients considered for osimertinib treatment

Abstract

Background: 𝘌𝘎𝘍𝘙 mutations are good predictive markers of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKI), but whether comprehensive genomic analysis beyond 𝘌𝘎𝘍𝘙 itself with circulating tumor DNA (ctDNA) adds further predictive or prognostic value has not been clarified.

Methods: Patients with NSCLC who progressed after treatment with EGFR-TKI, and with 𝘌𝘎𝘍𝘙 T790 M detected by an approved companion diagnostic test (cobas®), were treated with osimertinib. Plasma samples were collected before and after treatment. Retrospective comprehensive next-generation sequencing (NGS) of ctDNA was performed with Guardant360®. Correlation between relevant mutations in ctDNA prior to treatment and clinical outcomes, as well as mechanisms of acquired resistance, were analyzed.

Results: Among 147 patients tested, 57 patients received osimertinib, with an overall response rate (ORR) of 58%. NGS was successful in 54 of 55 available banked plasma samples; 𝘌𝘎𝘍𝘙 driver mutations were detected in 43 (80%) and T790 M in 32 (59%). The ORR differed significantly depending on the ratio (T790 M allele fraction [AF])/(sum of variant AF) in ctDNA (𝘱 = 0.044). The total number of alterations detected in plasma by NGS was higher in early resistance patients (𝘱 = 0.025). T790 M was lost in 32% of patients (6 out of 19) after acquired resistance to osimertinib. One patient with 𝘙𝘉1 deletion and copy number gains of 𝘌𝘎𝘍𝘙, 𝘗𝘐𝘒3𝘊𝘈, and 𝘔𝘠𝘊 in addition to T790 M, showed rapid progression due to suspected small cell transformation.

Conclusions: NGS of ctDNA could be a promising method for predicting osimertinib efficacy in patients with advanced NSCLC harboring 𝘌𝘎𝘍𝘙 T790 M.