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

• Published in: Cancer medicine (Malden, MA) MA), 2021-06, Vol.10 (12), p.3873-3885
• Main Authors: Sueoka‐Aragane, Naoko, Nakashima, Chiho, Yoshida, Hironori, Matsumoto, Naohisa, Iwanaga, Kentaro, Ebi, Noriyuki, Nishiyama, Akihiro, Yatera, Kazuhiro, Kuyama, Shoichi, Fukuda, Minoru, Ushijima, Sunao, Umeguchi, Hitomi, Harada, Daijiro, Kashiwabara, Kosuke, Suetsugu, Takayuki, Fujimoto, Nobukazu, Tanaka, Fumihiro, Uramoto, Hidetaka, Yoshii, Chiharu, Nakatomi, Katsumi, Koh, Genju, Seki, Nobuhiko, Aoe, Keisuke, Nosaki, Kaname, Inoue, Koji, Takamori, Ayako, Kawaguchi, Atsushi
• Format: Article
• Language: English
• Subjects: Acrylamides - therapeutic use; Adult; Aged; Aged, 80 and over; Aniline Compounds - therapeutic use; Antineoplastic Agents - therapeutic use; Biopsy; Cancer therapies; Carcinoma, Non-Small-Cell Lung - blood; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Circulating Tumor DNA - blood; Circulating Tumor DNA - genetics; Clinical Cancer Research; Copy number; Deoxyribonucleic acid; Diagnostic tests; Disease; Disease Progression; DNA; Drug Resistance, Neoplasm - genetics; Epidermal growth factor receptors; ErbB Receptors - genetics; Female; Genes, erbB-1; Genetic Profile; Genomic analysis; High-Throughput Nucleotide Sequencing; Humans; Lung cancer; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Middle Aged; molecular diagnosis; Mutation; mutations; Myc protein; next‐generation sequencing; Non-small cell lung carcinoma; non‐small cell lung cancer; Original Research; Patients; Plasma; Prognosis; Prospective Studies; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Retrospective Studies; Small cell lung carcinoma; Statistical analysis; Targeted cancer therapy; Treatment Outcome; Tumors
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.3929

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. A retrospective analysis of comprehensive next‐generation sequencing (NGS) of ctDNA in a multi‐center, prospective observational cohort study conducted to examine the efficacy of liquid biopsy as a predictive marker for third generation treatment with the EGFR tyrosine kinase inhibitor (EGFR‐TKI), osimertinib is reported in this paper. We demonstrated that the number of genomic alterations was significantly higher in non‐responders than in responders to osimertinib, suggesting that plasma NGS could be a better method for predicting osimertinib efficacy in patients with advanced NSCLC.