A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study)

• Published in: Cancers 2023-10, Vol.15 (20), p.4999
• Main Authors: Ang, Yvonne L. E., Zhao, Xiaotian, Reungwetwattana, Thanyanan, Cho, Byoung-Chul, Liao, Bin-Chi, Yeung, Rebecca, Loong, Herbert H., Kim, Dong-Wan, Yang, James Chih-Hsin, Lim, Sun Min, Ahn, Myung-Ju, Lee, Se-Hoon, Suwatanapongched, Thitiporn, Kongchauy, Kanchaporn, Ou, Qiuxiang, Yu, Ruoying, Tai, Bee Choo, Goh, Boon Cher, Mok, Tony S. K., Soo, Ross A.
• Format: Article
• Language: English
• Subjects: Binomial distribution; Biopsy; Blood; Consent; Deoxyribonucleic acid; Disease control; DNA; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; Genomes; Invasiveness; Kinases; Leukocytes; Lung cancer; Lung diseases; Mutation; Next-generation sequencing; Non-small cell lung carcinoma; Patients; Plasma; Polymerase chain reaction; Population studies; Protein-tyrosine kinase receptors; Sample size; Small cell lung carcinoma; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15204999

Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44–3.12) years. The ORR was 50.9% (95% CI 41.2–60.6) and the DCR was 84.5% (95% CI 76.4–90.7). Median PFS was 7.4 (95% CI 6.0–9.3) months; median OS was 1.63 (95% CI 1.35–2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs.