Plasma screening for the T790M mutation of EGFR and phase 2 study of osimertinib efficacy in plasma T790M–positive non–small cell lung cancer: West Japan Oncology Group 8815L/LPS study

Abstract

BACKGROUND: Liquid biopsy allows the identification of patients whose tumors harbor specific mutations in a minimally invasive manner. No prospective data have been available for the efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) who develop resistance to first-or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and who test positive for the TKI resistance-conferring T790M mutation of EGFR by liquid biopsy. Therefore, a phase 2 study was conducted to assess the efficacy and safety of osimertinib in such patients. METHODS: Eligible patients had advanced or recurrent NSCLC with known TKI-sensitizing mutations of EGFR, had documented disease progression after treatment with at least 1 first-or second-generation EGFR TKI, and were positive for the T790M mutation in plasma according to the Cobas EGFR Mutation Test v2 (Roche Diagnostics) or droplet digital polymerase chain reaction analysis. Patients were treated with osimertinib (80 mg/d) until disease progression. The primary endpoint was the overall response rate (ORR) in patients positive for T790M in plasma by the Cobas assay. RESULTS: Between June 2016 and November 2017, 276 patients were screened for their T790M status with a liquid biopsy. Seventy-four patients were positive for T790M in plasma, and 53 of these individuals were enrolled in the study. The ORR for evaluable patients positive for T790M in plasma by the Cobas assay (n = 49) was 55.1% (95% confidence interval [CI], 40.2%-69.3%). The median progression-free survival for all evaluable patients (n = 52) was 8.3 months (95% CI, 6.9-12.6 months). CONCLUSIONS: The results demonstrate the utility of liquid biopsy for the detection of T790M with the Cobas EGFR Mutation Test v2. Plasma genotyping with this assay is informative for treatment selection in clinical practice when tumor sampling is not feasible.

Egfr Tyrosine Kinase Inhibitors for EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Outcomes in Asian Populations

“…The detection rate of T790M following first-and second-generation EGFR TKIs varies from study-to-study but most analyses indicate a detection rate of around 50-70% [74,75]. Use of liquid biopsies and sensitive detection assays can complement tissue-based tests and help optimize the detection of T790M even when present in a small number of tumor cells [76][77][78][79]. Furthermore, some studies suggest that the detection rate of T790M is particularly high in patients with a Del19 mutation (73%) [80].…”

Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

“…Between June 2016 and November 2017, plasma samples of 276 NSCLC patients at 22 sites across Japan (WJOG8815LPS) were screened by cobas and ddPCR for the presence of EGFR T790M mutation in their plasma samples. EGFR T790M was detected in seventy‐four patients, and a total of 52 of these 74 patients were enrolled in WJOG8815L study and treated with osimertinib [12]. Plasma samples from the 52 patients were obtained prior to the start of treatment (Pre), day 1 of C4, day 1 of C9, and at disease progression or treatment discontinuation (PD/stop) ( n = 52, 46, 35, and 43, respectively) (Fig.…”

“…Baseline patient demographics and clinical characteristics are summarized in Table 1. All of the 52 patients had developed PD during the previous EGFR‐TKI treatment, and 16 patients (30.2%) received at least two prior chemotherapy regimens, including cytotoxic or EGFR‐TKIs [12].…”

“…Patients evaluated in this study were part of the WJOG8815L study which has been described in detail previously [12]. In brief, patients with the EGFR T790M mutation detected by cobas or ddPCR (QX100 Droplet Digital PCR System; Bio‐Rad, Hercules, CA, USA) in plasma specimens collected after confirmation of disease progression during treatment with first‐ or second‐generation EGFR‐TKIs received osimertinib until disease progression or treatment discontinuation.…”

“…We previously reported the safety and efficacy of osimertinib in patients with T790M mutation in ctDNA in the WJOG8815L/LPS study [12]. In this study, a total of 74 patients were identified as being positive for the T790M mutation in the plasma.…”