Kinetic Monitoring of EGFR Exon 19 del L858R and T790M in Urinary ctDNA Predicts Radiologic Progression and Response in Patients with Metastatic Lung Adenocarcinoma
Acquisition of the EGFR T790M resistance mutation is a mechanism of resistance among patients with metastatic EGFR mutant lung adenocarcinoma treated with first generation anti-EGFR inhibitors. Biopsies may be challenging in relapsed patients, and a noninvasive approach to detect T790M is desired. We sought to monitor urinary circulating tumor (ct)DNA for the early acquisition of T790M and understand ctDNA kinetics in patients on second line anti-EGFR treatment.
Clinical Study Design
Specific Aim 1: Determine the concordance between tissue and urine: 14 patients with tissue confirmed T790M; 3 tissue T790M negative but high clinical suspicion for T790M.
Specific Aim 2: Test the hypothesis that T790M could be identified prior to radiographic progression: 24 patients receiving treatment with erlotinib monitored longitudinally for acquisition of T790M mutation by urinary ctDNA; Collection frequency every 3-6 weeks.
Specific Aim 3: Test the hypothesis that early dynamics of T790M mutational load in ctDNA within the first week will provide insight into tumor biology and predict radiographic response to therapy with second line anti-EGFR tyrosine kinase inhibitors: 13 T790M+ patients by tissue biopsy received treatment with second line anti-EGFR TKIs; Urine specimens were collected from patients prior to treatment, daily for 1 week, then weekly for 3 weeks, then monthly.
Highlighted Tables and Graphs
Sensitivity of Urine ctDNA
Pharmacodynamics of Early Response Seen in Urine
Early Acquisition of EGFR T790M
- Concordance to urine: EGFR T790M mutation was detected in 24 of 35 (69%) patients receiving anti-EGFR treatment. Urine T790M detected in 14 out of 14 tissue-positive patients (100% sensitivity).
- Early acquisition of EGFR T790M: T790M mutation was detected as early as 3 months prior to radiological progression. Future studies are needed to characterize the therapeutic implications of earlier intervention with second line therapy.
- Pharmacodynamics of early response seen in urine: Spikes in ctDNA after daily collection may correlate with early tumor lysis. Further studies are underway to monitor a diversity of allelic fractions within these time points and understand the relationship with radiographic response.