Plasma pre-treatment T790M relative allelic frequency in patients with advanced EGFR-mutated non-small cell lung cancer predicts treatment response to subsequent-line osimertinib

Background: Approximately half of all patients with advanced EGFR-mutant NSCLC will develop acquired resistance to first or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) with a T790M mutation. In the AURA3 trial, patients with a T790M mutation had a response rate of 71% to osimertinib, a third-generation EGFR-TKI. The response to osimertinib may vary according to plasma T790M mutation frequency. Our aim was to determine the effect of plasma T790M mutation load on treatment response to osimertinib in an Australian multi-institutional cohort. Methods: We performed a retrospective study on patients treated with osimertinib in the second-line setting and beyond between 2016-2018 from ten centres in Australia, who had T790M mutations detected in tumour or plasma. The primary objective was to investigate if there was a difference in disease control rate (DCR) between patients with high vs. low T790M relative allelic frequency (RAF) as detected in plasma, using a 0.3 RAF cut-off, as determined by ddPCR or BEAMing PCR. Secondary objective was to determine the survival outcomes according to high versus low plasma T790M RAF. Additional analyses were performed to investigate the survival outcome for patients with plasma versus tissue T790M positivity. Results: A total of 139 patients were included in this study. Patients with higher RAF demonstrated higher DCR (74% vs. 36%, P=0.02), however there was no statistically significant difference in survival outcomes in the two groups. Exploratory analysis showed that patients with tissue T790M+ had improved DCR compared with those with plasma T790M+ (89% vs. 68%, P=0.01) and longer progression free survival (median 15.4 vs. 9.7 months; HR 0.51, 95% CI: 0.34 to 0.77, P=0.003) and overall survival (median not reached, HR 0.51, 95% CI: 0.30 to 0.86, P=0.02). Patients who were tissue T790M+ demonstrated superior survival compared to plasma T790M+ after correcting for confounding variables in a multivariate model. Conclusions: DCR was superior in patients with higher plasma T790M mutation load versus lower plasma T790M mutational load, without significant survival benefit. Plasma T790M RAF is a potential predictive biomarker which should be investigated and validated in larger prospective studies.