Plasma Predictive Features in Treating EGFR-Mutated Non-Small Cell Lung Cancer

SIMPLE SUMMARY: Patients with non-small cell lung cancer with an activating EGFR mutation in the tumor, are treated with targeted therapy against this mutation. In the end, all patients develop resistance against this therapy, but some patients have a very short or no benefit. In this study, the authors used blood samples from 41 patients to investigate predictive factors for lack of or short efficacy of targeted therapy. They found that lack of disappearance of the treated mutation in blood after 6 or 12 weeks, the presence of co-occurring TP53 mutations, and decrease of erlotinib therapy concentrations in time are correlated to a shorter time of benefit. Confirmation of these findings in a larger cohort is desirable, this may lead to implementation of blood sampling for DNA analysis and therapy concentration measurement in daily practice in the future, to identify patients in need of closer follow-up or more extensive treatment. ABSTRACT: Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the preferred treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC), not all patients benefit. We therefore explored the impact of the presence of mutations found in cell-free DNA (cfDNA) and TKI plasma concentrations during treatment on progression-free survival (PFS). In the prospective START-TKI study blood samples from 41 patients with EGFR-mutated NSCLC treated with EGFR-TKIs were available. Next generation sequencing (NGS) on cfDNA was performed, and plasma TKI concentrations were measured. Patients without complete plasma conversion of EGFR mutation at week 6 had a significantly shorter PFS (5.5 vs. 17.0 months, p = 0.002) and OS (14.0 vs. 25.5 months, p = 0.003) compared to patients with plasma conversion. In thirteen (second line) osimertinib-treated patients with a (plasma or tissue) concomitant TP53 mutation at baseline, PFS was significantly shorter compared to six wild-type cases; 8.8 vs. 18.8 months, p = 0.017. Erlotinib C(mean) decrease of ≥10% in the second tertile of treatment was also associated with a significantly shorter PFS; 8.9 vs. 23.6 months, p = 0.037. We obtained evidence that absence of plasma loss of the primary EGFR mutation, isolated plasma p.T790M loss after six weeks, baseline concomitant TP53 mutations, and erlotinib C(mean) decrease during treatment are probably related to worse outcome.