Search

In this thesis we searched for innovations in optimizing treatment of NSCLC with EGFR-TKI, which is started by the introduction in Chapter 1. In Chapter 2 we describe the results of the randomized phase III NVALT18 trial in patients with EGFR-WT non-squamous NSCLC. The detrimental effect of the combination of docetaxel and intercalated erlotinib was evident with shorter PFS (1.9 vs 4.0 months, p=0.01) as well as OS (4.7 vs 10.6 months, pThe exploration of the toxic limit of the 3rd generation EGFR-TKI osimertinib in patients with EGFR-mutated NSCLC is found in Chapter 3. The correlation between osimertinib exposure (defined as clearance) and severe toxicity, as well as the exposure-efficacy relationship were investigated. Osimertinib clearance (exposure) was significantly correlated with severe toxicity in multivariate competing risk analysis (HR 0.91, 95% CI 0.83-0.99), with an optimal toxic limit of 259 ng/mL determined by ROC curve. The results of chemotherapy regimens after progression on EGFR-TKI in patients with EGFR-mutated NSCLC are presented in Chapter 4. In this retrospective study patients do benefit substantially from chemotherapy after progression on EGFR-TKI, albeit shorter than the duration of response of first line targeted therapy. In Chapter 5 plasma ddPCR (Biorad) and NGS (Oncomine cfDNA lung assay v1) are compared to tissue NGS results in patients with EGFR-mutated NSCLC. The plasma results showed high agreement on the level of a specific mutation like p.T790M and p.L858R, but NGS provides a broader coverage and is therefore able to detect more different driver mutations. Concordance of plasma with tissue is high. In Chapter 6 we searched for targetable mutations in a population with suspected metastasized lung cancer when molecular analysis of tissue was not feasible. A possible target for treatment was detected in 7 out of 55 patients. Although the coverage of the Oncomine V1 panel was a limiting factor in the ability to detect all possible targets for treatment which are expanding rapidly, we still were able to identify patients with a possibility of targeted treatment who were otherwise not detected. Chapter 7 outlines the course of mutations in cfDNA upon start of targeted therapy, and identifies predictive features in plasma during treatment with EGFR-TKI in patients with EGFR-mutated NSCLC. Plasma clearance of the primary EGFR mutation, and of p.T790M when applicable, after 6 and 12 weeks of therapy was evaluated. The absence of this so called plasma conversion correlated with a shorter PFS (5.5 vs 17.0 months, p=0.002) and OS (14.0 vs 25.5 months, p=0.003). In Chapter 8 the summary, general discussion and future perspectives are presented.