Primary and secondary resistance mechanisms in EGFR mutated non-small cell lung cancer

Abstract

The primary goals of this thesis were to gain insights in primary and secondary resistance mechanisms in patients with EGFR mutated NSCLC and to develop new treatment strategies. The first part focuses on a specific subgroup of patients with an EGFR exon 20 insertion mutation. We reptrospectively and prospectively analyzed the activity of two different treatment regimens: (high dose) osimertinib and afatinib in combination with cetuximab, respectively. Osimertinib 80 mg once daily was not effective with a response rate of 5%. High dose osimertinib resulted in an overall response rate of 28%, however, this study did not meet its primary endpoint. The combination of afatinib and cetuximab was promising in a retrospective series of four patients. Three of four patients showed a partial repsonse. These results led to dedicated trial in which 37 patients were treated with this combination with modest activity. The second part focusses on genomic profiling of resistance mechanisms after treatment with a third generation EGFR TKI. In addition, we investigated the activity of combination treatment after cMET driven resistance. The addition of crizotinib to a third generation EGFR TKI proved effective with a response rate of 50%; however, responses were short-lasting and often heterogeneous.