EATON: An open-label, multicenter, phase I dose-escalation trial of nazartinib (EGF816) and trametinib in patients with EGFR-mutant non-small cell lung cancer – preliminary data on safety and tolerability

e20577 Background: Multiple mechanisms of resistance to EGFR TKIs therapy in EGFR-mutant non-small cell lung cancer (NSCLC) have been described, most often including the acquisition of the secondary resistance mutations in exon 20 of EGFR. Preclinical models and clinical findings have also shown that co-occurring activation of the RAS/MEK pathway may result in reduced EGFR dependency, which may be overcome by co-inhibition of MEK. We thus hypothesize that the combined inhibition of EGFR and MEK may restore sensitivity to EGFR inhibition in patients with acquired resistance to EGFR inhibition and may as well prolong the acquisition of resistance in treatment-naïve patients. Methods: EATON is an international, multicenter, phase I, dose escalation investigator-initiated trial investigating the recommended phase 2 dose (RP2D), safety and preliminary efficacy of the combination of the third-generation EGFR inhibitor EGF816 with the MEK inhibitor trametinib (NCT03516214). Eligibility criteria: Advanced NSCLC harboring EGFR del19 or p.L858R, first-line or after failure of any EGFR TKI including osimertinib, independently of p.T790M status. Patients with high-level MET amplification are excluded. Dose level escalation will be based on a modified traditional cumulative 3+3 design, i.e. “up and down” (dose level 1: 100 mg nazartinib (EGF816) QD + 1 mg trametinib QD). A total number of 24 patients is planned to be enrolled in 8 trial sites in Germany and Spain. At a first stage, 18 (6´3) patients will be treated and evaluated. Exploratory endpoints aim at the identification of potential mechanisms of resistance to the trial treatment by massively parallel sequencing (MPS), FISH, phospho-protein analyses and whole exome/genome sequencing of baseline and PD biopsy tumour tissue. Additionally blood samples for MPS of cell free DNA will be collected throughout the trial treatment. Results: At the time of data-cut off for this abstract, one patient received treatment at dose-level 1. Treatment was withdrawn due to a serious, bacterial soft tissue infection of the hand outside the DLT period. Conclusions: Data on safety and tolerability of the combination of nazartinib and trametinib is premature. Updated results will be presented at the conference. Clinical trial information: NCT03516214.