Abstract CT255: EATON: A phase I dose-escalation trial of nazartinib (EGF816) and trametinib in EGFR-mutant NSCLC
Authors: Michels Sebastian , Nogova Lucia , Scheffler Matthias , Deschler-Baier Barbara , Sebastian Martin , Schuler Martin , Wermke Martin , Felip Enriqueta , Rosell Rafael , Abreu Delvys Rodriguez , Abdulla Diana S.Y. , Fischer Rieke N. , Koleczko Sophia , Kron Anna , Riedel Richard , Weber Jan-Philipp , Fassunke Jana , Merkelbach-Bruse Sabine , Haverkammp Heinz , Hellmich Martin , Büttner Reinhard , Wolf Jürgen ,   Lung Cancer Group Cologne (LCGC) and Network Genomic Medicine (NGM)
Published: September 2020

Abstract
Background: EGFR tyrosine kinase inhibitor (TKI) treatment is highly effective in EGFR-mutant NSCLC. However, resistance to treatment inevitably develops. Multiple mechanisms of resistance to EGFR TKIs have been described. Besides secondary EGFR mutations, RAS/MEK pathway activation through different mechanisms has been found in cell models and in patients, resulting in TKI failure. Inhibition of MEK, resensitized cells to EGFR-targeted treatment in pre-clinical models. We thus hypothesize that combined MEK and EGFR inhibition may break resistance and delay treatment failure in EGFR-mutant NSCLC patients. Methods: EATON (NCT03516214) is an investigator-initiated, multicenter, phase I, dose-escalation trial investigating the recommended phase 2 dose (RP2D), pharmacokinetic parameters and safety/efficacy of the combination of EGF816 (nazartinib) and trametinib. Eligibility criteria: Advanced/metastatic EGFR-mutant (del19 or p.L858R) NSCLC, EGFR p.T790M-positive/-negative, absence of other secondary EGFR-mutations, MET amplification-negative (MET/CEN7 ratio ≥2.0 and/or average MET gene copy number per cell ≥6.0), first-line or after failure of any EGFR TKI, including osimertinib. Dose level escalation will be based on a 3+3 up-and-down design (total number: 24 patients) with a dose-limiting toxicity (DLT) period of 28 days. Minimum treatment exposure for DLT assessment is 21 days. Exploratory endpoints: Identification of mechanisms of resistance by analysis of baseline tissue, PD biopsies and ctDNA. Results: At the time of data cut-off, three patients received treatment at dose-level 1 (nazartinib (EGF816) 100 mg QD and trametinib 1 mg QD). All patients met the minimum exposure criterion for DLT assessment. In one patient a grade 3 creatinine phosphokinase elevation was observed and assessed as a DLT. No other DLTs were reported. Other related adverse events (AEs) grade ≥2 were rash (n=2), anemia (n=1), soft-tissue infection (n=1), diarrhea (n=1), and elevated liver enzymes (n=1). Two patients were evaluable for efficacy assessment. One stopped treatment prior to first assessment due to a grade 4 soft tissue infection at day 37. Best objective response according to RECIST 1.1 was stable disease in one patient (afatinib-resistant, T790M-negative), lasting for more than 4 months and progressive disease in the other patient (osimertinib-resistant, T790M-negative). Conclusions: Treatment with nazartinib 100 mg QD and trametinib 1 mg QD resulted in a DLT in one of three patients. Thus, three additional patients will be enrolled at the same dose level. Efficacy data is premature. But, a significant progression-free survival period was observed in one EGFR p.T790M-negative patient.
Citation Format: Sebastian Michels, Lucia Nogova, Matthias Scheffler, Barbara Deschler-Baier, Martin Sebastian, Martin Schuler, Martin Wermke, Enriqueta Felip, Rafael Rosell, Delvys Rodriguez Abreu, Diana S.Y. Abdulla, Rieke N. Fischer, Sophia Koleczko, Anna Kron, Richard Riedel, Jan-Philipp Weber, Jana Fassunke, Sabine Merkelbach-Bruse, Heinz Haverkammp, Martin Hellmich, Reinhard Büttner, Jürgen Wolf, Lung Cancer Group Cologne (LCGC) and Network Genomic Medicine (NGM). EATON: A phase I dose-escalation trial of nazartinib (EGF816) and trametinib in EGFR-mutant NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT255.