SP 9

A phase I study for combination of 3rd generation ERGF-inhibitor EGF816 with MEK-inhibitor Trametinib in adult patients with ERFG-mutation positive adenocarcinoma of the lung and acquired EGFRp.T790M resistance mutation

In the recent years a large number of genetic alterations was identified enabling targeted treatment approaches in selected patient subgroups. Inhibition of mutational activated EGFR in adenocarcinomas of the lung has led to increased response and PFS rates. However, re-sistance to EGFR TKIs will inevitably develop. The most common mechanism of resistance in this setting the acquisition of a secondary EGFRp.T790M mutation, blocking the allosteric inhibition of the receptor through EGFR TKIs. New compounds, called the 3rd generation EGFR TKIs are able to inhibit EGFRp.T790M and have led to impressive efficacy in this pa-tient subgroup. Unfortunately, all patient will again develop resistance or show a primary resistance to these drugs. The activation of the RAS/MEK pathway have been shown to trig-ger primary and acquired resistance to 3rd generation EGFR inhibitors. The combination of an inhibitors of the EGFR and the RAS/MEK cascade are promising treatment approaches in increasing the rate of responders and preventing the development of drug resistance. In this phase I trial patients with acquired resistance to EGFR inhibitors and documented EG-FRp.T790M mutation will be treated with a combination therapy of the 3rd-generation EGFR inhibitor EGF816 and the MEK inhibitor trametinib. The primary objective of the trial is to determine the recommended phase II dose or the maximum tolerated dosage of this combi-nation treatment. Patients eligible for the trial will be treated with escalating doses in a con-tinuous or intermittent therapy regimen. The primary objective will be determined by the safety and toxicity profile (DLT rate). The recommendations for the dose escalation of the continuous treatment will be based on a Bayesian Logistic Regression Model (BLRM) guided by the EWOC principle. The secondary endpoints of the trial are amongst others the objec-tive response rate (ORR), the progression free survival (PFS, both according to RECIST v1.1) and the definition of pharmacokinetic variables of the combination treatment (PK).  The de-termination of primary and acquired mechanisms of resistance to the treatment are explor-atory endpoints and will connect the clinical and pre-clinical research units of the Lung Cancer Group Cologne.