EATON: A phase I trial of nazartinib (EGF816) and trametinib in EGFR-mutant (EGFRmut) non-small cell lung cancer (NSCLC).

Abstract

8619 Background: EGFR inhibitors (EGFRi) are highly effective in EGFRmut NSCLC, but resistance inevitably emerges. Among the mechanisms of acquired resistance, RAS/MEK pathway activation has been identified in both cell models and patients. Preclinical and clinical data support efficacy of dual MEK and EGFR inhibition in this setting. In the EATON trial we investigated the combination of the MEK inhibitor (MEKi) trametinib (TMT) and the third-generation (3gen) EGFRi nazartinib (NAZ) in patients with EGFRmut NSCLC. Methods: EATON (NCT03516214, AIO-TRK-0216) is an academic multicenter, phase I, dose-escalation trial conducted in Spain and Germany. Primary endpoint: maximal tolerated dose (MTD)/recommended phase 2 dose (RP2D); secondary endpoints: pharmacokinetics (PK), safety, preliminary efficacy. Key eligibility criteria: Advanced/metastatic EGFRmut NSCLC, EGFR p.T790M-positive/-negative, no MET amplification, any treatment line. Dose escalation was based on a modified 3+3 up-and-down design in up to 18 patients [Storer, 1989]. TMT and NAZ were dosed once daily (qd) at pre-defined dose levels (DL) of 0.5 mg/100 mg (DL -1), 1.0 mg/100 mg (DL 1), 1.5 mg/100 mg (DL 2), 1.5 mg/150 mg (DL 3), 2 mg/150 mg (DL 4). The dose-limiting toxicities (DLT) period comprised the first 28 treatment days. Results: In total, 19 patients were dosed (mean age, 62 years (range, 44-81); 14 female (73.7%)). Prior EGFRi and 3gen EGFRi use were noted in 17 (89.5%) and 14 (73.7%), respectively. Patients were treated at DL -1 (N=4), DL 1 (N=13), and DL 2 (N=3), with 18 (94.7%) eligible for dose-escalation decisions. DLTs were observed in 4 (22.2%) patients (Grade 3 creatinine phosphokinase elevation, N=3; Grade 3 hypertension, N=1). The MTD was determined to be TMT 1.0 mg qd and NAZ 100 mg qd. After repeated dosing (C1D15) at the MTD, geo-mean C max of NAZ was 336 ng/ml (N=14, CV% 44.8) and of TMT 19.5 ng/ml (N=7, CV% 22.6). Geo-mean AUC tau of NAZ was 3950 ng/ml*h (N=14, CV% 48.7) and of TMT 301 ng/ml*h (N=7, CV% 27.3). Treatment-related adverse events (TRAEs) of any grade were observed in all patients (N=19; 100%) and of Grade ≥3 in nine (47.4%). Discontinuation rates were 26.3% (N=5) and 21.1% (N=4), for TMT and NAZ. Sixteen (84.2%) patients were evaluable for RECIST 1.1 response assessment and 19 (100%) for time-to-event outcomes. One patient had a partial response (ORR, 6.3%; 95% CI, 1.6-30.2) and six had stable disease (37.5%). Median progression-free survival was 2 months (95% CI, 1.7-2.2). Molecular determinants of response and resistance were investigated by 3’ RNA and DNA sequencing. Conclusions: At the MTD, treatment was safe and moderately tolerable. Preliminary efficacy in this unselected and heavily pre-treated population was limited. A comprehensive biomarker-driven approach may help identify patients more likely to derive clinical benefit. Clinical trial information: NCT03516214 .