Phase I Trial of Definitive Concurrent Chemoradiotherapy and Trametinib for KRAS-Mutated Non-Small Cell Lung Cancer

Abstract

ABSTRACT: OBJECTIVE: This phase I trial (NCT01912625) evaluated the safety and pharmacokinetics of definitive concurrent chemoradiotherapy (cCRT) and the radiosensitizer trametinib (MEK1/2 inhibitor) for KRAS-mutated nonmetastatic non-small cell lung cancer (NSCLC). METHODS: Patients received cCRT (carboplatin/paclitaxel and 60 Gy/30 fractions radiotherapy); oral trametinib (7 days/week) commenced on day 1 and completed on the final day of radiotherapy. Dose-finding of trametinib was done using the time-to-event continual reassessment method (TiTE-CRM); dose levels were 0.5mg (level -1), 1mg (initial, level 1), 1.5mg (level 2), and 2mg (level 3). Progression-free (PFS) and overall survival (OS) times were also recorded. RESULTS: Fifteen patients (stage III, variety of KRAS mutations) were treated, with 1/5/4/5 at dose levels -1/1/2/3, respectively. Five patients received dose reductions (n=2, levels 2 and 3; n=1, level 1). Twelve patients completed the full cCRT course. One patient (following 12d trametinib) was taken off protocol for an unrelated/unresolved grade 1 event and later experienced grade 5 sepsis/respiratory failure. There was one grade 4 retinal detachment; grade 3 events included skin rash (n=2) and ventricular dysfunction, pneumonitis, pain, fatigue, and diarrhea (n=1 each). The final dose selected by the TiTE-CRM of trametinib was 1.5 mg. Pharmacokinetic profiles were elucidated and extensively described. At median follow-up of 70 months, median PFS was 11 months and median OS was 38 months. CONCLUSIONS: The MTD for trametinib when combined with cCRT is 1.5 mg, with encouraging preliminary outcomes. This combination merits further study to combine with consolidation durvalumab in non-metastatic KRAS mutant NSCLC.

Keywords

• Non-small cell lung cancer
• KRAS
• chemoradiotherapy
• trametinib
• MEK