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

• Published in: Cancer treatment and research communications 2022-01, Vol.30, p.100514-100514, Article 100514
• Main Authors: Lin, Steven H, Lin, Heather Y, Verma, Vivek, Xu-Welliver, Meng, Thall, Peter F, Yao, Luyang, Kim, Peter Y, Gombos, Dan S, Kawedia, Jitesh D, Komaki, Ritsuko, Gomez, Daniel R, Nguyen, Quynh-Nhu, O'Reilly, Michael S, Lu, Charles, Fossella, Frank V, Skoulidis, Ferdinandos, Zhang, Jianjun, Tsao, Anne S, Heymach, John V, Blumenschein, George R
• Format: Article
• Language: English
• Subjects: chemoradiotherapy; KRAS; MEK; Non-small cell lung cancer; trametinib
• ISSN: 2468-2942; 2468-2942
• DOI: 10.1016/j.ctarc.2022.100514

•Trametinib with chemoradiation in Kras-mutated non-small cell lung cancer•1.5 mg trametinib determined as a safe dose to combine with chemoradiation•Trametinib did not alter the pharmacokinetics of concurrent chemotherapy•Preliminary long term disease and survival outcomes appear promising 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). 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. 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. 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.