TY - JOUR
T1 - Phase I Trial of Definitive Concurrent Chemoradiotherapy and Trametinib for KRAS-Mutated Non-Small Cell Lung Cancer
AU - Lin, Steven H.
AU - Lin, Heather Y.
AU - Verma, Vivek
AU - Xu-Welliver, Meng
AU - Thall, Peter F.
AU - Yao, Luyang
AU - Kim, Peter Y.
AU - Gombos, Dan S.
AU - Kawedia, Jitesh D.
AU - Komaki, Ritsuko
AU - Gomez, Daniel R.
AU - Nguyen, Quynh Nhu
AU - O'Reilly, Michael S.
AU - Lu, Charles
AU - Fossella, Frank V.
AU - Skoulidis, Ferdinandos
AU - Zhang, Jianjun
AU - Tsao, Anne S.
AU - Heymach, John V.
AU - Blumenschein, George R.
N1 - Funding Information:
This trial was supported by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) under the UM1 mechanism (NCI-9448), and NCI Cancer Center Support (Core) Grant CA016672 to the University of Texas MD Anderson Cancer Center. We thank the trial coordinators for logistical and technical support and appreciate the participation of all patients onto this trial. A portion of this work was presented at the 18 th Annual Targeted Therapies of Lung Cancer Meeting (Santa Monica, CA, USA: February 21-24, 2018).
Publisher Copyright:
© 2022 The Authors
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - KRAS
KW - MEK
KW - Non-small cell lung cancer
KW - chemoradiotherapy
KW - trametinib
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U2 - 10.1016/j.ctarc.2022.100514
DO - 10.1016/j.ctarc.2022.100514
M3 - Article
C2 - 35051703
AN - SCOPUS:85122791562
SN - 2468-2942
VL - 30
SP - 100514
JO - Cancer Treatment and Research Communications
JF - Cancer Treatment and Research Communications
M1 - 100514
ER -