Dataset Information

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

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.

SUBMITTER: Lin SH

PROVIDER: S-EPMC9259763 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

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

Lin Steven H SH Lin Heather Y HY Verma Vivek V Xu-Welliver Meng M Thall Peter F PF Yao Luyang L Kim Peter Y PY Gombos Dan S DS Kawedia Jitesh D JD Komaki Ritsuko R Gomez Daniel R DR Nguyen Quynh-Nhu QN O'Reilly Michael S MS Lu Charles C Fossella Frank V FV Skoulidis Ferdinandos F Zhang Jianjun J Tsao Anne S AS Heymach John V JV Blumenschein George R GR

Cancer treatment and research communications 20220107

<h4>Objective</h4>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).<h4>Methods</h4>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 usi ...[more]

PMID: 35051703

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Project description:Definitive chemoradiotherapy (CRT) has been a standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, locoregional recurrence occurs in about 30% of patients after definitive CRT. Recently, the addition of durvalumab as maintenance therapy has shown to improve the outcome of these patients. However, locoregional recurrence will still remain. "Salvage surgery" has been performed to achieve local control in clinical practice, although its clinical significance is unclear. In this review, we define salvage surgery as lung resection for local control of the tumor which was not planned initially, after failure or insufficient treatment effect of the initial CRT for locally advanced cancer and evaluated nine studies to gain some insights on its role in the treatment of lung cancer. The time from radiotherapy (RT) to salvage surgery varied considerably (range, 3 to 282 weeks). Salvage surgery was performed for persistent disease (47%) and locoregional recurrence (52%). Lobectomy (63%) and mediastinal lymph node dissections (90%) were the most common procedures. However, the rate of pneumonectomy was higher in salvage surgery (28%) compared to that in lung resection in general. The median morbidity was 41% (range, 15% to 62%) and the mortality was 4% (range, 0 to 11%) which appeared acceptable. The median recurrence-free survival and overall survival (OS) after salvage surgery ranged from 10 to 22 months and 13 to 76 months, respectively. Favorable prognostic factors of salvage surgery were longer period from RT to salvage surgery and radiological downstaging. The pathological response was also prognostic, although this information cannot be obtained preoperatively. We conclude that salvage surgery can be considered especially for those with late local recurrence or those with the metabolic response. Given the condition where phase III trials are difficult, the accumulation of real-world evidence in a prospective fashion will be necessary.

Dataset Information

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

Objective

Methods

Results

Conclusions

Publications

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

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