AI Article Synopsis
- Somatic mutations are found in 25% of patients with non-small cell lung cancer (NSCLC), but MEK inhibitors alone haven't shown effectiveness, prompting exploration of trametinib combined with ponatinib for KRAS-mutant cases.
- A phase 1 study treated 12 patients with varying doses of trametinib and ponatinib, observing side effects like rash and diarrhea, along with some serious adverse events, including one death.
- Although there were no confirmed positive treatment responses, the findings suggest that future studies could investigate this combination further, possibly with alternative drugs to enhance safety.
Article Abstract
Introduction: Somatic mutations occur in 25% of patients with NSCLC. Treatment with MEK inhibitor monotherapy has not been successful in clinical trials to date. Compensatory activation of FGFR1 was identified as a mechanism of trametinib resistance in KRAS-mutant NSCLC, and combination therapy with trametinib and ponatinib was synergistic in in vitro and in vivo models. This study sought to evaluate this drug combination in patients with KRAS-mutant NSCLC.
Methods: A phase 1 dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with mutations. A standard 3-plus-3 dose escalation was done. Patients were treated with the study therapy until intolerable toxicity or disease progression.
Results: A total of 12 patients with KRAS-mutant NSCLC were treated (seven at trametinib 2 mg and ponatinib 15 mg, five at trametinib 2 mg and ponatinib 30 mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in five patients, including one death in the study and four cardiovascular events. Serious events were observed at both dose levels. Of note, 75% (9 of 12) were assessable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days.
Conclusions: In this phase 1 study, in patients with KRAS-mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring the combination of MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8693267 | PMC |
| http://dx.doi.org/10.1016/j.jtocrr.2021.100256 | DOI Listing |
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