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Phase Ib Pharmacodynamic Study of the MNK Inhibitor Tomivosertib (eFT508) Combined With Paclitaxel in Patients With
Cristiano Ferrario1, John Mackey2, Karen A Gelmon3
1Lady Davis Research Institute, Jewish General Hospital, McGill University, Montreal, Canada.
Purpose:
Preclinical data motivate clinical evaluation of inhibitors of MAPK-interacting kinases 1 and 2 (MNK1/2). We conducted a phase 1b clinical trial to study target engagement and safety of tomivosertib, a MNK1/2 inhibitor, alone and in combination with paclitaxel.
Patients And Methods:
Eligible patients had metastatic breast cancer resistant to standard-of-care treatments. Biopsies were obtained at baseline and during treatment with tomivosertib, and then tomivosertib was continued with the addition of paclitaxel until disease progression or toxicity. Serum drug levels were measured, and pharmacodynamic endpoints included IHC, proteomics, translatomics, and imaging mass cytometry.
Results:
Tomivosertib alone and in combination with paclitaxel was well tolerated. There was no pharmacokinetic interaction between the drugs. We observed a clear reduction in phosphorylation of eIF4E at S209, a major substrate of MNK1/2, and identified tomivosertib-induced perturbations in the proteome, translatome, and cellular populations of biopsied metastatic breast cancer tissue.
Conclusions:
We conclude that tomivosertib effectively inhibits MNK1/2 activity in metastatic breast cancer tissue and that it can safely be combined with paclitaxel in future phase II studies. We demonstrate feasibility of using proteomic profiles, translatomic profiles, and spatial distribution of immune cell infiltrates for clinical pharmacodynamic studies.
Insights
Tomivosertib, a MAPK-interacting kinases 1 and 2 (MNK1/2) inhibitor, showed target engagement and was well tolerated in metastatic breast cancer patients. It can be safely combined with paclitaxel for future studies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Preclinical studies support evaluating MAPK-interacting kinases 1 and 2 (MNK1/2) inhibitors.
- MNK1/2 inhibition is a potential therapeutic strategy for cancers resistant to standard treatments.
Purpose of the Study:
- To assess the target engagement and safety of tomivosertib, an MNK1/2 inhibitor.
- To evaluate tomivosertib alone and in combination with paclitaxel in patients with metastatic breast cancer.
Main Methods:
- Phase 1b clinical trial involving patients with metastatic breast cancer resistant to standard care.
- Pharmacodynamic assessments included immunohistochemistry, proteomics, translatomics, and imaging mass cytometry on tumor biopsies.
- Pharmacokinetic analysis of serum drug levels was performed.
Main Results:
- Tomivosertib, alone and with paclitaxel, was well tolerated with no pharmacokinetic interactions.
- Significant reduction in eIF4E phosphorylation (a key MNK1/2 substrate) was observed.
- Tomivosertib induced measurable changes in proteome, translatome, and immune cell populations in tumor tissue.
Conclusions:
- Tomivosertib effectively inhibits MNK1/2 activity in metastatic breast cancer.
- Tomivosertib can be safely combined with paclitaxel, supporting further Phase II investigation.
- Proteomic, translatomic, and immune cell profiling are feasible for clinical pharmacodynamic studies.
