Abstract CT521: Phase 1b trial of the MNK1/2 inhibitor tomivosertib combined with paclitaxel in patients with metastatic breast cancer

Abstract

Abstract MNK is a serine/threonine kinase signaling node in the MAPK pathway, which is phosphorylated and activated by ERK. MNK phosphorylates eIF4E to promote translation of a subset of mRNAs that encode oncogenically relevant proteins including c-Myc, Cyclin D1 and PD-L1. We conducted a phase 1B study [NCT04261218] of tomivosertib (T), an orally administered inhibitor of MNK, to assess target engagement in metastatic breast cancer tissue and tolerability and pharmacokinetics of co-administration with paclitaxel (P). There are no prior reports of co-administration of a MNK inhibitor with a cytotoxic agent. All patients underwent pre-treatment baseline and on-treatment (day ~7) core biopsy of metastatic disease during the T monotherapy lead-in phase; subsequently patients continued oral T 100mg bid (without or with meal) with the addition of IV P at 80mg/m2 day 1 and 8 every 21 days. Results: We report here interim data for the first 14 patients with MBC refractory to standard treatments. Pharmacokinetics: T plasma levels were 21+/- 40 ng/ml throughout the day, and were not influenced by infusion of P. Peak P levels following infusion were 600 +/- 220 ng/ml and fell to below detection limit by 24 hours post infusion, similar to prior reports for single-agent P. Pharmacodynamics: The main endpoint was assessment of T -induced eIF4E phosphorylation in MBC biopsy tissue, estimated by immunostaining with an antibody specific for eIF4E phosphorylated at S209. Phospho-eIF4E staining intensity was generally high in the pre-treatment samples (indicating baseline activation of eIF4E in MBC). In contrast, the on- T biopsies revealed undetectable phopho-eIF4E staining in all patients. These results were confirmed by mass cytometry analysis, which also included a characterization of the immune microenvironment. We performed ribo-seq analysis on 2 mg flash frozen cancer specimens, and this provided preliminary evidence for decreased translation of mRNAs encoding proteins relevant to neoplasia including TMSB4X and MUCL1 on exposure to T. Preliminary analysis of comparison of proteomic data for each patient, comparing baseline and on-drug biopsies, revealed upregulation of proteins involved in fatty acid catabolic processes, consistent with prior experimental work (PMID 32712434). Safety and Clinical: Of 14 initial patients, 1 left the study for adverse reaction (nausea), 1 left study at physician’s discretion, and 5 left the study for progressive disease. There were no indications of increased P toxicity, and T was generally well tolerated in keeping with prior single agent phase I data. Two patients showed a decrease (36% and 45%) in size of metastases, but others showed disease progression, despite evidence for absence of phospho-eIF4E. The results indicate feasibility of a future phase 2 study of the T - P combination. (Supported by a Dream Team grant from Stand Up To Cancer - Canada) Citation Format: Cristiano Ferrario, John Mackey, Karen Gelmon, Poul HB Sorensen, Htoo Zarni Oo, Gregg B. Morin, Sonia del Rincon, Mehdi Amiri, Premal Patel, Harvey W. Smith, Nahum Sonenberg, Michael N. Pollak. Phase 1b trial of the MNK1/2 inhibitor tomivosertib combined with paclitaxel in patients with metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT521.