Phase II trial of avutometinib plus defactinib in RAF dimer-driven thyroid cancers - ABSTRACT/SUMMARY Two rare types of thyroid cancer currently have extremely poor outcomes. Radioiodine-refractory (RAIR), recurrent and/or metastatic (R/M) differentiated thyroid cancer (DTC) is incurable and has a 10-year survival of ~10%. Anaplastic thyroid cancer (ATC) is a highly aggressive, dedifferentiated thyroid cancer with a median survival of <6 months from the time of diagnosis. Both tumors are driven by mutually exclusive genetic alterations in the mitogen-activated protein kinase (MAPK) pathway. Targeted therapies against BRAFV600E and receptor tyrosine kinase (RTK) rearrangements (RET, NTRK, or ALK) have revolutionized outcomes for these genomic subsets of RAIR DTC and ATC. However, developing therapies for RAS, NF1, and non-V600 BRAF mutations, which activate MAPK signaling through RAF dimers (“dimer-driven”), has been significantly more challenging. Avutometinib is a next-generation MEK 1/2 inhibitor that inhibits both MEK and RAF to overcome the rebound pathway stimulation that limits the activity of other MEK inhibitors against dimer-driven disease. This has translated to promising clinical activity with avutometinib against RAS-mutant tumors. Nonetheless, on-treatment biopsies from patients have revealed that avutometinib treatment increases focal adhesion kinase (FAK) phosphorylation/activation, which has been well established to mediate intrinsic resistance to MAPK pathway inhibition in several tumor types. Subsequent randomized data has confirmed avutometinib plus the FAK inhibitor defactinib produces superior clinical efficacy compared to avutometinib alone in patients with low-grade serous ovarian carcinoma, including RAS-mutant tumors. These data, along with evidence from our studies of patient tumors and genetically engineered mouse models of advanced thyroid cancer, serve as the clinical and biologic basis for our phase II trial of avutometinib plus defactinib in dimer-driven thyroid cancers. To expeditiously identify promising clinical signals, we have developed an innovative basket trial design which will allow us to evaluate in both dimer-driven RAIR DTCs and ATCs the contribution of 3 putative, non-exclusive mechanisms to avutometinib + defactinib efficacy: tumor cell-autonomous antitumor effects, redifferentiation of tumors to restore and/or enhance RAI sensitivity, and modulation of the immune tumor microenvironment (TME). In Aim 1, we will evaluate overall response (primary) as well as progression-free survival and redifferentiation rates/efficacy (secondary). In Aim 2, we will interrogate in pre- and on-treatment biopsies the impact of avutometinib + defactinib upon MAPK- and FAK- regulated signaling and analyze how it relates to clinical response and redifferentiation. In Aim 3, we will analyze how combined MAPK and FAK pathway inhibition modulates the immune TME, specifically testing the hypothesis that inhibiting these signals will deplete immune-repressive tumor-associated macrophages (TAMs) in dimer-driven ATCs. This trial will identify the optimal application(s) for this novel combination in patients with advanced thyroid cancers to inform future drug development efforts.
