Phase II study of enasidenib in IDH2-mutated malignant sinonasal and skull base tumors.
Authors: Xue Elisabetta , Bracken-Clarke Dara Mark , Reed Michele , Turkbey Evrim B. , Cordes Lisa M. , Donahue Renee N. , Steinberg Seth M. , Marte Jenn , London Nyall R , Schlom Jeffrey , Gulley James L. , Floudas Charalampos S. 
Published: June 2024

TPS3183 Background: Advanced sinonasal malignancies are rare and heterogeneous cancers with limited therapeutic options. Tumor types include olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC) and large cell neuroendocrine carcinoma (LCNEC), chondrosarcoma, and sinonasal adenocarcinoma (SNAC). Pathogenic driver mutations in isocitrate dehydrogenases 1 and 2 ( IDH1 and IDH2) were identified first in glioma and myeloid malignancies. IDH1/2 enzymatic activity catalyzes conversion of isocitrate and NADP+ to α-ketoglutarate (α-KG) and NAPDH, which are critical for cellular metabolism and for α-KG-dependent dioxygenases; mutant IDH1/2 catalyze conversion of α-KG to the oncometabolite 2-hydroxyglutarate (2-HG), a competitive antagonist of α-KG in regulating dioxygenases activity, with subsequent impact on DNA histone methylation and cellular differentiation. R172S or R172T IDH2mut have been detected in up to 80% of SNUCs and in a minority of ONB, chondrosarcoma, LCNEC and SNAC. Enasidenib is an oral small molecule inhibitor of the mutant IDH2 protein which prevents 2-HG accumulation and releases cancer cells from the differentiation block. It is currently approved for relapsed/refractory IDH2mut myeloid malignancies with proven clinical efficacy. Methods: This is a phase 2, single arm clinical trial conducted at the Center for Cancer Research (CCR) of the National Cancer Institute. The trial investigates the activity of enasidenib in adult patients with histologically or cytologically confirmed locally advanced or metastatic IDH2mut sinonasal cancers (SNUC, ONB, LCNEC, chondrosarcoma, SNAC). Participants must have RECIST 1.1 measurable disease and must have progressed following at least one prior systemic treatment line administered in the recurrent/metastatic setting; those with locally advanced disease must not be amenable to potentially curative approaches. Participants must also have ECOG performance status ≤ 2, be 18 years old or higher, and have adequate organ function. Participants with active, either new or progressive brain metastases or leptomeningeal disease are excluded. Enasidenib will be given continuously at a fixed dose of 100 mg orally daily in a 28-day cycle, until disease progression, unacceptable toxicity, or consent withdrawal. Imaging will be performed every 8 weeks. Baseline and on-treatment research biopsies will be mandatory, where clinically feasible. The trial aims to accrue a total of 25 participants. The primary end point is progression free survival. Secondary outcomes include safety, overall survival, and clinical benefit rate, defined as complete response, partial response and stable disease (per RECIST 1.1) lasting above 4 months. Correlative studies include evaluating changes in 2-HG plasma levels during treatment, and transcriptomic profiling. The study has just started enrolling in the CCR. Clinical trial registry: NCT06176989. Clinical trial information: NCT06176989 .