Background: Cancers that do not respond to immunotherapy typically harbor a non-T cell-inflamed tumor microenvironment (TME), characterized by the absence of type I/II interferon signaling and CD8+ T cell infiltration. We previously reported IDH1 somatic mutations were enriched in this phenotype across histologies. Mutant IDH1 (mIDH1) drives immune exclusion via metabolic reprogramming of the TME, and preclinical models show that IDH inhibition can restore anti-tumor immunity. We conducted a Phase II study assessing the preliminary activity of ivosidenib, an IDH1 inhibitor, plus nivolumab, an anti-PD1 antibody, in patients with mIDH1 advanced solid tumors (NCT04056910).
Methods: Patients with advanced or refractory mIDH1 solid tumors and no prior exposure to IDH1 inhibitor were administered ivosidenib 500 mg by mouth daily with nivolumab 480 mg intravenously every 4 weeks. A composite primary endpoint included either six-month progression-free survival (PFS6) or overall response rate (ORR). Translational analyses incorporated pharmacodynamics, proteomics, and spatial transcriptomics.
Results: Fifteen patients were enrolled (median age, 54 years; female, 53.3%; ECOG 1, 60%; glioma, 46.7%; R132H, 40%). Three patients (20%) met the primary endpoint. Median PFS was 1.94 months. The most common adverse events were leukopenia (67%), rash (67%), and diarrhea (33%). Treatment reduced plasma (R)-2HG, with greater reductions observed in patients who experienced clinical benefit. Exploratory serum proteomic and tumor spatial transcriptomic analyses suggested treatment-induced immune-modulatory effects.
Conclusions: Ivosidenib plus nivolumab was safe with limited clinical benefit. Translational investigation highlights potential of IDH1 inhibition to alter tumor-immune interactions and provides hypotheses for future immune-checkpoint combinations.
Keywords: IDH1; PD1; immunotherapy; ivosidenib; nivolumab; spatial transcriptomics.
© The Author(s) 2025. Published by Oxford University Press.