Clinical and translational study of ivosidenib plus nivolumab in advanced solid tumors harboring IDH1 mutations.

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 (IFN) signaling and CD8 Methods: Patients with an advanced or refractory solid tumor harboring an Results: 15 patients were enrolled (median age, 54 years; female, 53.3%; ECOG 1, 60%; glioma, 46.7%; R132H, 40%). One patient had a partial response (ORR 6.7%) and was without progression at 6 months (PFS6) whereas two other patients achieved PFS6 alone. In total, 3 out of 15 patients met the primary endpoint (3/15; 20%). The median PFS was 1.94 months. The most common treatment adverse events were leukopenia (67%), rash (67%), diarrhea (33%), nausea (27%), and QTC prolongation (27%). Pharmacodynamic studies demonstrated combining ivosidenib and nivolumab significantly decreased the plasma (R)-2HG concentration and correlated with clinical benefit. Serum proteomic and spatial omic analysis suggested immune-modulatory effects of mIDH1 inhibition plus anti-PD1. Conclusions: In treatment refractory mIDH1 solid tumors, the combination of ivosidenib and nivolumab was safe however demonstrated similar anti-tumor activity (predominantly as disease stabilization) compared with that previously described for ivosidenib monotherapy. Translational investigation suggests further evaluation of IDH1 inhibition as a combination partner with immune-checkpoint inhibition may be justified.