Phase II Trial of Ixazomib Combined with Gemcitabine and Doxorubicin in Patients with SMARCB1-Deficient Renal Medullary Carcinoma

PURPOSE: SMARCB1-deficient renal medullary carcinoma (RMC) is an aggressive kidney cancer lacking mechanism-directed therapies. We conducted a single-center, single-arm, phase II study (NCT03587662) testing the proteasome inhibitor ixazomib combined with gemcitabine and doxorubicin. PATIENTS AND METHODS: Ixazomib 5.5 mg, gemcitabine 756 mg/m2, and doxorubicin 42 mg/m2 were given every 2 weeks for up to 13 cycles, followed by ixazomib plus gemcitabine maintenance. Coprimary endpoints were objective response rate (ORR) and 28-week disease-control rate (DCR) versus historic gemcitabine plus doxorubicin. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Thirty patients (median age 34.5 years old, 90% Black) were treated. The posterior ORR was 36% [95% credible interval (CrI), 21%-54%] with a 91.4% probability of exceeding historic doublet therapy. However, the 28-week DCR was 17% (95% CrI, 6%-31%), crossing the predefined futility boundary. Median PFS and OS were 3.5 and 7.4 months, respectively. Grade ≥3 toxicities were predominantly hematologic (thrombocytopenia 20%, leukopenia 17%) and manageable, with no treatment-related deaths. Single-cell and bulk multi-omics from 11 patients revealed that immune-inflamed tumors enriched for T cells and plasmacytoid/conventional dendritic cells correlated with response, whereas stromal-myeloid niches and proliferative or neuroendocrine-squamous plastic epithelial states associated with resistance. Resistant tumors upregulated unfolded protein response, proteostasis maintenance, and NF-κB pathways. CONCLUSIONS: Addition of ixazomib to gemcitabine plus doxorubicin modestly increased radiographic response but did not extend disease control in an all-comer biomarker-unstratified RMC cohort. The integrated correlatives nominate mechanisms and biomarkers to guide future mechanism-directed trials in RMC.