Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders

Abstract

<h3>Background</h3> <i>Microphthalmia Transcription Factor</i> (<i>MITF</i>)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring <i>TFE3</i>/<i>TFEB</i> translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population. <h3>Patients and methods</h3> This multicenter retrospective study identified patients with <i>MITF</i> family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients. <h3>Results</h3> Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1–22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1–40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (<i>PBRM1</i> and <i>BRD8</i>) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of <i>BRD8</i> mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10^{− 6}). <h3>Conclusions</h3> <i>MITF</i> family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.