Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma

Abstract

BackgroundFH-deficient renal cell carcinoma (RCC) is a rare and exceptionally aggressive RCC subtype. There is currently limited understanding of the molecular alterations, pathogenesis, survival outcomes, and systemic therapy efficacy for this cancer. ObjectiveTo perform a retrospective multicenter analysis of molecular profiling and clinical outcomes for patients with FH-deficient RCC, with an emphasis on treatment response to first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI/TKI) versus bevacizumab plus erlotinib (Bev/Erlo) combination therapy in patients with advanced disease. Design, setting, and participantsThe study included 77 cases of FH-deficient RCC from 15 centers across China. Outcome measurements and statistical analysisClinical characteristics, molecular correlates, 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, and treatment outcomes were analyzed. Results and limitationsA total of 77 patients were identified, including 70 cases with a germline FH alteration (hereditary leiomyomatosis RCC syndrome [HLRCC]-associated RCC) and seven patients with somatic FH loss. Recurrent pathogenic alterations were found in NF2 (six/57, 11%), CDH1 (six/57, 11%), PIK3CA (six/57, 11%), and TP53 (five/57, 8.8%). Sixty-seven patients were evaluable for response to first-line systemic therapy with Bev/Erlo (n = 12), TKI monotherapy (n = 29), or ICI/TKI (n = 26). ICI/TKI combination therapy was associated with more favorable overall survival on systemic treatment (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04–0.90) and progression-free survival on first-line therapy (HR 0.22, 95% CI 0.07–0.71) compared to Bev/Erlo combination therapy. The main limitation is the retrospective study design. ConclusionsWe described the genomic characteristics of FH-deficient RCC in an Asian population and observed a favorable response to ICI/TKI combinational therapy among patients with advanced disease. Patient summaryThis real-world study provides evidence supporting the antitumour activity of combining molecular targeted therapy plus immunotherapy for kidney cancer deficient in fumarate hydratase. Further studies are needed to investigate the efficacy of this combination strategy in this rare cancer.