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

Background: FH-deficient renal cell carcinoma (RCC) is a rare and exceptionally aggres-sive RCC subtype. There is currently limited understanding of the molecular alterations, pathogenesis, survival outcomes, and systemic therapy efficacy for this cancer.Objective: To 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 participants: The study included 77 cases of FH-deficient RCC from 15 centers across China.Outcome measurements and statistical analysis: Clinical characteristics, molecular cor-relates, 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, and treatment outcomes were analyzed.Results and limitations: A 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 (haz-ard 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 ther-apy. The main limitation is the retrospective study design.Conclusions: We 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 summary: This 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.(c) 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Automated summary

This retrospective multicenter analysis showed that immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy had better treatment response than bevacizumab plus erlotinib combination therapy in patients with FH-deficient RCC, providing evidence for the treatment of this rare cancer.