Impact of DNA damage repair gene mutations on response to combination immunotherapy in patients with FH-deficient renal cell carcinoma

Alterations in DNA damage response and repair (DDR) genes produce therapeutic biomarkers. However, the significance of DDR alterations in fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) remain undefined. Here, we investigate the DDR mutational landscape of the multi-centered FH-deficient RCC cohort and examine the relationship between DDR alterations and response to immunotherapy and tyrosine kinase inhibitor (immunotherapy/TKI). Genomic data and treatment outcomes were collected for patients with metastatic FH-deficient RCC. Tumors and matched blood samples from patients treated with systemic therapy were analyzed using targeted next-generation sequencing (NGS). Association between DDR mutation status and therapeutic benefit was investigated separately for immunotherapy/TKI combination therapy. A total of 105 patients were identified. Of 88 patients with successful NGS who received systemic treatment, 81 deleterious DDR gene alterations were identified in 44 DDR positive patients. Compared with DDR negative patients, DDR-positive patients had a significantly higher objective response rate (38.8% vs. 6.3%; P = 0.043), and longer median systemic treatment OS [not reached vs. 25.0 (95% CI, 13.33–36.68) months; HR, 0.149 (95% CI, 0.025–0.877); log-rank P = 0.035] with immunotherapy/TKI combination therapy. The association with response to immunotherapy/TKI combination therapy demonstrated that patients with FH-deficient RCC with altered DDR genes may be rational candidates for precision treatment.