Tislelizumab plus lenvatinib in advanced fumarate hydratase-deficient renal cell carcinoma: a single-arm, phase 2 trial with metabolic biomarker analysis.

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive kidney cancer with no established standard of care. This phase 2 trial (NCT05877820) assessed first-line tislelizumab plus lenvatinib in advanced FH-RCC (N = 20). The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. After a median follow-up of 20.2 months, ORR was 95% (95% CI 75.1-99.9), and DCR was 100% (95% CI 83.2-100). Median PFS was 20.7 months (95% CI 17.8-NR), median DOR was 19.2 months (95% CI 16.3-NR) and 2-year OS rate was 89.7% (95% CI 77.2-100). Grade ≥3 treatment-related adverse events occurred in 45% of patients. Circulating succinyl-adenosine and succinic-cysteine tracked radiographic tumor burden in 80% of patients. Limitations include the single-center, single-arm design, and limited sample size. These results support tislelizumab plus lenvatinib as a potential first-line option for advanced FH-RCC, with favorable antitumor activity and manageable safety profile. Circulating succinate-modifying metabolites may complement response monitoring but require further validation.