Tislelizumab plus lenvatinib as the first-line therapy in patients with advanced fumarate hydratase-deficient renal cell carcinoma: a single-arm, single-centre, phase 2 trial and metabolic biomarker analysis

Background Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare subtype of kidney malignancy with poor prognosis. Standard of care for advanced FH-RCC has not been established, although our prior retrospective study showed encouraging antitumor activity of immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) combinations. Objective We aimed to conduct an investigator-initiated prospective study to assess the efficacy and safety of tislelizumab plus lenvatinib as a first-line treatment for patients with advanced FH-RCC. Methods In this single-arm, open-label, phase 2 trial, adult patients with previously untreated, pathologically confirmed, unresectable advanced or metastatic FH-RCC, and at least one measurable lesion per RECIST 1.1 were eligible for enrollment. All enrolled patients received tislelizumab 200 mg intravenously every three weeks plus lenvatinib 20 mg orally once daily until disease progression, intolerable toxicity, or withdrawal of consent. This trial is registered with ClinicalTrials.gov (NCT05877820) and closed enrollment. The primary end point was objective response rate (ORR) as assessed by RECSIT 1.1. Secondary endpoints included progress-free survival, overall survival, disease control rate, duration of response, clinical benefit rate and treatment-related adverse events (TRAEs) assessment. Efficacy and safety were analyzed in all treated patients. Correlation between circulating metabolic biomarker dynamics and clinical response was investigated as an exploratory endpoint. Results From September 5, 2023, to December 10, 2024, 25 patients were screened and 20 were eligible to receive treatment. Median age was 41.5 years (IQR: 30–50) and 80% of patients were male. ECOG performance status was 1 or 2 in 40% of patients. Patients were classified as favorable, intermediate, or poor risk group in three (15%), eleven (55%), and six (30%) patients respectively per IMDC categorization. FH germline mutation was identified in 15/20 (75%) patients; the remainder were considered to carry biallelic somatic FH alterations. As data cutoff, the median follow-up was 17.8 months (IQR: 12.2–23.0). Nineteen patients achieved a confirmed objective response (ORR: 95%; 95% CI: 75.1–99.9), including four (20%) with a complete response and 15 (75%) with a partial response as the best response, with a median duration of response of 19.2 months (95%CI: 16.3-NR). The median PFS was 20.7 months (95%CI: 17.8-NR). Two-year overall survival rate was estimated as 89.7% (95% CI: 77.2–100). Grade ≥ 3 TRAEs occurred in 9/20 (45%) patients; and dose interruption, reduction or discontinuation of any study agent occurred in 14/20 (70%) patients. We found that circulating succinyl-adenosine and succinic-cysteine tracked radiographic tumor burden assessed by RECIST 1.1 in 16/20 (80%) patients. The main limitation is the single-centre and single-arm design, and the sample size is limited. Conclusions Tislelizumab plus lenvatinib has favorable antitumor activity in patients with previously untreated advanced FH-RCC, with a safety profile consistent to that of previous reports, which shows potential as a first-line treatment option. Circulating succinate-modifying metabolites may act as potential biomarkers for real-time treatment response monitoring and for the detection of early treatment failure.