Lenvatinib plus tislelizumab as first-line therapy for advanced fumarate hydratase-deficient renal cell carcinoma: A single-center, single-arm, phase II study.

443 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive subtype of RCC with dismal prognosis. Although bevacizumab plus erlotinib (Beva/Erlo) showed promising anti-tumor activity, treatment option was limited. Date from our retrospective study showed comparable response rates between tyrosine kinase inhibitors plus immune checkpoint inhibitors (TKI/ICI) and Beva/Erlo, while the TKI/ICI group had better overall survival. Here, we reported the preliminary result of an investigator-initiated phase II study evaluating lenvatinib plus tislelizumab for advanced FH-RCC in the first-line setting. Methods: Eligible patients were aged 18-80 years old, diagnosed with pathologically confirmed, unresectable advanced or metastatic FH-RCC, had measurable disease defined by RECIST 1.1 and no history of systemic therapy. A definitive diagnosis of FH-RCC was confirmed when germline or somatic FH mutations were detected via DNA sequencing. All eligible patients received concurrent therapy with lenvatinib 20 mg P.O. daily and tislelizumab 200 mg intravenously every 3 weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR). Secondary end points included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year and 2-year overall survival (OS) rate, and safety. Results: From September 2023 to October 2024, 17 patients were enrolled (male: 14, female: 3). The median age was 37 (24-61). FH germline alteration was identified in 12 patients, while the remaining 5 patients were considered carrying somatic biallelic FH mutations. Thirteen patients had a history of nephrectomy. The most common site of recurrence or metastasis was retroperitoneal space (14/17, 82.1%), followed by bone metastasis (9/17, 52.9%). The median follow up was 7.0 (1.0-12.0) months. Fifteen patients were available for efficacy assessment at data cutoff，fourteen of them had an objective response (ORR 93.3%), and the complete response rate was 20.0% (3/15). The median time to response was 6 weeks. One PFS and OS event occurred. Median PFS and OS were not reached, while 6-month PFS and OS rate were 93.3% and 100% respectively. All grades and ≥G3 AE occurred in 16 (94.1%) and 4 patients (23.5%) respectively. Treatment discontinuation or dosage reduction occurred 8 patients (47.1%). Conclusions: Lenvatinib plus tislelizumab combination showed encouraging anti-tumor efficacy and acceptable toxicity profile. The potential of TKI/ICI/ combination to be recommended as the first-line therapy in advanced FH-RCC patient needs further evaluation. Clinical trial information: NCT05877820 .