Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a distinct pathological subtype of RCC characterized by a well-defined driver mutation and high malignancy. In recent years, studies have shown that patients with somatic FH mutations and those with germline FH mutations share similar clinical behaviors and poor prognoses. FH-deficient RCC typically presents at a younger age, with atypical imaging features, heterogeneous pathological patterns, diagnostic challenges, and limited response to conventional therapies. These factors severely threaten patients’ lives and highlight the urgent need for novel treatment strategies.
Recently, a multi-center study led by Professor Hao Zeng from West China Hospital, Sichuan University—conducted in collaboration with several leading Chinese institutions—was published in JAMA Oncology. The study evaluated the efficacy and safety of first-line therapy with the PD-1 inhibitor sintilimab combined with the VEGFR tyrosine kinase inhibitor axitinib in advanced FH-deficient RCC.
This phase II, open-label, single-arm clinical trial was conducted across eight medical centers in China from July 1, 2021, to August 29, 2023. Eligible participants were treatment-naïve patients with pathologically confirmed advanced FH-deficient RCC and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2. Data were analyzed up to December 1, 2024.
Patients received intravenous sintilimab (200 mg every three weeks) combined with oral axitinib (5 mg twice daily) until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included safety, overall survival (OS), disease control rate (proportion of patients achieving complete response, partial response, or stable disease ≥6 months), duration of response, and exploratory genomic outcomes.
A total of 41 patients were enrolled, with a median age of 36 years (range 18–75); 10 patients (24%) were female. At a median follow-up of 26.0 months (range 0.7–41.6):
– ORR was 56% (23 patients; 95% CI, 40%–72%), with median duration of response not yet reached.
– Disease control rate was 73% (30 patients).
– Median PFS was 19.8 months (95% CI, 10.9 months–not reached).
Notably, patients with a lower somatic copy number variation burden demonstrated better outcomes. Treatment-related grade ≥3 adverse events occurred in 13 patients (32%), with the most common being hypertriglyceridemia (3 patients, 7%), rash (2 patients, 5%), and anemia (2 patients, 5%).
This non-randomized trial demonstrates that sintilimab combined with axitinib yields encouraging ORR and PFS with manageable safety in patients with FH-deficient RCC. The findings support further evaluation of this combination in randomized clinical trials.
Read the original article in JAMA Oncology:
