Safety and efficacy of immune checkpoint inhibitor rechallenge in metastatic fumarate hydratase-deficient renal cell carcinoma: A retrospective study.

500 Background: Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare subtype of kidney cancer characterized by FH-inactivating alterations. Studies have revealed highly immunogenic features in this lethal disease, providing molecular evidence for implement of immune checkpoint inhibitor (ICI). Due to the lethal nature of FH-deficient RCC, a significant proportion of patients continue to have disease progression after receiving ICI combination therapy (ICI plus tyrosine kinase inhibitors, TKI). Herein, we aim to evaluate the safety and efficacy of immune checkpoint inhibitor rechallenge in metastatic fumarate hydratase-deficient renal cell carcinoma in real-world settings. Methods: A multicenter database of patients diagnosed with FH-deficient RCC, identified through IHC evidence of negative FH and/or positive 2SC, was explored. The study enrolled patients with metastatic FH-deficient RCC who received ICI combination therapy within three months of discontinuing prior ICI treatments between January 2018 and July 2023. Results: A total of 18 patients, each receiving at least two lines of ICI combination therapy, were included in the study. The majority of patients (n=15) experienced disease progression following prior-line immunotherapy. Among these, with 66.7% (10/15) showed progression in the original lesions, while 33.3% (5/15) developed new metastatic lesions. Three patients transitioned to later-line immunotherapy due to immune-related adverse events (irAEs) of grade 3 or higher. The incidence of grade 1-2 irAEs was comparable between prior and later-line therapies (28.15% vs. 27.30%, p=0.8932), as was the incidence of grade 3 or higher irAEs (0.86% vs. 0.29%, p=0.594). For the entire cohort, the median progression-free survival (mPFS) for prior-line ICI combination therapy was 16.2 months (95% CI: 5.565-26.835 months), and the mPFS for later-line ICI combination therapy was 15.2 months (95% CI: 3.915-26.485 months). The objective response rate (ORR) and disease control rate (DCR) for later-line therapy were 17% and 78%, respectively, compared to an ORR of 28% and a DCR of 67% for prior-line therapy. Conclusions: This cohort study demonstrated that ICI rechallenge achieved mPFS of 15.2 months and DCR of 78%, with a favorable safety profile in patients with FH-deficient RCC. Therefore, the resumption of ICI combination therapy may be a viable option for managing this lethal subtype of RCC.