Cabozantinib/Nivolumab Combination Reveals Positive Activity in FH-Deficient RCC

Results from a small retrospective study evaluating cabozantinib (Cabometyx) plus nivolumab (Opdivo) revealed a response rate of 71% (95% CI, 41.9%-91.6%) in patients with fumarate hydratase–deficient renal cell carcinoma (FH–dRCC). Findings extend this combination’s efficacy beyond non–clear cell RCC.

Historically, the combination of erlotinib (Tarceva) and bevacizumab (Avastin) has demonstrated efficacy in advanced disease; however, the disease recurs in most patients, indicating a need for further effective approaches.

“In our database of patients with FH deficiency, we reviewed those who had received cabozantinib and nivolumab in the first or second line,” Maria I. Carlo, MD, said during a presentation at the International Kidney Cancer Symposium 2025 in Denver, Colorado.¹ Carlo is a genitourinary oncologist and clinical geneticist at Memorial Sloan Kettering Cancer Center in New York, New York.¹

An initial report from Lee et al,² which included 5 patients with FH-dRCC, suggested this combination could be active in this specific patient population, prompting a more focused analysis.

Patient Demographics

In the current study, 56 patients with FH-dRCC were assessed for eligibility. Sixteen received cabozantinib plus nivolumab, and 14 were deemed evaluable. Ten patients were treated with first-line therapy, and 4 were treated with second-line therapy.

The median age of the patients was 39 years (range, 23-73). Most patients (79%) were male, and 86% had germline FH mutations. Two patients (14.3%) had stable disease, no patients had a complete response, and 10 had a partial response (71.4%).

For all patients, the median progression-free survival (PFS) was 15.1 months (95% CI, 7.7-not reached [NR]), and the median overall survival (OS) was 37.3 months (95% CI, 28.1-NR).

Carlo noted that the investigators explored the difference in PFS and OS in patients who received the therapy in the prospective trial vs standard of care.

“The numbers were too small to make definite comparisons,” Carlo said, “But the median PFS among trial participants was 17.9 months vs 6.5 months among patients who received standard of care.” OS among trial participants was 41.5 months vs NR among patients who received standard of care.

“It’s difficult to make comparisons because patients were recruited asynchronously, so patients on protocol received treatment first and have longer follow-up than those who received standard of care,” Carlo added.

Case Study

Carlo then shared an illustrative case of a 23-year-old male patient with a germline FH mutation who was treated with frontline cabozantinib and nivolumab.

“He was diagnosed with de novo metastatic disease with widespread osseous metastasis,” Carlo said. Imaging studies performed after 2.5 months of therapy showed a significant reduction in tumor burden compared with baseline, providing a visual corroboration of the treatment's efficacy.¹

In conclusion, this retrospective analysis of 14 patients with advanced FH-RCC provides evidence that the combination of cabozantinib and nivolumab is an active regimen, yielding a high response rate and promising survival outcomes.

The observed efficacy appears comparable to that of other reported regimens for this disease, such as combinations of immunotherapy with TKIs or the bevacizumab and erlotinib combination.

Carlo noted that the optimal combination of tyrosine kinase inhibitors and immunotherapy, as well as the ideal sequence of treatments for this aggressive cancer, remains to be determined through future prospective studies.

REFERENCES

1. Jahn A, Chen YB, Doshi S, et al. Outcomes of patients with fumarate hydratase-deficient renal cell carcinoma treated with cabozantinib + nivolumab. Abstract presented at: International Kidney Cancer Symposium: North America 2025; November 13-15, 2025; Denver, CO.

2. Lee CH, Voss MH, Carlo MI, et al. Phase II trial of cabozantinib plus nivolumab in patients with non–clear-cell renal cell carcinoma and genomic correlates. J Clin Oncol. 2022;40(21):2333-2341. doi:10.1200/JCO.21.01944