Impact of prior immune checkpoint inhibition on the clinical efficacy of belzutifan in advanced renal cell carcinoma.

e16547 Background: Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor that plays a central role in the pathogenesis of clear-cell renal cell carcinoma (ccRCC). Loss of the von Hippel–Lindau (VHL) tumor suppressor, which is present in the vast majority of ccRCC cases, leads to constitutive stabilization of HIF-α subunits, particularly HIF-2α. Persistent HIF-2α activity drives oncogenic programs including angiogenesis (via VEGF upregulation), metabolic reprogramming, proliferation, and survival. Belzutifan, a selective HIF-2α inhibitor, targets this core molecular driver and is currently approved for patients previously exposed to both VEGF-targeted therapies and immune checkpoint inhibitors (ICIs). However, in real-world practice, many patients with severe autoimmune diseases are unable to receive ICIs and instead undergo sequential VEGF-targeted TKI therapy. It remains uncertain whether belzutifan requires prior immune “priming” to achieve its therapeutic effect. Methods: A retrospective cohort study was conducted using the TriNetX Global Collaborative Network, including adults ≥18 years with RCC who received belzutifan; patients with Von Hippel–Lindau syndrome were excluded. Two cohorts were compared: those who initiated belzutifan after prior ICI exposure and those who received belzutifan without prior ICI therapy. Propensity score matching was performed on demographic variables, laboratory parameters, prior nephrectomy, and cardiovascular/cerebrovascular/ autoimmune comorbidities. Outcomes were evaluated over 365 days from belzutifan initiation. The primary endpoint was all-cause mortality; secondary endpoints included hospitalization and ICU-level care. Results: Before matching, 369 patients received belzutifan after ICIs, and 241 received belzutifan without prior ICIs. The overall mean age was 65 years, with 70.1 % male patients. After matching, 174 patients remained in each cohort. One-year overall survival was similar between the prior-ICI and no-ICI groups (68.36% vs 69.34%, respectively), with median survival not reached in either cohort. Survival differences were not statistically significant (log-rank p = 0.583; HR 1.127). Rates of hospitalization (55.7% vs 51.1%) and ICU admission (17.2% vs 16.1%) were likewise not significantly different. Conclusions: Belzutifan showed comparable survival and healthcare utilization outcomes regardless of prior ICI exposure, supporting the premise that its efficacy is independent of immune priming. These findings suggest that belzutifan may be an appropriate therapeutic option for ICI-ineligible patients who have received VEGF-targeted TKIs. Prospective studies are warranted to evaluate TKI-to-belzutifan sequences and inform potential expansion of treatment indications.