Balancing effectiveness and toxicity: Cabozantinib versus belzutifan after ICI/VEGF therapy in older adults with renal cell carcinoma.

e16533 Background: First line therapy for favorable and intermediate/poor risk mRCC is Pembrolizumab and Axitinib. Multiple post–pembrolizumab/axitinib options exist, with sequencing still under study. While cabozantinib, everolimus, and lenvatinib have been available for several years, belzutifan is a newer agent. Cabozantinib and lenvatinib are typically used earlier than everolimus; however, the optimal timing of belzutifan remains unclear. Belzutifan’s approval was based on LITESPARK-005, which demonstrated improved progression free survivial in addition to improved overall response rate, when compared to everolimus. The benefit of sequencing belzutifan before cabozantinib remains to be determined. No head-to-head trials guide this decision, and cabozantinib’s toxicity may limit use in older adults, whereas belzutifan’s HIF-2α inhibition may overcome VEGF-TKI resistance. This study compares the real-world effectiveness and safety of these agents in an elderly population. Methods: Using TriNetX database, we conducted a retrospective cohort study of RCC patients aged ≥60 years treated initially with pembrolizumab/axitinib and subsequently with either cabozantinib or belzutifan ≥1 month later. Patients with von Hippel-Lindau syndrome were excluded. 1:1 propensity score matching (PSM) was performed using demographics, comorbidities (COPD, IHD, CVD, HTN, CKD, DM, O₂ dependence), disease factors (bone, liver, brain metastases; partial nephrectomy), baseline CBC, and confounders like non-infective colitis. Outcomes included 3-year overall survival (OS), 3-yr venous thromboembolism (VTE), 90-day hospitalization, 90-day acute renal failure (ARF), and 180-day gastrointestinal (GI) toxicity. Results: Post PSM (n = 95/arm), both cohorts had similar 3-year survival probability (41.7% vs 36.7%) with median OS longer with cabozantinib (25 vs 17 months), though this difference was not statistically significant (HR 0.728, long rank p = 0.175). 3-year VTE risk [24.2% vs 18.9%, RR 1.28 (0.74–2.21) p = 0.38], and 90-day ARF risk [16.8% vs 14.7%, RR 1.143 (0.59–2.21) p = 0.69] were comparable between groups. Notably, Cabozantinib was associated with significantly fewer 90-day hospitalizations [25.3% vs 43.2%, RR 0.58 (0.39–0.89) p = 0.01] but a higher incidence of GI toxicity at 180 days [26.3% vs 13.7% RR 1.923 (1.048–3.528) p = 0.0295] as compared to belzutifan. Conclusions: In elderly RCC patients, previously treated with ICI/VEGF therapy, Cabozantinib and Belzutifan were associated with similar overall survival and rates of serious adverse outcomes. Cabozantinib was linked to fewer early hospitalizations, but a higher incidence of gastrointestinal toxicity. This reflects efficacy-tolerability trade-offs to individualize care in older adults. Further studies combining Belzutifan with other TKI’s have been in progress and show promising results.