49 Effect of Co-Morbidity Burden on the Efficacy and Tolerability of Belzutifan in Patients with Metastatic Renal Cell Carcinoma

Abstract

Abstract Background Belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, has demonstrated efficacy in advanced clear-cell renal cell carcinoma (ccRCC) in patients previously received immunotherapy (IO) and anti-angiogenics. However, comorbidities pose a challenge in cancer management and often limit inclusion in clinical trials. While the impact of comorbidities on clinical outcomes and tolerability has been studied with IO and anti-angiogenics, it remains unclear in patients with metastatic ccRCC (mccRCC) treated with belzutifan. Methods Data from patients with mccRCC treated with belzutifan beyond the first-line setting were collected. Comorbidity burden was assessed at baseline using the Charlson Comorbidity Index (CCI). Patients were stratified by CCI into low (≤3) and high (>3) groups. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and multivariable Cox regression models adjusting for age, International Metastatic RCC Database Consortium (IMDC) risk group, line of therapy, Karnofsky performance status (KPS), sarcomatoid features, and metastatic burden. Toxicity outcomes included grade ≥3 anemia, grade ≥3 hypoxia, and treatment discontinuation due to toxicity. Results A total of 108 patients were included, with 63 (58.3%) and 45 (41.7%) categorized as CCI-low and CCI-high, respectively. The most prevalent comorbidities were cardiovascular (23%) and pulmonary (21%). Patients with high CCI were significantly older (mean age 71.3 vs 60.8 years, p < 0.001), with otherwise similar baseline characteristics. Comorbidity burden was not associated with OS or PFS with adjusted hazard ratios (aHR) of 0.94 (95% CI: 0.48-1.83), and 1.18 (95% CI: 0.69-2.02), respectively. Poor IMDC risk and later lines of therapy (≥4L) were associated with worse outcomes (OS: aHR 3.33, 95% CI 1.11-10.31, p = 0.03; PFS: aHR 3.01, 95% CI 1.28-7.04, p = 0.01, respectively) (Figure 1). Toxicity rates were also comparable between CCI groups. Grade ≥3 anemia occurred in 17.8% vs 9.5% (p = 0.33), and grade ≥3 hypoxia in 11.1% vs 7.9% (p = 0.82). Additionally, there were no significant differences between the rates of treatment discontinuation due to toxicity in the CCI-low and CCI-high groups (17% vs 28%, p = 0.24) Conclusions In mccRCC, belzutifan demonstrated consistent efficacy and tolerability regardless of comorbidity status. These findings extend the results of the LITESPARK-005 trial to a real-world population, supporting the use of belzutifan even in older, medically complex patients. DOD Funding no49 Figure 1 Forest plots of multivariable Cox regression for PFS (top panel) and OS (bottom panel). Hazard ratios and 95% confidence intervals are shown. Abbreviations: PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; CCI, Charlson Comorbidity Index; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; KPS, Karnofsky performance status; Brain/Bone/Liver mets, Brain or Bone or Liver Metastasis.