At the first interim analysis of the LITESPARK-005 trial, belzutifan was shown to improve the progression-free survival (PFS) and overall response rate (ORR) compared to everolimus in the treatment of previously treated patients with advanced clear cell renal cell carcinoma (ccRCC). With a median follow-up of 25.7 months, the results of the second interim analysis continued to demonstrate the PFS and ORR superiority of belzutifan over everolimus, solidifying HIF-a inhibition as a novel and promising therapeutic mechanism of action for advanced ccRCC.
The hypoxia-inducible factor (HIF) pathway is central to the pathophysiology of clear cell renal carcinoma (ccRCC) and von Hippel-Lindau (VHL) disease. Belzutifan, is a first-in-class oral HIF-2a inhibitor that blocks heterodimerisation with HIF-1b and downstream oncogenic pathways. In the US, belzutifan is already approved for the treatment of patients with certain VHL-associated RCC, pancreatic neuroendocrine tumours (pNET) or central nervous system hemangioblastomas (CNS-HB). Additionally, it has demonstrated clinical activity in pretreated advanced RCC. The phase III LITESPARK-005 study compared the efficacy and safety of belzutifan to that of everolimus in patients with advanced ccRCC. At the first interim analysis (IA1) with 18.4 months of follow-up, belzutifan was associated with a significantly better progression-free survival (PFS) and overall response rate (ORR) than everolimus. The results of the second interim analysis (IA2), with a total follow up of 25.7 months, were presented at ESMO 2023.
The phase 3 LITESPARK-005 study enrolled adult patients (aged ≥18 years) with unresectable, locally advanced or metastatic ccRCC who experienced disease progression after 1-3 prior lines of systemic therapy, including ≥1 anti-PD-(L)-1 antibody and ≥1 VEGFR-TKI. In total, 746 patients were randomly assigned (1:1) to belzutifan 120 mg QD (n=374) or everolimus 10 mg QD (n=372). The co-primary endpoints of this trial consist of PFS and OS, with ORR being a key secondary endpoint. Other secondary endpoints included the duration of response (DoR), safety, and the time to deterioration (TTD) of cancer therapy-kidney symptom index (FKSI)- disease-related symptoms (DRS) and quality-of-life (EORTC QLQ-C30).
After a median follow-up of 25.7 months, results for PFS, OS and ORR were consistent with those obtained at IA1. At IA2, a 25% reduction in the risk of progression or death was observed with belzutifan vs. everolimus (HR[95%CI]:0.74[0.63-0.88]). At the 18-month landmark, the PFS rate for patients treated with belzutifan was reported at 22.5% as compared to and 9.0% with everolimus. The difference in OS did not reach statistical significance at this IA, with a median OS of 21.4 vs. 18.1 months in the belzutifan and everolimus arms, respectively (HR[95%CI]: 0.88[0.73-1.07]; p=0.099). ORR was reported at 22.7% vs. 3.5% for patients treated with belzutifan and everolimus arms, respectively. This included 3.5% of complete responses (CR) in the belzutifan arm as compared to 0% with everolimus. The median DoR was reported at 19.5 vs. 13.7 months, with a median TTR of 3.8 vs. 3.7 months.
Grade ≥3 adverse events (AEs) were observed in 61.8% vs. 62.5% of patients who received belzutifan and everolimus, respectively. These complications led to discontinuation in 5.9% vs. 14.7% of cases. The most common grade 3-4 AEs in the belzutifan arm included anaemia and hypoxia. Quality of life favoured belzutifan, both by FKSI-DRS (HR[95%CI]: 0.53[0.41-0.69]; p<0.0001) and QLQ30 GHS/QoL (HR[95%CI]: 0.75[0.58-0.96]; p=0.019).
LITESPARK-005 is the first positive phase 3 study in patients with advanced kidney cancer who have already undergone immune checkpoint and anti-angiogenic therapies. In patients with advanced ccRCC, belzutifan demonstrated a statistically significant improvement in PFS and ORR compared to everolimus, with no new safety concerns. While the statistical significance for OS was not achieved at this point, upcoming analyses with longer follow-up are eagerly awaited. Based on these outcomes, LITESPARK-005 solidifies HIF-a inhibition as a novel and promising therapeutic mechanism of action for advanced ccRCC.
Reference
Albiges L. Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): randomized open-label phase 3 LITESPARK-005 study. Presented at ESMO 2023; Abstract LBA88.
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