Belzutifan vs. Everolimus - Treating Advanced Renal-Cell Carcinoma

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Belzutifan vs. Everolimus - Treating Advanced Renal-Cell Carcinoma
By Sunita Pirmal, PharmD - InpharmD Fellow

Renal cell carcinoma (RCC), responsible for 85% of kidney tumors, is the eighth most common cancer in the United States. In 2021, over 13,000 deaths and 76,080 diagnoses were related to kidney and renal pelvic cancers in Americans. Renal cell carcinoma predominantly affects men at a 2:1 ratio and those aged 50 to 70 with key risk factors like smoking, obesity, and sickle cell trait. Clear-cell carcinoma (ccRCC) accounts for 70-80% of RCC cases and is identified by its sporadic, unilateral tumor growth and microscopic appearance of white/clear and pink cells. The 2024 National Comprehensive Cancer Network (NCCN) guidelines for kidney cancer recommend targeted therapies for advanced RCC, which include tyrosine kinase inhibitors (TKIs) and/or anti-vascular endothelial growth factor (VEGF) antibodies. Additionally, agents that target mammalian target of rapamycin (mTOR), such as everolimus, may be employed after the failure of TKIs. Nevertheless, many continue to experience disease progression despite receiving these preferred treatments, underscoring the need for new therapies like belzutifan. [1-3]

Mutations, deletions, or methylations of the von Hippel-Lindau (VHL) gene occur in over 90% of ccRCC tumors, leading to the accumulation of HIF-2-alpha, which drives tumor growth, angiogenesis, and metastasis. Belzutifan is a potent, small-molecule HIF-2-alpha inhibitor that prevents heterodimerization with HIF-1-beta, forming an active transcription factor that has demonstrated efficacy in ccRCC. This novel mechanism of action was previously considered “undrugable” due to the disordered nature of DNA-binding domains. The 2024 LITESPARK-005 trial (NCT04195750), compared the efficacy of belzutifan to everolimus in adult patients with advanced RCC who experienced disease progression after receiving first- and second-line immune checkpoint and antiangiogenic therapies. [3,4]

This phase 3, multicenter, open-label, active-controlled trial randomized adult patients with stage IV ccRCC in a 1:1 ratio to receive either oral belzutifan 120 mg (n= 374) or everolimus 10 mg (n= 372) daily until disease progression or unacceptable toxic effects occurred. Blood transfusions were administered for cases of anemia or hypoxia. The primary endpoints included median progression-free survival and overall survival [See TABLE 2 for results]. The key secondary endpoint was the occurrence of an objective partial or complete response. Other endpoints included duration of response, safety, and time to confirmed worsening of disease symptoms, as well as deterioration in global health status and quality of life. [See TABLE 1 for baseline characteristics] [4]

At the first interim analysis (median follow-up of 18.4 months), the median progression-free survival was 5.6 months for both groups. Twenty-four percent of patients receiving belzutifan and 8.3% of those receiving everolimus were alive and progression-free at 18 months (p= 0.002). A confirmed objective response was observed in 21.9% (95% confidence interval [CI] 17.8 to 26.5) of patients receiving belzutifan and 3.5% (95% CI 1.9 to 5.9) of patients receiving everolimus (p < 0.001), respectively. In the second interim analysis, the median overall survival was 21.4 months for belzutifan compared to 18.1 months for everolimus. [See TABLE 2 for results] [4]

Grade 3 or higher adverse events of any cause occurred in 61.8% of the belzutifan group, compared to 62.5% in the everolimus group. Grade 5 events were observed in 3.5% and 5.3% of participants, respectively. The most common Grade 3-5 adverse events in the belzutifan group included anemia (32.5%) and hypoxia (10.5%), while the most common adverse events of any grade were anemia (82.8%) and fatigue (31.5%). Notably, the mortality ratio did not meet the prespecified significance criterion, with a hazard ratio (HR) of 0.88 (95% CI 0.72 to 1.07, p= 0.20). Approximately 14.7% of the everolimus cohort discontinued treatment due to adverse events, which exceeded belzutifan’s 5.9% adverse event discontinuation rate. [4]

A potential limitation of the trial is using everolimus monotherapy as the comparator, as other agents like nivolumab, cabozantinib, and lenvatinib plus everolimus have shown greater efficacy. This may skew the results, as the control may not represent the current standard of care due to the use of a less effective agent. However, participants in LITESPARK-005 were more resistant to treatment, as inclusion criteria required failure of both first- and second-line therapies, with about half having prior exposure to cabozantinib, lenvatinib, or both. Additionally, Black patients were underrepresented (1.1%) in this trial, which limits the generalizability of these findings. This is particularly concerning, as sickle cell disease and African American race are known risk factors for renal cell carcinoma (RCC), with Black patients having the highest incidence of renal and renal pelvic cancers at 24.7 per 100,000 person-years in men and 12.4 in women. [2-6]

As belzutifan was not evaluated against current first- or second-line therapies, such as immune checkpoint or antiangiogenic agents, it remains unclear how its efficacy compares to these treatments. However, this drug may benefit patients who do not respond adequately to preferred therapies. Notably, the objective response rates for current preferred treatments range from 42% to 71%, exhibiting a need for new therapies with novel mechanisms of action to further advance cancer treatment. [4,5]

 

TABLE 1- Baseline Characteristics
	Belzutifan (n= 374)	Everolimus (n= 372)
Age, years (range)	62 (22 to 90)	63 (33 to 87)
Male	79.4%	76.3%
Race American Indian/Alaskan Native Asian Black Multiple Pacific Islander White Data missing	0.8% 11.5% 1.1% 1.6% 0% 79.4% 5.6%	0.5% 12.6% 1.1% 3.0% 0.3% 78.2% 4.3%
Karnofsky performance-status score 90 or 100 70 or 80 Data missing	63.6% 36.1% 0.3%	64.5% 35.2% 0.3%
IMDC prognostic risk categories Favorable, score 0 Intermediate, score 1-2 Poor, score 3-6	21.1% 66.6% 12.3%	22.3% 65.6% 12.1%
Sarcomatoid features Yes No Unknown	11.2% 68.2% 20.6%	8.3% 66.7% 25%
No. of previous therapies 1 2 3 4*	12.3% 42.0% 45.2% 0.5%	14.0% 44.6% 40.3% 1.1%
No. of previous VEGFR-TKIs 1 2-3	50% 50%	51.1% 48.9%
Sites of metastasis Lung Lymph node Bone Liver Adrenal gland	65.8% 62.0% 50.0% 23.8% 19.5%	63.4% 57.8% 48.7% 27.7% 19.1%
Abbreviations: IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; VEGFR-TKI, vascular endothelial growth factor receptor tyrosine kinase inhibitor * Four previous therapies were deemed a protocol violation
Reference: Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906

 

TABLE 2- Results
Endpoint		Belfutifan (n= 374)	Everolimus (n= 372)	p-value
Median progression-free survival, months1		5.6	5.6	-
Alive and free from progression at 18 months		24%	8.3%	0.002
Objective response, % (95% CI) First interim analysis Second interim analysis		21.9 (17.8 to 26.5) 22.7 (18.6 to 27.3)	3.5 (1.9 to 5.9) 3.5 (1.9 to 5.9)	<0.001 -
Overall survival, months (median)		21.4 (18.2 to 24.3)	18.1 (15.8 to 21.8)	-
Duration of response,  months (median)2,3		19.5 (1.9+ to 31.6+)	13.7 (3.8 to 21.2+)	-
Time of response, months (median)2		3.8 (1.8 to 22.0)	3.7 (1.8 to 5.4)	-
Death, HR (95% CI)		0.88 (0.73 to 1.07)	-	0.20
Abbreviations: CI, confidence interval; HR, hazard ratio 1 Median follow-up was 18.4 months 2 Second interim analysis (median follow-up was 25.7 months) 3 Plus signs indicate ongoing response at time of data cutoff
Reference: Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906

 

References

1. Tenold M, Ravi P, Kumar M, et al. Current Approaches to the Treatment of Advanced or Metastatic Renal Cell Carcinoma. Am Soc Clin Oncol Educ Book. 2020;40:1-10. doi:10.1200/EDBK_279881
2. Garfield K, LaGrange CA. Renal Cell Cancer. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 31, 2023.
3. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney Cancer, Version 2.2024, Featured Updates to the NCCN Guidelines. J Natl Compr Canc Netw 2024;22(1):4–16 doi:10.6004/jnccn.2024.0008
4. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906
5. Vento JA, Rini BI. Treatment of Refractory Metastatic Renal Cell Carcinoma. Cancers (Basel). 2022;14(20):5005. Published 2022 Oct 13. doi:10.3390/cancers14205005
6. Sims JN, Yedjou CG, Abugri D, et al. Racial Disparities and Preventive Measures to Renal Cell Carcinoma. Int J Environ Res Public Health. 2018;15(6):1089. Published 2018 May 28. doi:10.3390/ijerph15061089

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