Efficacy outcomes with belzutifan versus everolimus by baseline disease characteristics and burden subgroups in the phase 3 LITESPARK-005 study.
Authors: de Velasco Guillermo , Albiges Laurence , Powles Thomas , Suárez Cristina , Jalkanen Katriina Johanna , Burotto Mauricio , Ghatalia Pooja , Iacovelli Roberto , Lam Elaine T , Verzoni Elena , Gumus Mahmut , Stadler Walter Michael , Kollmannsberger Christian K. , Melichar Bohuslav , Venugopal Balaji , Lin Jingyi , Perini Rodolfo F. , Vickery Donna , Rini Brian I. , Choueiri Toni K. 
Published: February 2025

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Background:
At first interim analysis of the randomized, multicenter, open-label, phase 3 LITESPARK-005 study (NCT04195750), belzutifan was associated with a significant and clinically meaningful improvement in progression-free survival (PFS) and objective response rate (ORR) vs everolimus in participants (pts) with advanced clear cell renal cell carcinoma (ccRCC) after both anti–PD-(L)1 and VEGF-targeted therapy. PFS and ORR results remained consistent at final analysis (FA); significant improvement in overall survival (OS) in this heavily pretreated population was not observed. Efficacy outcomes by baseline disease characteristics and tumor burden at FA are presented here.
Methods:
Pts were aged ≥18 years, had advanced ccRCC, and 1–3 prior systemic regimens (including ≥1 prior PD-[L]1 inhibitor and VEGFR-TKI in combination or in sequence). Belzutifan 120 mg QD or everolimus 10 mg QD were administered to randomized (1:1) pts until disease progression or unacceptable toxicity. An exploratory analysis of PFS and ORR per RECIST 1.1 by central review and OS was conducted in subgroups by bone metastasis (present at baseline, yes vs no), liver metastasis (present at baseline, yes vs no), and baseline tumor burden (sum of diameters of target lesions, < median vs ≥ median). No formal statistical testing was performed.
Results:
A total of 374 pts were randomized to belzutifan, and 372 to everolimus. At FA (data cutoff: April 15, 2024), median follow-up was 35.8 mo (range 26.9–49.2) for the total population. PFS and ORR benefits with belzutifan vs everolimus were generally consistent with the total population across all analyzed subgroups (Table). In line with the total population at FA, improvement in OS was not observed across most subgroups.
Conclusions:
Belzutifan is a novel treatment option for patients with advanced ccRCC after prior anti–PD-(L)1 and VEGF-targeted therapies. Exploratory analysis suggests that PFS and ORR benefits with belzutifan vs everolimus are generally consistent across subgroups by baseline disease characteristics and tumor burden. Clinical trial information:
NCT04195750
.

Bone mets, yes
Bone mets, no
Liver mets, yes
Liver mets, no
Sum target lesion diameters,< median
Sum target lesion diameters,≥ median

Bel
Eve
Bel
Eve
Bel
Eve
Bel
Eve
Bel
Eve
Bel
Eve

N
187
181
187
191
89
103
285
269
174
193
198
171

PFS, median, mo
3.7
4.3
7.0
6.3
4.6
3.7
5.6
5.8
7.3
5.7
4.2
4.8

PFS HR(95% CI)
0.88(0.69–1.11)
0.65(0.51–0.82)
0.55(0.39–0.77)
0.84(0.69–1.02)
0.67(0.52–0.86)
0.80(0.63–1.01)

OS, median, mo
15.0
15.1
26.5
23.7
19.1
12.9
21.7
21.8
26.4
26.5
17.3
12.3

OS HR(95% CI)
0.95(0.75–1.20)
0.89(0.69–1.15)
0.63(0.45–0.88)
1.06(0.86–1.30)
0.95(0.73–1.24)
0.76(0.61–0.96)

ORR, %
17.6
2.8
27.8
4.2
24.7
3.9
22.1
3.3
28.7
4.1
17.7
2.9

Bel=belzutifan; eve=everolimus; mets=metastasis.