Casdatifan (Cas) monotherapy in patients (pts) with previously treated clear cell renal cell carcinoma (ccRCC): Safety, efficacy and subgroup analysis across multiple doses from ARC-20, a phase 1 open-label study.
Authors: Choueiri Toni K. , Lee Jae Lyun , Merchan Jaime R. , Patnaik Amita , Garmezy Benjamin , Drakaki Alexandra , Ornstein Moshe C. , McGregor Bradley Alexander , Hauke Ralph J. , Tsao Kai , Rini Brian I. , Barata Pedro C. , Foster Paul G. , Mukhopadhyay Sutapa , Gupta Neal , Chen Jianfen , Monga Manish , Nuyten Dimitry S. A. , Rha Sun Young 
Published: February 2025

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Background:
ccRCC, the most common histologic subtype of renal cancer, is universally associated with dysregulation of the VHL pathway, leading to HIF-2α accumulation and upregulation of multiple oncogenic pathways. Cas is an orally bioavailable, small-molecule HIF-2α inhibitor that potently inhibits transcription of HIF-2α-dependent genes.
Methods:
ARC-20 (NCT05536141) is a phase 1, open-label study evaluating Cas monotherapy in pts (age ≥18) with ccRCC who are HIF-2α inhibitor naïve and previously treated with anti-PD-(L)1 and VEGFR-TKI therapies. Trial endpoints included incidence of treatment-emergent adverse events (TEAES) and objective response rate (ORR) by RECIST v1.1.
Results:
Prior to dose expansion, dose escalation occurred in 4 pts with ccRCC (3 pts 50 mg BID; 1 pt 50 mg QD) of which 2 pts had SD,1 pt had PR, and 2 remain on study as of 30Aug2024. In dose expansion, 64 pts received Cas (33 pts 50 mg BID, 31 pts 50 mg QD). Median prior lines of treatment were 3 (range 1–7) across doses. Median follow-up (months, range) was 11 (3–15+) and 8 (4–10+) for 50 mg BID and 50 mg QD, respectively. Cas-related grade ≥3 TEAE occurred in 42% (n=14) and 36% (n=11) of pts, respectively. Notably 36% of pts experienced grade 3 anemia, regardless of dose, and grade 3 hypoxia occurred in 9% and 6% of pts, respectively. No grade ≥4 TEAEs occurred. Activity was seen across all IMDC risk groups, regardless of dose, and in pts with or without prior mTOR inhibitor (Table). Cas 100 mg demonstrated optimal sustained EPO reduction. Biomarker analysis, including HIF-1α and HIF-2α immunohistochemistry, mutational status of VHL/ccRCC relevant genes, predictive transcriptomic signatures and efficacy data with longer follow up will be presented.
Conclusions:
In heavily pretreated pts with ccRCC, Cas monotherapy was well tolerated with promising early clinical activity across IMDC risk groups. Cas 100 mg QD will be combined with VEGFR-TKI (cabozantinib) in the phase 3 PEAK-1 trial and immunotherapy (volrustomig) in a separate upcoming first-line trial. Clinical trial information:
NCT05536141
.

Cas50 mg BID(n = 32
a
)

Cas50 mg QD(n = 28
a
)

IDMC Favorable(n=15)
IMDC intermediate/ poor/unknown(n=45)
Without prior mTOR inhibitor treatment (n=51)
With prior mTOR inhibitor treatment (n=9)

Unconfirmed ORR, % (n) (95% CI)

34 (11
b
)(19, 53)

25 (7)(11, 45)
40 (6)(16, 68)
27 (12)(15, 42)
31 (16)(19, 46)
22 (2)(3, 60)

Confirmed ORR, % (n) (95% CI)
25 (8)(11, 43)
21 (6)(8, 41)
33 (5)(12, 62)
20 (9)(10, 35)
26 (13)(14, 40)
1 (11)(<1, 48)

Disease control rate, % (95% CI)
81(64, 93)
86(67, 96)
93(68, 100)
80(65, 90)
82(69, 92)
89(52, 100)

a
Efficacy-evaluable pts: all pts who had measurable disease at BL, received ≥1 dose and had ≥1 post-BL efficacy assessment, or who discontinued study treatment due to progression or death. Disease control rate: ORR+SD.

b
Includes 1 pt who achieved PR after data cut-off.