493 Background: HIF-2α is a validated target in refractory ccRCC. ARC-20 is an open-label platform study evaluating Cas, a HIF-2α inhibitor, in metastatic ccRCC with prior anti–PD-(L)1 and VEGFR-TKI treatment. Cas elicits deep and enduring reductions in serum erythropoietin (sEPO). The approved HIF-2α inhibitor loses its effect on sEPO reduction after approximately 13 weeks (Choueiri, 2021). Here, we present updated efficacy with progression-free survival (PFS), safety, and exploratory biomarker findings including the relationship between sEPO changes and clinical outcomes. Methods: Data are reported from Cas monotherapy expansion cohorts from the phase 1 ARC-20 study (NCT05536141): Cas 100 mg QD (100QD) and a total group comprising all monotherapy cohorts (50 mg QD, 50 mg BID, 100 mg QD, 150 mg QD). Primary endpoint was safety. Secondary endpoint was ORR. PFS was an exploratory endpoint. Change in sEPO was assessed and correlated with efficacy. Results: As of August 15, 2025, median (range) follow-up was 12 (6–14) months (100QD; n=32) and 15 (6–26) months (all patients pts; n=127). At baseline, 72% (100QD) and 71% (all pts) had intermediate/poor IMDC risk score; all pts received prior IO/VEGFR-TKI therapy (median 3 prior lines; range: 1–6 100QD, 1–11 all pts). The confirmed ORR was 35% (95% CI: 19, 55) in the 100QD cohort (all PR) and 31% (23, 40) in all pts (1 CR, 37 PR). Median PFS was not reached (95% CI: 5.7 months, not evaluable) and 12.2 (9.4, 20.6) months, respectively. Deep sEPO reduction was observed by study week 2 and sustained through study week 52. Deeper sEPO reduction was associated with higher rates of CR/PR and lower rates of PD (Table); sEPO reduction was significantly greater in those with disease control (CR, PR, SD) vs without ( P = .0018), with median best reduction of 86% vs 79%. Dose reductions due to Cas-related TEAEs occurred in 22% (100QD) and 24% (all pts). Most dose reductions were due to anemia (9% 100QD and 14% all pts) and hypoxia (3% 100QD and 7% all pts). Treatment discontinuation due to Cas-related TEAEs was infrequent in the 100QD cohort (3%) and in all pts (3%); no pts in the 100QD cohort discontinued due to anemia despite deep EPO suppression. No treatment-related deaths occurred. Conclusions: In heavily treated metastatic ccRCC, Cas monotherapy showed encouraging clinical activity and durable responses across cohorts. The extent of sEPO reduction correlated with clinical benefit, providing important linkage between tumor HIF-2α biology and clinical outcomes. The safety profile of Cas monotherapy remains manageable, supporting evaluation of the 100 mg QD dose now in phase 3 development. Clinical trial information: NCT05536141 . BOR by max sEPO reduction quartile. BOR < 25th (least deep)n = 29 25–50thn = 29 50–75thn = 29 ≥ 75th (deepest)n = 30 CR/PR 10% (3) 31% (9) 45% (13) 43% (13) PD a 38% (11) 21% (6) 7% (2) 10% (3) a Including 2 pts who had PD before 1st scan.
Choueiri et al. (2026) studied this question.