3 Safety Profile of Casdatifan Monotherapy in Patients with Clear Cell Renal Cell Carcinoma: Pooled Analysis of the ARC-20 Study (NCT05536141)

Abstract

Abstract Background Hypoxia-inducible factor 2α (HIF-2α) is highly dysregulated in clear cell renal cell carcinoma (ccRCC), resulting in increased expression of proteins involved with angiogenesis, proliferation, and metastasis. Casdatifan is a potent, selective, orally bioavailable HIF-2α inhibitor that has demonstrated encouraging clinical activity as monotherapy in 2L+ metastatic ccRCC. In the ongoing ARC-20 study, the reported median progression-free survival (mPFS) is not yet reached for the recommended phase 3 dose (100 mg QD) and 12.2 months across pooled doses (50 mg QD, 50 mg BID, 100 mg QD, and 150 mg QD). We present a detailed analysis characterizing the safety profile of casdatifan monotherapy based on data from the ARC-20 study. Methods ARC-20 included adults with metastatic ccRCC who were HIF-2α inhibitor naive and previously treated with anti–PD-(L)1 and VEGFR-TKI therapies. This analysis included data from the cohort receiving 100 mg casdatifan QD monotherapy—which is the dose being investigated in the phase 3 PEAK-1 trial (NCT07011719)—and from all patients receiving casdatifan monotherapy in the late-line setting, which pooled the 50 mg QD, 50 mg BID, 100 mg QD, and 150 mg QD cohorts. Results At data cutoff (15Aug2025), 32 patients in the casdatifan 100 mg QD cohort and 127 patients in the total late-line population were safety evaluable (enrolled and received any amount of study treatment). Patients in the 100 mg QD cohort and the total late-line population had received a median (range) of 3 (1–6) and 3 (1–11) prior lines of therapy, respectively. The median (range) study follow-up was 12.4 months (6.3–13.5) in the 100 mg QD cohort and 15.5 months (6.3–26.0) in the total late-line population. Overall, 97% and 98% had any treatment-emergent adverse event (TEAE), and 50% and 60% had grade ≥3 TEAEs, respectively. Treatment-related adverse events (TRAE) led to dose reduction in 22% (100 mg QD cohort) and 24% (total late-line population), most commonly from anemia (9% and 14%), hypoxia (3% and 7%), and fatigue (6% and 4%). In both the 100 mg QD cohort and the total population, treatment discontinuation due to TRAEs was 3%. There were no treatment-related deaths. There are 2 on-target AEs, hypoxia and anemia. Among the 5 patients in the 100 mg QD cohort and the 23 patients in the total late-line population experiencing hypoxia from any cause, 80% and 70%, respectively, received temporary supplemental oxygen therapy. A total of 84% and 89% experienced any-grade treatment-related anemia in the 100 mg QD cohort and total late-line population, respectively, of which 28% and 35% led to interruption of treatment, although none led to treatment discontinuation. Treatment-related grade ≥3 anemia occurred in 25% of the 100 mg QD cohort and 41% of the total late-line population. Details on the management of patients with TEAEs of any-grade anemia are provided in the Table. Median PFS differed based on anemia management. Patients with erythropoietin-stimulating agent (ESA) use only (n = 47) had mPFS (95% CI) of 21.7 months (13.9–not estimable). Patients receiving a transfusion regardless of ESA use had mPFS of 9.4 months (5.3 -- 12.2); 17 patients received transfusions with ESA use, and 16 received transfusions only (no ESA use). Conclusions The safety profile of casdatifan was consistent with that of the therapeutic class, and previously reported efficacy demonstrated improvement upon the class. Anemia, an on-target AE of HIF-2α inhibition, was managed with intermittent ESA support and/or transfusions that allowed patients to remain on casdatifan. Among patients with anemia, those treated with ESAs had a longer mPFS than those treated with transfusions, regardless of ESA use, suggesting that ESA use did not negatively affect mPFS. 3 Table