A first-in-human phase 1 dose-escalation study of the oral HIF-2α inhibitor JMKX003948 in patients with renal cell carcinoma.

Abstract

4544 Background: Hypoxia inducible factor-2 alpha (HIF-2α) is a transcription factor and key tumorigenic driver of clear cell renal cell carcinoma (ccRCC). JMKX003948 is a novel, orally administered, selective small-molecule HIF-2α inhibitor that has shown significant antitumor activity in preclinical models of ccRCC. Herein, we present preliminary results from a phase 1 dose-escalation study of JMKX003948 in advanced ccRCC (NCT06321250). Methods: In this study, Patients with advanced ccRCC who had received at least 1 prior standard therapy were enrolled in 40, 80, 120, 180, and 270 mg escalating-dose cohorts sequentially, and received JMKX003948 monotherapy once daily (QD) until progression or unacceptable toxicity. The primary endpoints included safety/tolerability, the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D). Results: As of Dec 23, 2025, 22 patients (17 male) were enrolled. Median age was 57.5 years (range, 32-73 years). 13 patients (59.1%) have received ≥ 2 prior lines of therapy, 20 patients (90.9%) have received immune checkpoint inhibitor, and all patients (100%) have received vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI). At data cutoff, the median follow-up was 9.7 months. One dose-limiting toxicity (grade 3 transaminase elevation) was observed at the 120 mg QD dose level, and the MTD was not reached. Treatment-related adverse events (TRAEs) were reported in all patients, with most graded 1-2. The most common TRAEs were anemia (86.4%). Grade 3 TRAEs occurred in 6 patients (27.3%), including hypoxia (13.6%), anemia (9.1%), proteinuria (4.5%), transaminase elevation (4.5%), and hyperkalemia (4.5%). No grade 4 TRAEs occurred. No TRAEs led to treatment discontinuation or death. Of 20 efficacy-evaluable patients, 5 patients (2 patients in 270 mg cohort and 1 patient each in 80, 120, 180 mg cohort) had partial response (PR), and 9 patients had stable disease (SD), objective response rate (ORR) and disease control rate (DCR) per RECIST 1.1 were 25% and 70%, respectively. Mean time to response (TTR) was 3.2 months. Median progression-free survival (PFS) was 7.7 months (95% CI, 1.3-not available). Conclusions: JMKX003948 is well tolerated and shows promising antitumor activity in patients with advanced ccRCC. Clinical trial information: NCT06321250 .