Phase 1 study of HRS-6209, a highly selective CDK4 inhibitor, in patients with advanced solid tumors

Background: This first-in-human, open-label, multicenter, dose-escalation and dose-expansion phase 1 study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of HRS-6209, a highly selective CDK4 inhibitor, in patients (pts) with advanced solid tumors. Methods: Pts with advanced solid tumors who progressed on standard therapies or lacked available options were eligible and received HRS-6209 monotherapy at 5 dose cohorts (100 mg QD, 50 mg BID, 75 mg BID, 100 mg BID and 200 mg BID). The primary objectives were to assess the safety/tolerability of HRS-6209 and determine the recommended phase 2 dose. Results: As of November 15, 2025, 56 pts were enrolled, including 48 (85.7%) with HR+/HER2− breast cancer. In HR+/HER2− breast cancer pts, the median prior lines of endocrine therapy and chemotherapy in the metastatic setting were 1.5 and 1.0, respectively; 32 (66.7%), 39 (81.3%), and 29 (60.4%) had received prior CDK4/6 inhibitor, aromatase inhibitor, and fulvestrant, respectively. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. TRAEs occurred in 55 (98.2%) pts. Grade ≥3 TRAEs were reported in 22 pts (39.3%), with the most common being decreased neutrophil count (18 [32.1%]), decreased WBC count (8 [14.3%]), and anemia (3 [5.4%]). No pts discontinued treatment due to TRAEs, and there were no treatment-related deaths. In HR+/HER2− breast cancer, ORR was 6.3% (3/48; 1 pt each at 50, 75, and 100 mg BID); CBR was 26.7%, 56.3%, and 53.8%, and median PFS was 1.8, 7.4, and 9.1 months at 50, 75, and 100 mg BID, respectively (Table 1). PK exposure was approximately dose proportional across 50-200 mg BID, with median T max 2-4 h, mean t 1/2 8.94-9.96 h, and accumulation ratios of 1.27-1.61 for C max and 1.45-1.70 for AUC 0-12 . Conclusions: HRS-6209 was well-tolerated, exhibiting favorable safety and PK profiles in patients with advanced solid tumors, and demonstrated promising anti-tumor activity in pretreated patients with HR+/HER2- breast cancer. Table 1. Key baseline characteristics and efficacy in patients with HR+/HER2- breast cancer 50 mg BID (n=15) 75 mg BID (n=16) 100 mg BID (n=13) All (n=48) Prior lines of endocrine therapy in metastatic setting (median) 2.0 1.0 2.0 1.5 Prior lines of chemotherapy in metastatic setting (median) 1.0 0 1.0 1.0 Confirmed ORR, % (n/N; 95% CI) 6.7 (1/15; 0.2-32.0) 6.3 (1/16; 0.2-30.2) 7.7 (1/13; 0.2-36.0) 6.3 (3/48; 1.3-17.2) Clinical benefit rate*, % (n/N; 95% CI) 26.7 (4/15; 7.8-55.1) 56.3 (9/16; 29.9-80.3) 53.8 (7/13; 25.1-80.8) 43.8 (21/48; 29.5-58.8) Median PFS, mo (95% CI) 1.8 (1.7, 4.2) 7.4 (1.9, NA) 9.1 (1.9, 14.5) 5.5 (3.7, 7.7) * Defined as complete or partial response, or stable disease lasting ≥24 weeks.