Background: H3B-6545 — a novel selective ER covalent antagonist (SERCA) that potently inactivates wild-type and mutant ERα— has shown preliminary antitumor activity and tolerable safety in pts with advanced/metastatic, ER+, HER2– BC. Palbociclib (palbo), an oral CDK4/6 inhibitor, has shown activity in metastatic disease when combined with endocrine therapy. The dose escalation part of this open-label, multicenter, phase 1b study of H3B-6545 + palbo in pts with ER+, HER2– BC aimed to identify the recommended phase 2 dose (RP2D) of H3B-6545 + palbo and characterize safety and efficacy. Methods: Females aged ≥18 years with ER+, HER2–, locally advanced/recurrent/metastatic BC, ECOG PS 0–1, and progression on/after standard therapy were eligible. In the dose escalation phase, pts had to have received ≥2 prior hormonal therapies. Palbo was to be escalated no higher than 125 mg orally QD (days 1–21) and H3B-6545 no higher than 450 mg orally QD (days 1–28). The MTD was the highest dose at which ≤1 of 6 pts had a dose-limiting toxicity (DLT). The primary endpoint was determination of the MTD and/or RP2D. Secondary endpoints included safety and efficacy (by investigator per RECIST v1.1). Results: At data cutoff (16 Sept 22), 31 pts were treated: Cohort (C) 1: H3B-6545 300 mg + palbo 100 mg (n=7); C2: H3B-6545 300 mg + palbo 125 mg (n=8); C3: H3B-6545 450 mg + palbo 125 mg (n=8); C3b: H3B-6545 450 mg + palbo 100 mg (n=8). 3 DLTs (grade 3/4 neutrophil count decreased [n=2] and grade (G) 3 QTcF prolongation [n=1]) were observed in C3 (5 DLTs were observed at C3b); C2 dose was deemed the MTD. Of all pts, 90.3% had G ≥3 TEAEs, 32.3% had serious TEAEs, and 6.5% had TEAEs leading to drug withdrawal. Sinus bradycardia (67.7% [G ≥3, 0%]) and anemia (54.8% [G ≥3, 19.4%]) were the most frequent TEAEs. QT prolongation and rash occurred in 19.4% [G ≥3, 12.9%] and 16.1% [G ≥3, 9.7%] of pts, respectively. ORR in response evaluable pts was 23.1% (95% CI 9.0–43.6). The Table shows additional results. Conclusions: H3B-6545 300 mg + palbo (100/125 mg) had manageable safety and encouraging preliminary antitumor activity. Further studies are warranted to identify the RP2D. Clinical trial information: NCT04288089.

n = response evaluable set; N = full analysis set (for PFS/OS analyses).

CBR, clinical benefit rate; DCR, disease control rate; NE, not evaluable.