SIM0270 in combination with palbociclib in patients with ER+/HER2-advanced breast cancer: The phase Ib study.

SIM0270 is a highly potent oral selective estrogen receptor degrader (SERD) which has shown ER degradation and robust antitumor activity across variety of preclinical models. Here, we present results of SIM0270 combined with palbociclib cohort(dose escalation and dose expansion) from Phase I study in patients with ER+/HER2-advanced breast cancer (NCT05293964). Methods: Patients with ER+/HER2-advanced breast cancer were enrolled. The key inclusion criteria for dose escalation and dose expansion were the same as follows: ≥ 1 prior endocrine therapy (ET) with disease recurrence/progression while being treated with adjuvant ET for ≥ 24 months and/or first line ET for ≥ 6 months in advanced setting; ≤2 prior chemotherapies in advanced setting; and prior fulvestrant was allowed. A Bayesian Optimal Interval design (BOIN) was adopted for dose escalation. The key endpoint of dose escalation was dose limiting toxicities (DLT), and the key endpoints of dose expansion included safety and tolerability, pharmacokinetics (PK) and efficacy. Results: As of December 26, 2024, 44 patients were enrolled including 12 from dose escalation and 32 from dose expansion, with a median follow up of 11.8 months. No DLT was reported in dose escalation. In total, 38 patients (86.4%) had visceral disease, and 8 patients (18.2%) had ESR1 mutation at baseline. 22 patients (50%) received prior endocrine therapy in the advanced setting, of which, 15 patients (34.1%) had aromatase inhibitor (AI), 12 patients (27.3%) had fulvestrant. 13 patients (29.5%) received prior chemotherapy in the advanced setting. The most common treatment emerged adverse events (TEAEs) were white blood cell count decreased (95.5% ) and neutropenia (95.5%). Sinus bradycardia was reported in 77.3% (34/44) of the patients, 85.3% (29/34) were grade 1 (asymptomatic) requiring no dose modification. Grade 3/4 treatment-related AEs (TRAEs) occurred in 77.3% of the patients with most commonly reported events including neutropenia (70.5%) and white blood cell count decreased (40.9%). No fatal AEs were reported. TRAEs led to dose reduction were reported in 38.6% for palbociclib and 9.1% for SIM0270. No TRAEs led to treatment discontinuation. And 24 patients remain on study treatment. In the response evaluable patients, confirmed overall response rate (ORR) was 41.5% (17/41) and clinical benefit rate (CBR, defined as complete response, partial response or stable disease ≥ 24 weeks) was 82.5% (33/40). Median progression free survival (PFS) was not reached (NR). In patients with ESR1 mutation at baseline, ORR and CBR were 87.5% (7/8) and 100% (8/8), respectively. Conclusions: SIM0270 in combination with palbociclib showed acceptable safety and tolerability, promising clinical activity in patients with ER+/HER2-advanced breast cancer. Clinical trial information: NCT05293964. Research Sponsor: Simcere Zaiming Pharmaceutical Co., Ltd.