Background: SY-5609 is an oral, reversible, potent, and selective inhibitor of CDK7, a key regulator of transcription and cell cycle, currently under investigation in a Phase 1 study in patients (pts) with select advanced solid tumors (NCT04247126). Single agent (SA) dose escalation is ongoing, using a 7 days on/7 days off (7/7) dosing schedule that optimized tolerability (Sharma 2021) and showed a correlation of antitumor activity with higher exposures. SY-5609 may address multiple CDK4/6 inhibitor resistance mechanisms and potentiates SERD activity in CDK4/6 inhibitor-resistant xenograft models (Johannessen 2019). In this Phase 1 study, it was combined with the SERD fulvestrant in advanced HR+, HER2- BC pts who are refractory to CDK4/6 inhibitor + hormonal therapy. Methods: Evaluation of SY-5609 + fulvestrant began with a SY-5609 dose that had cleared the SA dose-limiting toxicity (DLT) evaluation period. SY-5609 was dosed once daily at 3 mg or 4 mg on a 21 days on/7 days off (21/7), 5 days on/2 days off (5/2), or 7/7 schedule and was escalated using a 3+3 design, guided by safety and reports of Cycle 1 qualifying safety events (QSEs), which matched SA DLT criteria. Fulvestrant was dosed at the approved dose/schedule. Safety and tolerability of SY-5609 + fulvestrant and SY-5609 PK were secondary objectives. Exploratory objectives included preliminary antitumor activity (RECIST v1.1.). Results: As of 12 Oct 2022, 14 pts (median age 63; range 46 - 83) received SY-5609 at 3 mg on a 21/7 schedule (n=8) or at 4 mg on a 5/2 (n=5) or 7/7 (n=1) schedule in combination with fulvestrant. Pts had advanced disease, including 79% with liver lesions, and a median of 5.5 (range 2 - 12) prior therapies; 100% had prior hormonal therapy, including 71% who received prior fulvestrant. The majority of adverse events (AEs) were low-grade and reversible. Related AEs (≥10%) included nausea, diarrhea, fatigue, thrombocytopenia, and hot flush. Related ≥Grade 3 AEs were reported in 3 pts (21%), including 1 QSE of Grade 3 thrombocytopenia at 4 mg 5/2. The highest tolerated dose in combination with fulvestrant was not reached. Stable disease (SD) was observed in 5/12 (42%) evaluable pts. SD with tumor shrinkage and/or SD >6 months was observed in 4 pts previously treated with fulvestrant and in pts with liver lesions and/or TP53 mutations. SY-5609 exposure in combination with fulvestrant appeared comparable to SA at Day 1. Conclusions: SY-5609 + fulvestrant has an acceptable safety profile consistent with SA SY-5609 or fulvestrant. The mechanistic rationale for CDK7 inhibition in HR+, HER2- BC and the tolerability and encouraging early activity in this heavily pretreated population support future investigation of SY-5609 in combination with SERDs, including defining the maximum tolerated combination dose using the 7/7 SY-5609 schedule. Clinical trial information: NCT04247126.