Dose optimization of PF-07248144, a first-in-class KAT6 inhibitor, in patients (pts) with ER+/HER2− metastatic breast cancer (mBC): Results from phase 1 study to support the recommended phase 3 dose (RP3D).

Abstract

1020 Background: PF-07248144 is a selective catalytic inhibitor of KAT6, a histone lysine acetyltransferase. To inform the RP3D, we evaluated two pharmacokinetically distinguishable doses of PF-07248144 in combination with fulvestrant (FUL) from a phase 1 study in ER+/HER2− mBC in a dose expansion phase. Methods: Pts with ER+/HER2− mBC after prior CDK4/6i and endocrine therapy (ET) received PF-07248144 at recommended doses for expansion (RDEs) of 5 mg QD alone, 5 mg QD plus FUL, or 1 mg QD plus FUL (N = 107) and were followed up (at least 6 months across all cohorts) to assess for safety and efficacy. Primary objective wassafety/tolerability per CTCAE 5.0 and RDE selection. Other objectives included antitumor activity per RECIST 1.1, PK, PD, and predictive biomarkers. Results: 5 mg QD was identified as the RDE for both PF-07248144 monotherapy (35 pts treated) and FUL combination (43 pts treated) based on safety, PK, PD, and antitumor activity. 1 mg PF-07248144 plus FUL (29 pts treated) was selected as the lower RDE based on a distinguishable PK and safety profile while achieving maximal blood and tumor PD marker reduction and efficacious concentrations supported by preclinical models. As of Oct 11, 2024, a total of 107 pts were treated at RDEs. Baseline pt characteristics from the two RDEs plus FUL were comparable. All pts received prior CDK4/6i and ET in the metastatic setting. Positive dose-response relationships were identified for both safety (neutropenia) and efficacy (objective response rate [ORR]) endpoints. At 5 mg and 1 mg doses plus FUL, the most common treatment-related adverse event (TRAE) was dysgeusia (G1+G2: 83.7% vs 89.7%). The most common G≥3 TRAE was neutropenia (G3: 39.5% vs 20.7%; G4: 7.0% vs 0.0%). The neutropenia was reversible and manageable with dose modifications. No febrile neutropenia was observed. The safety profile of 5 mg PF-07248144 monotherapy was consistent with 5 mg RDE plus FUL. No events of pneumonitis were reported in the 107 pts treated. For FUL plus 5 mg and 1 mg PF-07248144, ORR was 37.2% (95% CI: 23.0–53.3) vs 24.1% (10.3–43.5); median duration of response was 15.8 mos (9.2–not estimable [NE]) vs 4.6 mos (3.4–NE); clinical benefit rate was 55.8% (39.9−70.9) vs 37.9% (20.7–57.7). With median duration of follow-up 21.9 mos and 11.0 mos for pts receiving FUL plus 5 mg and 1 mg PF-07248144, the median progression-free survival was 10.7 mos (95% CI: 5.3−13.8) vs 3.6 mos (1.8–5.6), respectively. Conclusions: Based on a thorough benefit–risk assessment of two pharmacokinetically distinguishable doses with sufficient number of pts and follow up, 5 mg QD PF-07248144 was identified as the optimal dose in combination with FUL with acceptable safety and encouraging activity. A pivotal phase 3 trial is planned to address the high unmet medical need in ER+/HER2− mBC after progression on CDK4/6i plus ET. Clinical trial information: NCT04606446 .