Background: KAT6A and KAT6B regulate gene transcription via acetylation of histone H3K23 and their dysregulation drives lineage-specific gene expression in cancer. We report dose escalation data from the first-in-human phase 1 (Part 1A and 1B; NCT04606446) study of the KAT6-selective inhibitor PF-07248144. Methods: Part 1A (monotherapy dose escalation) enrolled patients (pts) with advanced/metastatic ER+/HER2− breast cancer (mBC), CRPC, or NSCLC, resistant/intolerant to standard therapy. Part 1B (PF-07248144 + fulvestrant combination dose escalation) enrolled pts with advanced/metastatic ER+/HER2- mBC with disease progression after ≥1 line of CDK4/6 inhibitor and endocrine therapy (ET). PF-07248144 (1-15 mg in Part 1A) was administered orally once per day (QD) in 28-day cycles following Bayesian design with overdose control. Study objectives: primary - assess PF-07248144 safety and tolerability, including dose limiting toxicities (DLT); secondary - evaluate PF-07248144 pharmacokinetics (PK); and exploratory - evaluate pharmacodynamics (PD; peripheral blood mononuclear cells [PBMC] and tumor H3K23Ac inhibition) and antitumor activity (using RECIST 1.1 by investigator assessment). Results: At data cut off (30 Sep 2022), 29 pts were enrolled: 25 in Part 1A (12 mBC, 11 CRPC, 2 NSCLC) and 4 in Part 1B (mBC). Part 1A evaluated 5 dose levels (1-15 mg QD) and Part 1B evaluated 5 mg PF-07248144 QD + 500 mg fulvestrant. Median age across Part 1A and 1B was 67 yrs (range 48-90). A total of 83% (Part 1A) and 75% (Part 1B) of pts with mBC had received > 3 prior lines of systemic anticancer therapy. Three DLTs (Grade 3 [G3] neutropenia) were observed: 2 in Part 1A (8 mg and 2 mg QD) and 1 in Part 1B (5 mg QD). A maximum tolerated dose was not identified; 5 mg QD was identified as the recommended dose for expansion for both monotherapy and fulvestrant combination. Across Parts 1A and 1B, treatment-related AEs (TRAEs; any grade) in ≥20% pts were dysgeusia (72%), anemia (52%), neutropenia (48%), thrombocytopenia (31%), diarrhea (31%), white blood cells (WBC) decreased (28%), fatigue (24%), and aspartate aminotransferase increased (21%); the majority of TRAEs were G1-2. TRAEs ≥G3 seen in > 1 pt were neutropenia (6/29; 21%), anemia (5/29; 17%), and WBC decreased (2/29; 7%). PF-07248144 PK was linear between 1 and 15 mg. H3K23Ac inhibition (≥70%) in PBMCs was achieved at steady state at doses of ≥1 mg. Tumor H3K23Ac levels were reduced by > 50% in 4 paired tumor biopsies at exposures associated with preclinical anti-tumor activity. Confirmed and durable partial responses were observed in 1/8 (Part 1A) and 2/4 (Part 1B) response-evaluable pts with ER+/HER2- mBC who progressed on prior ET+CDK4/6 inhibitor treatment. Conclusions: PF-07248144 was well tolerated and associated with strong KAT6 inhibition in PBMCs and tumors and confirmed partial responses in pts with heavily treated ER+/HER2- mBC during dose escalation. Clinical trial information: NCT04606446.