A phase 1 dose expansion study of a first-in-class KAT6 inhibitor (PF-07248144) in patients with advanced or metastatic ER+ HER2− breast cancer.

3006 Background: Histone lysine acetyltransferase KAT6 regulates lineage specific gene transcription via H3K23 acetylation. PF-07248144 is a novel selective catalytic inhibitor of KAT6 (6A 95% CI) was 11.4% (3.2, 26.7), median (range) duration of response (DOR) was 12.0 mos (7.4, NE), and clinical benefit rate (CBR; 95% CI) was 31.4% (16.9, 49.3). For the fulvestrant combination (n=43), with median duration of follow-up of 9.2 mos, the ORR was 30.2% (17.2, 46.1), median DOR was 9.2 mos (7.2, NE), CBR was 51.2% (35.5, 66.7), and the median progression-free survival (mPFS) was 10.7 mos (n=43; 95% CI 5.3, NE). 57% (24/42) of the pts had baseline ESR1 mutations. Durable activity was observed in pts with both ESR1 mutant (n=24; ORR 33.3%; mPFS 10.7 mos) and ESR1 wild-type (n=18; ORR 27.8%; mPFS not reached) tumors. Similarly, antitumor activity was observed in pts with (n=19; ORR 26.3%, mPFS 7.2 mos) and without PIK3CA/AKT1/PTEN gene mutations (n=23; ORR 34.8%, mPFS 10.8 mos). After 8-wk treatment, the median reduction in total ctDNA and ESR1 mutant allele frequency was 95.0% and 100.0%, respectively. In all pts, the most frequent treatment-related adverse event (TRAE) was grade (G) 1/2 dysgeusia (84.6%; 65.4% G1). The G3 TRAEs > 5% were neutropenia (38.5%), leukopenia (11.5%), and anemia (9.0 %). The only G4 TRAE was neutropenia (3.8%), which was reversible and well managed by dose modifications. No G5 TRAEs. Conclusions: PF-07248144 demonstrated a tolerable safety profile and durable efficacy in pts with heavily pretreated ER+ HER2− mBC with and without ESR1 or PIK3CA/AKT1/PTEN mutations. We have provided strong clinical proof of concept targeting KAT6, a novel epigenetic target and opened a new avenue to treat ER+ HER2− mBC. Clinical trial information: NCT04606446 .