KAT6 Inhibitor PF-07248144 + Fulvestrant Posts 37% ORR and 10.7-Month PFS After CDK4/6 Failure in ER+/HER2⁻ mBC

PF-07248144, an oral catalytic inhibitor of the histone acetyltransferases KAT6A/B, was given at 5 mg QD to 43 heavily pre-treated ER+/HER2⁻ metastatic breast-cancer patients alongside standard fulvestrant (Phase 1 dose-expansion, NCT04606446). All had progressed on CDK4/6i + endocrine therapy; 59% carried baseline ESR1 mutations. Treatment-related events were mostly grade 1–2 dysgeusia (85%); reversible grade 3/4 neutropenia occurred in 43%, with no febrile cases. Confirmed objective response rate reached 37.2% (16/43), clinical-benefit rate 55.8%, and median PFS 10.7 months—outperforming post-CDK4/6 benchmarks for fulvestrant alone (~3.8 mo) or capivasertib + fulvestrant (7.2 mo). Activity was consistent across ESR1-mutant versus wild-type tumors (~41% vs 33% ORR) and across PIK3CA/AKT1/PTEN status. ctDNA fell 95% overall; patients with undetectable ctDNA at week 8 had longer PFS.

https://aacrjournals.org/clincancerres/article/31/12_Supplement/P4-04-28/762700/Abstract-P4-04-28-PF-07248144-a-first-in-class