Abstract P4-04-28: PF-07248144, a first-in-class KAT6 inhibitor, in patients with HR+ HER2− metastatic breast cancer: Updated results from phase 1 dose expansion study

Abstract Background: Histone lysine acetyltransferase KAT6A, and its paralog, KAT6B regulate lineage specific gene transcription via H3K23 acetylation. PF-07248144 is a novel selective catalytic inhibitor of KAT6 (6A & 6B). We report updated results (with 7 months additional follow-up) of clinical safety, efficacy, and additional subgroup analyses from the phase 1 study (NCT04606446) of PF-07248144 as monotherapy and with fulvestrant (fulv) in heavily pretreated ER+HER2− metastatic breast cancer (mBC). Methods: Patients (pts) had metastatic ER+ HER2− mBC and had progressed after a CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET). Pts received PF-07248144 at the recommended expansion dose (RDE) of 5 mg QD as monotherapy or with fulv. Primary objective: safety and tolerability per CTCAE 5.0. Secondary objectives: antitumor activity per RECIST 1.1 and pharmacokinetics. Exploratory objectives: Pharmacodynamics and predictive biomarkers. Circulating tumor DNA (ctDNA) and gene mutations were evaluated by Guardant 360 assay. Results: 35 pts received PF-07248144 monotherapy and 43 pts with fulv. All 78 pts had received prior CDK4/6i and ET in the metastatic setting. 59% (46/78) had detectable ESR1 mutations at baseline. PF-07248144 demonstrated tolerable safety profile at RDE and encouraging antitumor activity as monotherapy and with fulv. In all 78 pts, the most frequent treatment-related adverse event (TRAE) was grade (G) 1/2 dysgeusia (n=66, 84.6%), mainly G1 (n=50, 64.1%); no dose reduction and treatment discontinuation due to dysgeusia. The most frequent G≥3 TRAE was neutropenia (G3: n=29, 37.2%; G4: n=5, 6.4%), reversible and manageable with dose modification. No febrile neutropenia or G5 TRAEs. As of 30 Apr 2024, we observed increased antitumor activity with longer follow-up (median 16.4 mos) for fulv combination (n=43). The objective response rate (ORR) was 37.2% (95% CI 23.0, 53.3), median duration of response was not reached (95% CI 7.2 mos, not evaluable), clinical benefit rate was 55.8% (95% CI 39.9, 70.9), and the median progression-free survival (mPFS) was 10.7 mos (95% CI 5.3, 13.8). Antitumor activity was observed irrespective of ESR1 (wild-type [WT] n=18, mutant [MT] n=24; ORR 33.3 vs 41.7%; mPFS 10.9 vs 10.7 mos) and PIK3CA/AKT1/PTEN (WT n=23, MT n=19; ORR 43.5 vs 31.6%; mPFS 13.7 vs 7.3 mos) mutation status. Additional subgroup analyses revealed broad antitumor activity of PF-07248144 fulv combination in pts treated as second-line (2L) therapy (following 1L CDK4/6i + ET) or as third-line or beyond (3L+) therapy (ET, targeted therapy or chemotherapy in between; ORR 30.4% [7/23] vs 45.0% [9/20]; mPFS 13.8 vs 10.7 mos); and irrespective of primary or secondary endocrine resistance (ORR 57.1% [4/7] vs 33.3% [12/36]; mPFS 9.0 vs 10.8 mos), presence or absence of prior treatment with fulv (ORR 60.0% [3/5] vs 34.2% [13/38]; mPFS not reported [n≤5] vs 7.5 mos), and rapid progression on prior CDK4/6i (duration of treatment <6 mos) or prior CDK4/6i treatment duration >12 mos (ORR 50.0% [2/4] vs 36.4% [12/33]; mPFS not reported [n≤5] vs 10.9 mos). After 8-wk treatment, the median reduction in total ctDNA and ESR1 mutant allele frequency was 95.0% and 100.0%. Pts with non-detectable ctDNA after the initial 8-wk treatment had longer PFS compared with those with detectable ctDNA. Conclusions: PF-07248144 in combination with fulv demonstrated an acceptable safety profile and promising efficacy in pts with ER+ HER2− mBC post CDK4/6i and ET. Antitumor activity was observed irrespective of ESR1 and PIK3CA/AKT1/PTEN mutation status, endocrine sensitivity or resistance, duration of prior CDK4/6i treatment (<6 mos or >12 mos), prior fulvestrant treatment, and 2L or later line therapy. These findings suggest that PF-07248144 in combination with ET may potentially overcome endocrine resistance and CDK4/6i resistance and provide a novel mechanism to address high unmet medical need in HR+ mBC after prior CDK4/6i and ET. Citation Format: Toru Mukohara, Patricia M. LoRusso, David Sommerhalder, Kan Yonemori, Erika Hamilton, Sung-Bae Kim, Seock-Ah Im, Geoffrey J. Lindeman, Hope S. Rugo, Hiroji Iwata, Rachel M. Layman, Gun Min Kim, Toshinari Yamashita, Jee Hyun Kim, Fengting Yan, Toshio Shimizu, Yee Soo Chae, Timothy Clay, Rohit Joshi, Monica Mita, Mun Hui, Brian Dong, Brooke Holbrook, Sean Kent, Athanasia Skoura, Li Liu, Meng Li, Yeon Hee Park. PF-07248144, a first-in-class KAT6 inhibitor, in patients with HR+ HER2− metastatic breast cancer: Updated results from phase 1 dose expansion study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-04-28.