prifetrastat (PF-07248144) / Pfizer - LARVOL DELTA

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). (ASCO 2025) - P1 | "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... 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 • Metastases • P1 data • P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Febrile Neutropenia • HER2 Breast Cancer • HER2 Positive Breast Cancer • Neutropenia • Oncology • Pneumonia • Solid Tumor • CDK4 • ER • HER-2

Dancing with KAT6A: Current advances and therapeutic potential in oncology of KAT6A inhibitors. (PubMed, Bioorg Chem) - "PF-07248144 has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer models and is currently undergoing clinical evaluation...This review provides a comprehensive overview of the structural and biological functions of KAT6A, its role in tumor progression, and the therapeutic potential of its inhibition. It summarizes the advancements in KAT6A inhibitor development from 2019 to the present, emphasizing the optimization processes from lead compounds to clinical candidates."

Journal • Review • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • KAT6A

Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial. (PubMed, Nat Med) - P1 | "In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC). These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 ."

Journal • Metastases • P1 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • ER • HER-2 • KAT6A • KAT6B

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. (ASCO 2024) - P1 | "We report the clinical safety, efficacy, PK, PD, and biomarker results of a phase 1 dose expansion study (NCT04606446) of PF-07248144 as monotherapy and in combination with fulvestrant in heavily pretreated ER+ HER2− metastatic breast cancer (mBC). 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 • Metastases • P1 data • Anemia • Breast Cancer • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Leukopenia • Neutropenia • Oncology • Solid Tumor • AKT1 • ER • HER-2 • PIK3CA • PTEN

A Study to Learn if Itraconazole Changes How the Body Processes PF-07248144 (Study Medicine) (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open

EPIBREAST: Clinical Trial Evaluating the Biological Activity of a New Drug Identified as Prifetrastat (PF-07248144), Combined With Fulvestrant for the Treatment of Patients With Hormone Receptor Positive (HR+) and HER2 Negative (HER2-) Breast Cancer Extended to Other Organs. (clinicaltrials.gov) - P2 | N=51 | Not yet recruiting | Sponsor: UNICANCER

Biomarker • New P2 trial • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Melanoma • Oncology • Solid Tumor • ER • HER-2

A Study to Learn if Itraconazole Changes How the Body Processes PF-07248144 (Study Medicine) (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: Pfizer

New P1 trial

A phase 1/2 trial evaluating the safety, tolerability, and efficacy of the KAT6 inhibitor, PF-07248144, in combination with vepdegestrant in patients with ER+/HER2− locally advanced or metastatic breast cancer (SABCS 2025) - P1 | "Patients may have received fulvestrant. Primary endpoints are dose-limiting toxicities (Part 1E only), safety, and tolerability. Secondary endpoints include pharmacokinetics of PF-07248144 and vepdegestrant in both Parts 1E and 2E, and best overall response, duration of response, clinical benefit rate, progression-free survival, time to progression, and overall survival in Part 2E."

Clinical • Combination therapy • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • KAT6A • KAT6B

Randomized phase 3 trial evaluating KAT6 inhibitor PF-07248144 plus fulvestrant in HR+HER2− advanced/metastatic breast cancer after progression on CDK4/6 inhibitor-based therapy (SABCS 2025) - " This open-label, randomized phase 3 trial is comparing PF-07248144 plus FUL versus everolimus (EVE) plus ET [FUL or exemestane (EXE)]) in patients with HR+HER2− ABC. The primary endpoint is progression-free survival by blinded independent central review. Overall survival is a key secondary endpoint; other secondary endpoints include objective response, duration of response, clinical benefit rate, safety, and pharmacokinetics of PF-07248144."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • KAT6A • KAT6B • PIK3CA • PTEN

Dose optimization of PF-07248144, a first-in-class KAT6 inhibitor, in patients with ER+/HER2− metastatic breast cancer: results from phase 1 study to support the recommended phase 3 dose (SABCS 2025) - "Based on a thorough benefit-risk assessment of two pharmacokinetically distinguishable doses with sufficient number of patients 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 ongoing to address the high unmet medical need in ER+/HER2− mBC after progression on CDK4/6i plus ET."

Clinical • Metastases • P1 data • P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2

Randomized phase 3 trial evaluating KAT6 inhibitor PF-07248144 plus fulvestrant in HR+HER− advanced/metastatic breast cancer after progression on CDK4/6 inhibitor-based therapy (ESMO 2025) - "Trial design This open-label, randomized phase 3 trial is evaluating PF-07248144 plus FUL versus everolimus (EVE) plus ET [FUL/exemestane (EXE)]) in patients with HR+HER2− ABC. The primary endpoint is progression-free survival by blinded independent central review. Overall survival is a key secondary endpoint; other secondary endpoints include objective response, duration of response, clinical benefit rate, safety, and pharmacokinetics of PF-07248144."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • KAT6A • KAT6B • PIK3CA • PTEN

PF-07248144 – First-in-class potent, selective KAT6i in ER+HER2−breast cancer (AACR-NCI-EORTC 2025) - "In the Ph1 study, PF-07248144 + Fulvestrant demonstrated deep and durable anti-tumor activity with 37.2% ORR and 10.7 months mPFS. Based on the strength of these data, a pivotal Ph3 trial of PF-07248144 + Fulvestrant is planned in HR+HER2- mBC after progression on CDK4/6i + ET."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2 • KAT6A • KAT6B • PIK3CA

PF-07248144 – First-in-class potent, selective KAT6i in ER+HER2− breast cancer (AACR-NCI-EORTC 2025) - "In the Ph1 study, PF-07248144 + Fulvestrant demonstrated deep and durable anti-tumor activity with 37.2% ORR and 10.7 months mPFS. Based on the strength of these data, a pivotal Ph3 trial of PF-07248144 + Fulvestrant is planned in HR+HER2- mBC after progression on CDK4/6i + ET."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2 • KAT6A • KAT6B • PIK3CA

A Study to Learn if Multiple Doses of the Study Medicine Called Carbamazepine Changes How the Body Processes the Other Study Medicine PF-07248144 (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Pfizer

New P1 trial

C4551001: Study of PF-07248144 in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=320 | Recruiting | Sponsor: Pfizer | Trial completion date: Jan 2028 ➔ Sep 2029

Trial completion date • Breast Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • CDKN2A • ER • HER-2

A Study to Learn About the Study Medicine Called PF-07248144 in Combination With Fulvestrant in People With HR-positive, HER2-negative Advanced or Metastatic Breast Cancer Who Progressed After a Prior Line of Treatment. (clinicaltrials.gov) - P3 | N=400 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting | Trial primary completion date: Nov 2027 ➔ Jul 2027

Enrollment open • Trial primary completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

A Study to Learn About How Different Forms of Study Medicine PF-07248144 Are Taken Up Into the Blood in Healthy Adults (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Pfizer

New P1 trial

A Study to Learn About the Study Medicine Called PF-07248144 in Combination With Fulvestrant in People With HR-positive, HER2-negative Advanced or Metastatic Breast Cancer Who Progressed After a Prior Line of Treatment. (clinicaltrials.gov) - P3 | N=400 | Not yet recruiting | Sponsor: Pfizer

New P3 trial • Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

C4551001: Study of PF-07248144 in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=320 | Recruiting | Sponsor: Pfizer | N=186 ➔ 320 | Trial completion date: Mar 2027 ➔ Jan 2028 | Trial primary completion date: Aug 2025 ➔ Jan 2028

Enrollment change • Trial completion date • Trial primary completion date • Breast Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • CDKN2A • ER • HER-2

Yale Cancer Center Experts set to Present Advances in Cancer Research at the World’s Largest Clinical Oncology Conference (Newswise) - "Over 40 Yale Cancer Center (YCC) physicians and scientists will present new research at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago from May 30 to June 3. This is the largest and most attended conference for oncology professionals, who are interested in learning about the latest, practice-changing cancer research....YCC researchers will share advances for new therapies with research areas covering breast, lung, prostate, head and neck, early onset, and metastatic cancers."

Clinical data • Acute Myelogenous Leukemia • Clear Cell Renal Cell Carcinoma • Estrogen Receptor Positive Breast Cancer • Head and Neck Cancer • HER2 Negative Breast Cancer • Non Small Cell Lung Cancer • Prostate Cancer

Identification of novel KAT6A/B inhibitors with enhanced antitumor activity and reduced hematologic toxicity (AACR 2025) - "Additionally, the inhibition of H3K23 acetylation in ZR-75-1 cells was analyzed by Western blotting. HLX97-069/053 emerged as the top two candidates, exhibiting superior enzymatic inhibition and enhanced selectivity against KAT5/7/8, along with more potent cytotoxic effects in ZR-75-1 cells, in head-to-head comparisons with PF-07248144. In summary, these preclinical data provide compelling evidence that we have identified novel KAT6A/B inhibitors with best-in-class potential. Confirmation of the final candidate will depend on the outcomes of the forthcoming pilot toxicity studies, with an IND application anticipated by the end of 2025."

Breast Cancer • Oncology • Solid Tumor • KAT6A

Discovery and development of IST-477, a selective KAT6A histone acetyl transferase inhibitor and characterization of its anti-tumor efficacy in ER+ HER2- breast cancer and other tumor indications (AACR 2025) - "An inhibitor of KAT6A and KAT6B, PF-07248144, has entered phase 2 clinical studies with durable partial responses reported in estrogen-receptor positive (ER+) HER2- breast cancer patients who had progressed on a prior endocrine therapy and CDK4/6 inhibitor (Mukohara et al, 2024, Nature Medicine 30:2242). Pharmacologic efficacy of this targeted therapeutic will be discussed with an analysis of the relationship to KAT6A and 6B expression in these models. All IND-enabling studies to support clinical progression of IST-477 are planned for completion in mid-2025."

Clinical • Epigenetic controller • Breast Cancer • Esophageal Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • KAT6A • KAT6B

PF-07248144 Plus Fulvestrant Is Safe, Active in Pretreated ER+/HER2– Metastatic Breast Cancer (OncLive) - P1 | N=186 | NCT04606446 | Sponsor: Pfizer | "Findings presented at the 42nd Annual Miami Breast Cancer Conference, an event held by Physicians’ Education Resource, LCC, demonstrated that evaluable patients treated with PF-07248144 at 5 mg per day plus fulvestrant (n = 43) achieved an objective response rate (ORR) of 37.2% (95% CI, 23.0%-53.3%) and a clinical benefit rate of 55.8% (95% CI, 39.9%-70.9%). The median duration of response was not reached (95% CI, 7.2-not evaluable [NE]), and the median progression-free survival (PFS) was 10.7 months (95% CI, 5.3-13.8)."

P1 data • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

C4551001: Study of PF-07248144 in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=186 | Recruiting | Sponsor: Pfizer | Trial completion date: Nov 2026 ➔ Mar 2027 | Trial primary completion date: May 2025 ➔ Aug 2025

Trial completion date • Trial primary completion date • Breast Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • CDKN2A • ER • HER-2

Pfizer Showcases Scientific Leadership in Breast Cancer…at…SABCS (Pfizer Press Release) - "Key SABCS Presentations: Data from 30 company-sponsored, investigator-sponsored, and collaborative research abstracts will be presented at SABCS, including nine real-world analyses affirming IBRANCE (palbociclib) as a first-line standard-of-care treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). The company will also present new data from its expanding pipeline of innovative, next-generation therapy candidates that have the potential to address critical unmet patient needs across all subtypes and stages of breast cancer, including new and updated Phase 1 data for atirmociclib, vepdegestrant, and the novel KAT6 inhibitor, PF-07248144."

Clinical data • Real-world • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer