Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER⁺) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. 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). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3–4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144–fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2–46.1%) and the median PFS was 10.7 (5.3–not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER⁺HER2⁻ 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.

The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na⁺/K⁺ pump. Accordingly, FXYD3⁺ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3⁺ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3⁺ CSCs were sensitive to senolytic Na⁺/K⁺ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3⁺ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na⁺/K⁺ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.

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Purpose: The discovery that cyclin E overexpression is a key cyclin-dependent kinase (CDK) 4/6 inhibitor resistance mechanism has reinvigorated interest in targeting CDK2 and the simultaneous inhibition of CDK2/4/6 as a novel therapeutic approach. This first-in-human study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of PF-06873600, the first-in-class inhibitor of CDK2/4/6. Patients and Methods: Dose escalation included 78 patients with advanced breast cancer, triple-negative breast cancer, or ovarian cancer who received oral PF-06873600 at doses ranging from 1 to 50 mg twice daily (part 1A, n = 51) or PF-06873600 with endocrine therapy (part 1B, n = 16; part 1C, n = 11) to determine the recommended dose for expansion (RDE). Dose expansion (part 2A, n = 45; part 2C, n = 28) assessed preliminary antitumor activity, safety, and tolerability at the RDE in combination with fulvestrant in patients with hormone receptor+/HER2− metastatic breast cancer. Pharmacodynamics and translational readouts were assessed by measuring phosphorylated Rb and Ki67 in tumor biopsies and ctDNA. Results: The RDE of PF-06873600 was 25 mg twice daily. During dose escalation, 6 of 42 (14.3%) evaluable patients had treatment-related dose-limiting toxicities. The most common all-causality adverse events (N = 151) were nausea (62.9%), anemia (44.4%), and fatigue (43.7%). Reductions in Ki67-positive cells, phosphorylated Rb histo-score, and ctDNA levels were observed. Three RECIST partial responses (PR) were observed in part 1. In part 2A, there were three PRs (objective response rate, 6.7%; 95% confidence interval, 1.4%–18.3%), and in part 2C, there were five PRs (objective response rate, 22.7%; 95% confidence interval, 7.8%–45.4%). Conclusions: PF-06873600 demonstrated a benefit–risk profile consistent with the CDK4/6 inhibitor class of drugs, with preliminary clinical activity in hormone receptor+/HER2− metastatic breast cancer.

Background: The phase 3 DESTINY-Breast04 trial demonstrated superior efficacy and acceptable safety with trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy in previously treated patients with human epidermal growth factor receptor 2 (HER2)–low metastatic breast cancer (mBC). We report the patient-reported outcomes (PROs), focusing on the hormone receptor–positive cohort. Patients and Methods: Patients were randomized 2:1 to T-DXd (5.4 mg/kg intravenously every 3 weeks) or physician’s choice of chemotherapy and prospectively assessed for PRO measures. Change from baseline and time to definitive deterioration (TDD) were calculated from the EORTC QLQ-C30 and QLQ-BR45 and the EQ-5D-5L questionnaires. Results: Baseline global health status/quality of life (GHS/QoL) scores were similar between groups (T-DXd, 331 patients; physician’s choice, 163 patients); there were no clinically meaningful changes while on either treatment (median duration: T-DXd, 8.2 months; physician’s choice, 3.5 months). Median TDD for GHS/QoL was delayed with T-DXd vs physician’s choice (11.4 vs 7.5 months, respectively; hazard ratio, 0.69; 95% CI, 0.52-0.92). Median TDD for all prespecified PROs, including pain, favored T-DXd. In an additional analysis, the median TDD was shorter for nausea and vomiting with T-DXd vs the physician’s choice. Conclusions: Trastuzumab deruxtecan maintained GHS/QoL scores despite a longer treatment course compared with standard chemotherapy and delayed definitive deterioration across all prespecified PROs vs the physician’s choice. Appropriate management of adverse events and use of preventive measures (ie, antiemetic prophylaxis) may further support patient health-related quality of life. These findings reinforce the benefit of T-DXd as an option for patients with HER2-low mBC. ClinicalTrials.gov: NCT03734029

HER2‐targeted anticancer therapies may be associated with cardiovascular adverse events. This study evaluated effects of the HER2‐targeted antibody–drug conjugate trastuzumab deruxtecan (T‐DXd, DS‐8201a) on QT/QTc interval and its pharmacokinetics. Patients with heavily pretreated, metastatic HER2‐expressing breast cancer were enrolled at seven study sites in Japan. T‐DXd was administered intravenously at 6.4 mg/kg on day 1 of each 21‐day cycle. Primary end points were baseline‐adjusted QTcF interval and pharmacokinetics parameters. Key secondary end points included safety events, serum concentration of T‐DXd and DXd at the time of electrocardiographic measurements, and antitumor activity parameters. Among 51 total patients, 47 (92.2%) had HER2‐low breast cancer (immunohistochemistry 1+ or 2+ and in situ hybridization–negative/equivocal/missing). Pharmacokinetic parameters after a single dose of T‐DXd were consistent with previous studies. After multiple doses, T‐DXd showed moderate accumulation (accumulation ratio (cycle 3/cycle 1), 1.35), but DXd showed minimal accumulation (1.09). The upper bound of the 90% confidence interval for mean ΔQTcF interval was < 10 ms at all timepoints, and at mean maximum serum concentration was also < 10 ms. Based on concentration‐QT analysis, ΔQTcF increased with increasing concentrations of T‐DXd and DXd. No clinically meaningful QTcF prolongation was observed. T‐DXd had a manageable safety profile and showed antitumor activity in HER2‐low breast cancer. In this study, a T‐DXd dose of 6.4 mg/kg, higher than the 5.4‐mg/kg dose currently approved for breast cancer, was not associated with clinically relevant QTcF prolongation in heavily pretreated patients with HER2‐expressing metastatic breast cancer. This study adds to our understanding of T‐DXd for treatment of HER2‐low breast cancer.