PF-07248144 Plus Fulvestrant Is Safe, Active in Pretreated ER+/HER2– Metastatic Breast Cancer

Treatment with the first-in-class KIT6 inhibitor PF-07248144 in combination with fulvestrant (Faslodex) produced durable responses and was safe in patients with heavily pretreated estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer, according to data from the dose-expansion portion of a phase 1 trial (NCT04606446).

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).

“These findings suggest that PF-07248144 may overcome endocrine and CDK4/6 inhibitor resistance, and provide a novel mechanism of action to address a high, unmet medical need in hormone receptor–positive metastatic breast cancer after prior CDK4/6 [inhibition] and endocrine therapy,” lead study author Toru Mukohara, MD, DMedSci, of National Cancer Center Hospital East in Kashiwa, Japan, and colleagues, wrote in a poster presentation of the data.

Safety data for patients treated with PF-07248144 at 5 mg per day as monotherapy or in combination with fulvestrant (n = 78) showed that the most common treatment-related adverse effect (TRAE) experienced was grade 1/2 dysgeusia (84.6%), cases of which were primarily grade 1 (64.1%). Dysgeusia did not lead to dose reductions or treatment discontinuation in any patients. The most common grade 3 or higher TRAE was neutropenia (37.2%), which was reversible and manageable with dose modifications. No instances of febrile neutropenia or grade 5 TRAEs were reported.

PF-07248144 Background and Phase 1 Study Design

Mukohara and colleagues explained that KAT6A amplifications occur in approximately 12% to 15% of patients with breast cancer. KAT6A inhibition could repress ER gene transcription and overcome ESR1 mutations that promote endocrine therapy resistance.

The multicenter phase 1 trial comprised dose-escalation and -expansion portions. During dose expansion, investigators included patients with ER-positive/HER2-negative metastatic breast cancer, castration-resistant prostate cancer, or non–small cell lung cancer for the monotherapy portion. The combination portion of dose escalation and both parts of dose expansion included patients with second-line or later ER-positive/HER2-negative metastatic whose disease progressed following endocrine therapy and a CDK4/6 inhibitor.

Across all stages of the study, patients were required to be at least 18 years of age with an ECOG performance status of 0 or 1 and adequate bone marrow, renal, and liver function.

During dose escalation, PF-07248144 was evaluated at doses of 8 mg, 15 mg, 5 mg, 2 mg, or 1 mg once per day with or without fulvestrant at 500 mg; 5 mg per day of PF-07248144 alone or in combination with 500 mg of fulvestrant was selected as the recommended dose for expansion (RDE).

The study’s objectives were safety and tolerability, pharmacokinetics, antitumor activity per RECIST 1.1 criteria, and pharmacodynamics. Investigators also evaluated circulating tumor DNA (ctDNA) and gene mutations.

Among patients treated with PF-07248144 monotherapy at the RDE in dose expansion (n = 35) and those given PF-07248144 at the RDE in combination with fulvestrant in either portion of the study (n = 43), the median age was 57.0 years (range, 39.0-76.0) and 55.0 years (range, 24.0-76.0), respectively. The majority of patients were female (monotherapy, 100%; combination, 97.7%), Asian (74.3%; 67.4%), had visceral disease (88.6%; 95.3%), and harbored ESR1 mutations (62.9%; 57.1%). In the monotherapy group, 51.4% of patients had an ECOG performance status of 0, and 48.6% had a status of 1; these rates were 39.5% and 60.5%, respectively, in the combination group. Additionally, 57.1% of patients in the monotherapy arm harbored PIK3CA, AKT1, or PTEN mutations; this rate was 44.2% in the combination arm.

Patients received a median of 5.0 prior lines of therapy (range, 1-13) in the monotherapy group and 1.0 prior lines (range, 1-6) in the combination arm. All patients in both groups received prior endocrine therapy and a CDK4/6 inhibitor. Prior chemotherapy was administered to 74.3% of patients in the monotherapy group and 27.9% of those in the combination group; the median number of prior chemotherapies in the advanced/metastatic setting was 1.0 (range, 0-8) for the monotherapy group and 0.0 (range, 0-3) for the combination group. Moreover, 40.0% and 4.7% of patients in the respective arms received other prior targeted therapies. Notably, 54.3% of patients in the monotherapy group and 76.7% of patients in the combination group received CDK4/6 inhibitors more than 12 months prior to baseline. In the monotherapy group, 85.7% and 80.0% of patients, respectively, received prior aromatase inhibitors and prior fulvestrant; these respective rates were 88.4% and 11.6% in the combination group.

Subgroup Efficacy Data for PF-07248144 Plus Fulvestrant

Additional data for the combination group showed that the ORR was 30.4% (95% CI, 13.2%-52.9%) for patients treated in the second line (n = 23); 45.0% (95% CI, 23.1%-68.5%) for those treated in the third line or later (n = 20); 33.3% (95% CI, 13.3%-59.0%) for those with ESR1 wild-type disease (n = 18); 41.7% (95% CI, 22.1%-63.4%) for those harboring ESR1 mutations (n = 24); 43.5% (95% CI, 23.2%-65.5%) for patients with PIK3CA/AKT1/PTEN wild-type disease (n = 23); 31.6% (95% CI, 12.6%-56.6%) for patients harboring PIK3CA/AKT1/PTEN mutations (n = 19); 57.1% (95% CI, 18.4%-90.1%) for patients with primary endocrine therapy resistance (n = 7); 33.3% (95% CI, 18.6%-51.0%) for those with secondary endocrine resistance (n = 36); 60.0% (95% CI, 14.7%-94.7%) for patients previously treated with fulvestrant (n = 5); 34.2% (95% CI, 19.6%-51.4%) for those naïve to fulvestrant; 40.0% (95% CI, 12.2%-73.8%) for patients who received a prior CDK4/6 inhibitor for less than 12 months (n = 10); and 36.4% (95% CI, 20.4%-54.9%) for those treated with a prior CDK4/6 inhibitor for more than 12 months (n = 33).

The median PFS in the respective subgroups was 13.8 months (95% CI, 3.5-NE), 10.7 months (95% CI, 5.5-13.7), 10.9 months (95% CI, 3.5-NE), 10.7 months (95% CI, 5.3-16.5), 13.7 months (95% CI, 5.6-NE), 7.3 months (95% CI, 2.8-13.8), not applicable (NA), 10.8 months (95% CI, 3.7-16.5), NA, 7.5 months (95% CI, 3.7-13.8), 7.4 months (95% CI, 3.5-NE), and 10.9 months (95% CI, 3.7-16.5).

“Consistent antitumor activity was observed irrespective of biomarker mutation status; endocrine and [CDK4/6] inhibitor–sensitive or –resistant tumors; and second- or later-line therapy,” study authors wrote.

Among evaluable patients from the combination group (n = 31), the median reduction in total ctDNA was 95.0% after 8 weeks of treatment, and the median reduction in ESR1 mutation allele frequency was 100%. Study authors noted that PFS outcomes were improved in patients with undetectable ctDNA vs those with detectable ctDNA.

Additional Safety Data for PF-07248144 With or Without Fulvestrant

Further findings from the monotherapy group showed that the rates of any-grade and grade 3 or higher TRAEs were 94.3% and 51.4%, respectively. The most common TRAEs reported included dysgeusia (any-grade, 85.7%; grade ≥3, 0%), neutropenia (68.6%; 40.0%), anemia (45.7%; 8.6%), leukopenia (45.7%; 11.4%), thrombocytopenia (37.1%; 0%), increased aspartate aminotransferase (AST) levels (22.9%; 0%), and fatigue (17.1%; 0%).

In the combination group, any-grade TRAEs occurred in all patients, and 62.8% of patients experienced grade 3 or higher TRAEs. The most common TRAEs comprised dysgeusia (any-grade, 83.7%; grade ≥3, 0%), neutropenia (65.1%; 46.5%), anemia (44.2%; 14.0%), leukopenia (32.6%; 11.6%), thrombocytopenia (14.0%; 2.3%), increased AST levels (9.3%; 0%), and fatigue (44.2%; 2.3%).

Reference

Mukohara T, LoRusso PM, Sommerhalder D, et al. PF-07248144, a first-in-class KAT6 Inhibitor, in patients with HR+ HER2– metastatic breast cancer: updated results from phase 1 dose expansion study. Presented at: 42nd Annual Miami Breast Cancer Conference; March 6-9, 2025; Miami Beach, FL. Poster 050.