International phase 3 clinical trial evaluating PF-07220060 plus fulvestrant in patients with HR+/HER2− advanced/metastatic breast cancer with progression after a prior CDK4/6 inhibitor.

TPS1129 Background: Substantial improvement in survival outcomes has been achieved with cyclin-dependent kinase (CDK) 4/6 inhibitors plus endocrine therapy (ET) in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced/metastatic breast cancer (BC); however, resistance to this therapy ultimately occurs. PF-07220060 is an oral, highly potent, selective, next generation inhibitor of CDK4 with sparing of CDK6. A first-in-human phase 1/2a study evaluated PF-07220060 (300/400 mg BID) plus ET in patients with HR+/HER2− advanced/metastatic BC who progressed on a prior CDK4/6 inhibitor plus ET (n = 26). At the data cutoff date of November 1, 2022, in patients with measurable disease (n = 21), 6 (29%) had confirmed objective response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and 11 (52%) had a clinical benefit response (CBR). Of all patients (n = 26), median progression-free survival (PFS) was 24.7 weeks, and 8 (31%) patients continued treatment without progression for 60 or more weeks (1). Methods: This international (29 countries; 356 proposed sites), phase 3, open-label, randomized, parallel-group clinical trial will evaluate whether PF-07220060 plus fulvestrant improves clinical outcomes compared with the investigator-chosen therapies in adult female and male patients with HR+/HER2− advanced/metastatic BC with progression after prior therapy of CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor.Key eligibility criteria include advanced/metastatic BC with measurable disease or non-measurable bone-only disease, documented HR+/HER2− status, and progressive disease/recurrence during or within 12 months after the last dose of prior CDK4/6 inhibitor given in the advanced or adjuvant setting, respectively. One additional prior line of approved treatment in the advanced setting targeting ESR1, PIK3CA, AKT1, PTEN, or BRCA is allowed. Approximately 500 patients will be randomly assigned (1:1) to receive PF-07220060 (orally and continuously in a 28-day cycle) plus fulvestrant (intramuscular injection on days 1 and 15 of cycle 1 and then on day 1 of each cycle thereafter) or investigator’s choice of fulvestrant alone or everolimus plus exemestane, which must be declared before randomization. The primary endpoint is PFS by blinded independent central review, which is defined as the time from the date of randomization to the date of first documented disease progression, as determined per RECIST v1.1, or death due to any cause, whichever occurs first. Secondary objectives include overall survival, OR, duration of response, CBR, safety, patient-reported outcomes, and pharmacokinetics. 1. Yap. JCO. 2023;41:3009. Clinical trial information: NCT06105632 .