184MO First-in-human phase I/IIa study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 in combination with endocrine therapy (ET) in patients (pts) with HR+/HER2− metastatic breast cancer (mBC) who progressed on prior CDK4/6 inhibitors (CDK4/6i): Safety and efficacy update

PF-07220060 is a novel potent oral CDK4i with significant sparing of CDK6. Preliminary safety and dose escalation data from this phI/IIastudy were previously presented. Here we report updated safety and efficacy data in pts with HR+/HER2− mBC, who progressed on prior CDK4/6i and ET, treated with PF-07220060 + ET. This study in pts with advanced solid tumors was enriched for pts with HR+/HER2− mBC who received ≥2 lines of treatment including ET and CDK4/6i. Prior fulvestrant and chemotherapy were allowed. Study objectives were to assess safety, tolerability, and antitumor activity of PF-07220060 alone and in combination with ET. At data cutoff (Nov 1, 2023), 33 pts received PF-07220060 (300mg/400mg BID) in combination with letrozole or fulvestrant (Parts 1B + 1C). Median age was 62.0y (range 41–82); ECOG PS was 0 (36.4%) or 1. Median prior lines of systemic therapy (advanced setting) was 4.0 (range 1–11). All pts had prior CDK4/6i treatment, 24 (72.7%) had prior fulvestrant, and 22 (66.7%) had prior chemotherapy in the advanced/metastatic setting. Most frequent treatment-emergent adverse events (TEAEs) were neutropenia (54.5%; 18.2% Grade 3 [G3]), diarrhea (42.4%; 0% G3), and nausea (42.4%; 3.0% G3), with no >G3 TEAEs. Dose modifications due to TEAEs included: 1 (3.0%) pt discontinued PF-07220060, 5 (15.2%) pts had dose reduction, and 10 (30.3%) pts had dose interruptions. In 25 pts with measurable disease who progressed on prior CDK4/6i + ET, 8 (32.0%) had confirmed RECIST v1.1 objective responses (1 CR, 7 PR). Clinical benefit response (CR, PR, or ≥24 wks stable disease) was seen in 20/33 (60.6%) pts. Median progression-free survival was 8.1 months (95% CI: 5.3, 10.9). Confirmed objective responses (PRs) were observed irrespective of ESR1 or PI3K pathway mutations. PF-07220060 + ET showed a favorable safety profile with few hematologic adverse events and infrequent dose modifications, and promising efficacy despite prior CDK4/6i treatment, irrespective of key mutations.