206P Capivasertib (C) + palbociclib (P) and fulvestrant (F) in patients (pts) with HR+/HER2- advanced breast cancer (ABC): Phase Ib data from CAPItello-292

Abstract

AKT pathway activation is implicated in resistance to endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in pts with HR+/HER2– ABC. In CAPItello-291, C+F significantly improved progression-free survival vs F in pts with aromatase inhibitor-resistant HR+/HER2– ABC (HR 0.60; 95% CI 0.51–0.71; p<0.001) and pts with AKT pathway-altered tumours (HR 0.50; 95% CI 0.38–0.65; p<0.001). Simultaneous inhibition of AKT and CDK4/6 pathways may improve clinical outcomes by resensitising tumours to ET and CDK4/6i. This phase Ib/III study is evaluating the safety/efficacy of C+P+F vs placebo+P+F in HR+/HER2− ABC. Phase Ib used a Keyboard design (mTPI-2), and pts received C (320mg [C320] or 400mg [C400] twice daily, 4 days on/3 days off), P (100mg [P100] or 125mg [P125] once daily for 21 days of each 28-day cycle) and F (500mg [F500] every 28 days + loading dose on cycle 1 day 15); prior CDK4/6i was permitted. Phase Ib primary endpoints: safety/tolerability; confirmation of recommended phase III dose (RP3D). Serial ctDNA monitoring was performed and C/P pharmacokinetics were evaluated. Data cut-off: 31 Oct 2022. In 39 heavily pre-treated (median prior chemotherapies: 2 [range 0–8]) pts with a median age of 59 years (range 38–82), 7 dose-limiting toxicities (DLTs; mainly neutropenia related) were seen in 6 pts across doses and did not prevent escalation/expansion. C400+P125+F500 (n=12) was identified as the RP3D (1 DLT; Grade [G] 3 neutropenia). Most common adverse events were diarrhoea (69%; 1/27 G3), neutropenia (54%; 19/21 G≥3), fatigue and nausea (both 41%; all G1/2). No treatment-related deaths or new safety risks were identified. Preliminary efficacy and ctDNA data from pts treated at the RP3D will be presented. No clinically relevant drug–drug interaction was observed. C+P+F was tolerable in heavily pre-treated pts with HR+/HER2− ABC, with no marked safety differences among dose levels. DLTs were consistent with the expected safety profile.