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.
NCT04862663.
AstraZeneca-funded medical writing support was provided by Suzanne Patel, PhD, from BOLDSCIENCE Inc.
AstraZeneca.
AstraZeneca.
E. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, Arcus, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals; Financial Interests, Institutional, Cascadian Therapeutics. B. Pistilli: Financial Interests, Institutional, Advisory Board: AstraZeneca, Seagen, Lilly, Daiichi Sankyo, MSD; Financial Interests, Institutional, Invited Speaker: Gilead, Novartis, AstraZeneca, Gilead, Seagen, MSD, Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre, Daiichi Sankyo; Financial Interests, Personal, Other, travel support: AstraZeneca, Pierre Fabre, MSD, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Funding: Daiichi Sankyo; Non-Financial Interests, Project Lead: Unicancer. V. Borges: Financial Interests, Personal and institutional, Invited Speaker: Seagen, AstraZeneca, Cogent, Olema; Financial Interests, Personal and institutional, Advisory board: Seagen, AstraZeneca, Cogent, Olema; Financial Interests, Personal and institutional, Advisory role: Seagen, AstraZeneca, Cogent, Olema; Financial Interests, Personal and institutional, Principal investigator: Seagen, AstraZeneca, Cogent, Olema. M. Campone: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Sanofi, Menarini, Gilead, Seagen; Financial Interests, Personal, Invited Speaker: Novartis, Lilly; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Lilly. T. Foukakis: Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Gilead Sciences; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Expert Testimony: Veracyte, Exact Sciences, Affibody; Financial Interests, Personal, Royalties, Authorship of two chapters in UpToDate: Wolters Kluwer; Financial Interests, Institutional, Invited Speaker, Clinical trial support (research grant and study drug): Pfizer, AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical trial support (research grant and study drug): Novartis. P.K.H. Lau: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Institutional, Invited Speaker, Clinical trial: AstraZeneca, Roche/Genentech, MSD, Beigene, Ambrx, Pimera, Gilead Sciences. E. Lim: Financial Interests, Institutional, Advisory Board: Gilead, Novartis, Pfizer, Roche, AstraZeneca, MSD, Lilly; Financial Interests, Institutional, Invited Speaker: Roche, Gilead, Novartis, Lilly, AstraZeneca, Roche, Lilly, Novartis, Gilead, AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer, Novartis; Non-Financial Interests, Leadership Role, Scientific Advisory Committee: Breast Cancer Trials Australia; Non-Financial Interests, Leadership Role, Principal Cancer Theme Lead, Faculty of Medicine: University of New South Wales; Non-Financial Interests, Leadership Role, Faculty: Garvan Institute of Medical Research; Non-Financial Interests, Leadership Role, Director Cancer Research: St Vincent's Hospital Sydeny. I. Lugowska: Financial Interests, Personal, Invited Speaker, The reports of clinical trials: Roche, BMS, Macrogenics, Amgen; Financial Interests, Institutional, Other, Research grants: Roche; Financial Interests, Institutional, Other, Research grant: Agenus; Financial Interests, Personal and Institutional, Invited Speaker: Agenus, Roche, BMS, Janssen, Astra, Incyte, Macrogenics, Checkpoint Inhibitors, Celon, Pfizer, MSD, Debio; Non-Financial Interests, Project Lead: MSCI; Non-Financial Interests, Advisory Role, Board Member: EORTC. J. Collins, C. Gresty, C. Miller, R. Sommavilla: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. D. Sudhan: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. H.S. Rugo: Financial Interests, Personal, Advisory Role: Napo Pharmaceuticals, Scorpion Therapeutics, Blueprint Medicines, Puma Biotechnology; Other, Personal, Other, Travel, Accommodations, Expenses: Merck, AstraZeneca, Gilead Sciences; Financial Interests, Institutional, Funding: OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Pionyr, Taiho Oncology, Veru, GlaxoSmithKline. All other authors have declared no conflicts of interest.