Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study.

Autor:	Rugo HS; Department of Medicine (Hematology/Oncology), University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, USA. Electronic address: hope.rugo@ucsf.edu., Oliveira M; Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona; Breast Cancer Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Howell SJ; Breast Oncology, Division of Cancer Sciences, The University of Manchester, Manchester; The Christie NHS Foundation Trust, Manchester, UK., Dalenc F; Institut Claudius Regaud, Institut Universitaire du Cancer-Oncopole, Toulouse, France., Cortes J; Oncology Department, International Breast Cancer Center (IBCC), Pangaea Oncology, Quiron Group, Barcelona; Medica Scientia Innovation Research (MedSIR), Barcelona; Department of Medicine, Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Madrid, Spain., Gomez HL; Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima; Institute of Investigations in Biomedical Sciences, Universidad Ricardo Palma, Lima, Peru., Hu X; Shanghai Cancer Center, Fudan University, Shanghai, China., Jhaveri KL; Memorial Sloan Kettering Cancer Center, New York; Weill Cornell Medical College, New York, USA., Krivorotko P; Petrov Research Institute of Oncology, Saint Petersburg, Russia., Loibl S; GBG Forschungs GmbH, Neu-Isenburg; Centre for Haematology and Oncology, Bethanien, Frankfurt, Germany., Morales Murillo S; Institut de Recerca Biomèdica, Barcelona, Spain., Nowecki Z; The Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland., Okera M; ICON Cancer Centre, Adelaide, Australia., Park YH; Sungkyunkwan University School of Medicine, Samsung Medical Centre, Seoul., Sohn J; Yonsei University College of Medicine-Yonsei Cancer Center, Seoul, Republic of Korea., Toi M; Kyoto University Hospital, Kyoto., Iwata H; Aichi Cancer Center Hospital, Nagoya, Japan., Yousef S; Emek Medical Center, Afula, Israel., Zhukova L; Loginov Moscow Clinical Scientific Center, Moscow, Russia., Logan J; Oncology R&D, AstraZeneca, Cambridge, UK., Twomey K; Oncology R&D, AstraZeneca, Cambridge, UK., Khatun M; Oncology R&D, AstraZeneca, Cambridge, UK., D'Cruz CM; Oncology R&D, AstraZeneca, Waltham, USA., Turner NC; Royal Marsden Hospital, Institute of Cancer Research, London, UK.
Jazyk:	angličtina
Zdroj:	ESMO open [ESMO Open] 2024 Sep 05; Vol. 9 (9), pp. 103697. Date of Electronic Publication: 2024 Sep 05.
DOI:	10.1016/j.esmoop.2024.103697
Abstrakt:	Background: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit. Patients and Methods: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted. Results: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs. Conclusions: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit. (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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