Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial

Howell, Sacha J.; Casbard, Angela; Carucci, Margherita; Ingarfield, Kate; Butler, Rachel; Morgan, Siân; Meissner, Magdalena; Bale, C.; Bezecny, Pavel; Moon, Sarah; Twelves, Chris; Venkitaraman, Ramachandran; Waters, Simon; Bruin, Elza C. de; Schiavon, Gaia; Foxley, Andrew; Jones, Robert H.

doi:10.1016/s1470-2045(22)00284-4

Cited by 89 publications

(41 citation statements)

References 35 publications

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“…A randomized study assessed the effects of capivasertib plus fulvestrant in ER+, HER2− advanced breast cancer patients resistant to endocrine therapy (FAKTION). This trial and its updated analysis showed that the addition of capivasertib to fulvestrant resulted in a significant improvement of progression-free survival, objective response rate (ORR) [ 102 ] and overall survival [ 103 ] in participants with aromatase inhibitor-resistant ER-positive, HER2−negative advanced breast cancer. Additionally, the expanded biomarker testing suggested that capivasertib was predominantly effective in patients with PI3K/AKT/PTEN pathway-altered tumors (38.9 vs. 20.0 months, p = 0.0047) [ 103 ].…”

Section: Preclinical and Clinical Development Of Pam Pathway Inhibito...mentioning

confidence: 99%

“…This trial and its updated analysis showed that the addition of capivasertib to fulvestrant resulted in a significant improvement of progression-free survival, objective response rate (ORR) [ 102 ] and overall survival [ 103 ] in participants with aromatase inhibitor-resistant ER-positive, HER2−negative advanced breast cancer. Additionally, the expanded biomarker testing suggested that capivasertib was predominantly effective in patients with PI3K/AKT/PTEN pathway-altered tumors (38.9 vs. 20.0 months, p = 0.0047) [ 103 ]. The grade 3–4 adverse events were hypertension (capivasertib arm vs. placebo: 32% vs. 24%), diarrhea (14% vs. 4%) and rash (20% vs. 0) [ 102 ].…”

Section: Preclinical and Clinical Development Of Pam Pathway Inhibito...mentioning

confidence: 99%

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PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer

Zhu

et al. 2022

Cells

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Phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB/AKT) and mechanistic target of rapamycin (mTOR) (PAM) pathways play important roles in breast tumorigenesis and confer worse prognosis in breast cancer patients. The inhibitors targeting three key nodes of these pathways, PI3K, AKT and mTOR, are continuously developed. For breast cancer patients to truly benefit from PAM pathway inhibitors, it is necessary to clarify the frequency and mechanism of abnormal alterations in the PAM pathway in different breast cancer subtypes, and further explore reliable biomarkers to identify the appropriate population for precision therapy. Some PI3K and mTOR inhibitors have been approved by regulatory authorities for the treatment of specific breast cancer patient populations, and many new-generation PI3K/mTOR inhibitors and AKT isoform inhibitors have also been shown to have good prospects for cancer therapy. This review summarizes the changes in the PAM signaling pathway in different subtypes of breast cancer, and the latest research progress about the biomarkers and clinical application of PAM-targeted inhibitors.

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Section: Preclinical and Clinical Development Of Pam Pathway Inhibito...mentioning

confidence: 99%

Section: Preclinical and Clinical Development Of Pam Pathway Inhibito...mentioning

confidence: 99%

PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer

Zhu

et al. 2022

Cells

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“…Several AKT inhibitors are in different clinical stages for various tumor types, especially for breast cancer, prostate cancer, and RCC, such as ipatasertib, capivasertib, afuresertib, and MK‐2206. 360 , 361 Their toxicities are acceptable as a single agent or in combination with other agents. The activation of the PI3K/AKT/mTOR signaling pathway caused by gene mutation and/or deletions of PTEN is associated with drug sensitivity.…”

Section: Selective Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

“…To date, no AKT inhibitors have been approved. Several AKT inhibitors are in different clinical stages for various tumor types, especially for breast cancer, prostate cancer, and RCC, such as ipatasertib, capivasertib, afuresertib, and MK‐2206 360,361 . Their toxicities are acceptable as a single agent or in combination with other agents.…”

Section: Selective Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

Small molecule inhibitors targeting the cancers

Liu

Chen

Zhang

et al. 2022

MedComm

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Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.

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“…We noticed that designing small-molecule inhibitors to target PPA1 is a promising therapeutic strategy. To this end, designing molecular inhibitors of PPA1 or exploring more miRNAs to regulate PPA1 expression in malignant tumors, or combining with JNK (54) or PI3K-AKT inhibitors (55,56,59,60) may be sensible choices.…”

Section: Future Perspectivesmentioning

confidence: 99%

PPA1, an energy metabolism initiator, plays an important role in the progression of malignant tumors

Wang

Wei

et al. 2022

Front. Oncol.

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Inorganic pyrophosphatase (PPA1) encoded by PPA1 gene belongs to Soluble Pyrophosphatases (PPase) family and is expressed widely in various tissues of Homo sapiens, as well as significantly in a variety of malignancies. The hydrolysis of inorganic pyrophosphate (PPi) to produce orthophosphate (Pi) not only dissipates the negative effects of PPi accumulation, but the energy released by this process also serves as a substitute for ATP. PPA1 is highly expressed in a variety of tumors and is involved in proliferation, invasion, and metastasis during tumor development, through the JNK/p53, Wnt/β-catenin, and PI3K/AKT/GSK-3β signaling pathways. Because of its remarkable role in tumor development, PPA1 may serve as a biological target for adjuvant therapy of tumor malignancies. Further, PPA1 is a potential biomarker to predict survival in patients with cancer, where the assessment of its transcriptional regulation can provide an in-depth understanding. Herein, we describe the signaling pathways through which PPA1 regulates malignant tumor progression and provide new insights to establish PPA1 as a biomarker for tumor diagnosis.

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Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial

Cited by 89 publications

References 35 publications

PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer

PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer

Small molecule inhibitors targeting the cancers

PPA1, an energy metabolism initiator, plays an important role in the progression of malignant tumors

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