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Ref Type | Journal Article | ||||||||||||
PMID | (32312891) | ||||||||||||
Authors | Smyth LM, Tamura K, Oliveira M, Ciruelos EM, Mayer IA, Sablin MP, Biganzoli L, Ambrose HJ, Ashton J, Barnicle A, Cashell DD, Corcoran C, de Bruin EC, Foxley A, Hauser J, Lindemann JPO, Maudsley R, McEwen R, Moschetta M, Pass M, Rowlands V, Schiavon G, Banerji U, Scaltriti M, Taylor BS, Chandarlapaty S, Baselga J, Hyman DM | ||||||||||||
Title | Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer. | ||||||||||||
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Abstract Text | The activating mutation AKT1E17K occurs in approximately 7% of estrogen receptor-positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1E17K-mutant ER+ MBC.Patients with an AKT1E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort.From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Capivasertib | Capivasertib | 20 | 5 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Capivasertib | Truqap | AZD5363|AZD 5363|AZD-5363 | Akt Inhibitor (Pan) 21 | Truqap (capivasertib) decreases PI3K/AKT/mTOR signaling by inhibition of AKT1, AKT2, and AKT3, potentially resulting in decreased cell proliferation (PMID: 22294718, PMID: 32532747, PMID: 32312891). Truqap (capivasertib) in combination with Faslodex (fulvestrant) is FDA-approved for use in patients with hormone receptor-positive, ERBB2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations (FDA.gov). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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