Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with
| Autor: | Lillian M, Smyth, Kenji, Tamura, Mafalda, Oliveira, Eva M, Ciruelos, Ingrid A, Mayer, Marie-Paule, Sablin, Laura, Biganzoli, Helen J, Ambrose, Jack, Ashton, Alan, Barnicle, Des D, Cashell, Claire, Corcoran, Elza C, de Bruin, Andrew, Foxley, Joana, Hauser, Justin P O, Lindemann, Rhiannon, Maudsley, Robert, McEwen, Michele, Moschetta, Martin, Pass, Vicky, Rowlands, Gaia, Schiavon, Udai, Banerji, Maurizio, Scaltriti, Barry S, Taylor, Sarat, Chandarlapaty, José, Baselga, David M, Hyman |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Breast Neoplasms Middle Aged Progression-Free Survival Article Pyrimidines Receptors Estrogen Chemotherapy Adjuvant Antineoplastic Combined Chemotherapy Protocols Mutation Humans Female Pyrroles Breast Fulvestrant Proto-Oncogene Proteins c-akt Mastectomy Response Evaluation Criteria in Solid Tumors Aged |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 |
| Popis: | PURPOSE: The activating mutation AKT1(E17K) occurs in ~7% of 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 AKT1(E17K)-mutant ER+ MBC patients. PATIENTS AND METHODS: Patients with an AKT1(E17K) mutation, detected by local (NGS) or central (plasma-based BEAMing) testing, received capivasertib 480 mg bid, 4 days on, 3 days off, weekly or 400 mg bid 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 (CBR(24)). Biomarker analyses were conducted in the combination cohort. RESULTS: 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 this latter group may have had more aggressive disease at baseline. AKT1(E17K) mutations were detectable in plasma by BEAMing (95%, 41/43), ddPCR (80%, 33/41) and NGS (76%, 31/41). A ≥50% decrease in AKT1(E17K) 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%]). CONCLUSIONS: Capivasertib demonstrated clinically meaningful activity in heavily pretreated AKT1(E17K)-mutant ER+ MBC patients, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination. |
| Databáze: | OpenAIRE |
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