Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients withAKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer
| Autor: | Ingrid A. Mayer, Sarat Chandarlapaty, Gaia Schiavon, Vicky Rowlands, Martin Pass, Elza C. de Bruin, Helen Ambrose, Claire Corcoran, Andrew Foxley, Kenji Tamura, David M. Hyman, Maurizio Scaltriti, Eva Ciruelos, Jack Ashton, José Baselga, Lillian M. Smyth, Joana Hauser, Justin P.O. Lindemann, Des D. Cashell, Michele Moschetta, Robert McEwen, Mafalda Oliveira, Barry S. Taylor, Udai Banerji, Rhiannon Maudsley, Alan Barnicle, Laura Biganzoli, Marie-Paule Sablin |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty Chemotherapy Fulvestrant Combination therapy business.industry medicine.medical_treatment medicine.disease Metastatic breast cancer 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Tolerability Response Evaluation Criteria in Solid Tumors 030220 oncology & carcinogenesis Internal medicine medicine Progression-free survival Adverse effect business medicine.drug |
| Zdroj: | Clinical Cancer Research. 26:3947-3957 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-19-3953 |
| Popis: | Purpose: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 and Methods: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.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 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%)].Conclusions: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. |
| Databáze: | OpenAIRE |
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