Capivasertib, an AKT kinase inhibitor, as monotherapy or in combination with fulvestrant in patients with AKT1(E17K)-mutant, ER-positive metastatic breast cancer Journal Article
| Authors: | Smyth, L. M.; Tamura, K.; Oliveira, M.; Ciruelos, E. M.; Mayer, I. A.; Sablin, M. P.; Biganzoli, L.; Ambrose, H. J.; Ashton, J.; Barnicle, A.; Cashell, D. D.; Corcoran, C.; de Bruin, E. C.; Foxley, A.; Hauser, J.; Lindemann, J. P. O.; Maudsley, R.; McEwen, R.; Moschetta, M.; Pass, M.; Rowlands, V.; Schiavon, G.; Banerji, U.; Scaltriti, M.; Taylor, B. S.; Chandarlapaty, S.; Baselga, J.; Hyman, D. M. |
| Article Title: | Capivasertib, an AKT kinase inhibitor, as monotherapy or in combination with fulvestrant in patients with AKT1(E17K)-mutant, ER-positive metastatic breast cancer |
| Abstract: | 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. ©2020 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 26 |
| Issue: | 15 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-08-01 |
| Start Page: | 3947 |
| End Page: | 3957 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-19-3953 |
| PUBMED: | 32312891 |
| PROVIDER: | scopus |
| PMCID: | PMC7415507 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2020 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work