Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer
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, 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
Abstract
Purpose: The activating mutation AKT1 E17K 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 AKT1 E17K-mutant ER+ MBC.
Patients and methods: Patients with an AKT1 E17K 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. AKT1 E17K 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 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 patients with AKT1 E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.
Conflict of interest statement
Conflicts of interest
LMS has acted in a consultancy or advisory role for AstraZeneca and Roche Genentech and has received research funding from AstraZeneca, Puma Biotechnology, and Roche Genentech, travel or accommodation expenses from AstraZeneca, Pfizer, Puma Biotechnology, and Roche Genentech, and honoraria from Pfizer. KT has received research funding from Daiichi Sankyo, Pfizer, and Lilly. MO has received research funding from AstraZeneca, Boehringer Ingelheim, GSK, Immunomedics, Novartis, Puma Biotechnology, Roche Genentech, and Seattle Genetics and consultancy fees from AstraZeneca, Eisai, GP Pharma, Grünenthal, GSK, Novartis, Pierre-Fabre, Puma Biotechnology, Roche Genentech, and Seattle Genetics. EC has received consultancy fees from Lilly, Novartis, Pfizer, and Roche. IAM has participated in advisory boards (compensated) for Abbvie, AstraZeneca, Genentech, GSK, Lilly, Macrogenics, Novartis, Immunogenics, Pfizer, Puma Biotechnology, and Seattle Genetics and has received institutional research funding from Genentech, Novartis, and Pfizer. LB has acted in a consultancy or advisory role for AstraZeneca, Celgene, Eisai, Genomic Health, Ipsen, Lilly, Novartis, Pfizer, Pierre Fabre, and Roche and received research funding from Celgene, Genomic Health, and Novartis, honoraria from Lilly, Novartis, and Pfizer, and travel or accommodation expenses from Celgene, Pfizer, Ipsen, and Roche. UB has received research grants from AstraZeneca, Chugai, and Onyx Pharmaceuticals and consultancy fees from Astex and Novartis. MS has received research funds from Daiichi Sankyo, Immunomedics, Menarini Ricerche, Puma Biotechnology, and Targimmune, has participated in scientific advisory boards for Menarini Ricerche and Bioscience Institute, and is a cofounder of Medendi. BST has received honoraria and research funding from Genentech and participated in advisory boards for Boehringer Ingelheim and Loxo Oncology, a wholly owned subsidiary of Eli Lilly. SC has received a research grant from Daiichi Sankyo and consultancy fees from BMS, Context Therapeutics, Eli Lilly, Novartis, Revolution Medicines, and Sermonix Pharmaceutical. DMH reports stock ownership in Fount Therapeutics, has acted in a consultancy or advisory role for AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Genentech, and Pfizer, and has received research funding from AstraZeneca, Bayer, Loxo Oncology, and Puma Biotechnology and travel or accommodation expenses from Chugai Pharma and Genentech. HA, JA, AB, DC, CC, ECdB, AF, JH, JPOL, RM, RMc, MM, MP, VR, GS, and JB are employees of AstraZeneca. M-PS declared no competing interests.
©2020 American Association for Cancer Research.
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Source: PubMed