Dataset Information

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 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.

SUBMITTER: Smyth LM

PROVIDER: S-EPMC7415507 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with <i>AKT1</i> <sup>E17K</sup>-Mutant, ER-Positive Metastatic Breast Cancer.

Smyth Lillian M LM Tamura Kenji K Oliveira Mafalda M Ciruelos Eva M EM Mayer Ingrid A IA Sablin Marie-Paule MP Biganzoli Laura L Ambrose Helen J HJ Ashton Jack J Barnicle Alan A Cashell Des D DD Corcoran Claire C de Bruin Elza C EC Foxley Andrew A Hauser Joana J Lindemann Justin P O JPO Maudsley Rhiannon R McEwen Robert R Moschetta Michele M Pass Martin M Rowlands Vicky V Schiavon Gaia G Banerji Udai U Scaltriti Maurizio M Taylor Barry S BS Chandarlapaty Sarat S Baselga José J Hyman David M DM

Clinical cancer research : an official journal of the American Association for Cancer Research 20200420 15

<h4>Purpose</h4>The activating mutation <i>AKT1</i> <sup>E17K</sup> occurs in approximately 7% of estrogen receptor-positive (ER<sup>+</sup>) 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 <i>AKT1</i> <sup>E17K</sup>-mutant ER<sup>+</sup> MBC.<h4>Patients and methods</h4>Patients with an <i>A ...[more]

PMID: 32312891

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Project description:ImportanceIn the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, agents targeting genetic tumor abnormalities are administered to patients. In the NCI-MATCH subprotocol EAY131-Y trial, patients with an AKT1 E17K-mutated metastatic tumor received the pan-AKT inhibitor capivasertib.ObjectiveTo assess the objective response rate (ORR) of capivasertib in patients with an AKT1 E17K-mutated tumor.Design, setting, and participantsBetween July 13, 2016, and August 10, 2017, patients in the NCI-MATCH trial were enrolled and assigned to the subprotocol EAY131-Y nonrandomized trial. Patients included adults with an AKT1 E17K-mutated metastatic tumor that had progressed with standard treatment, and these patients were assigned to receive capivasertib. Tumor assessments were repeated every 2 cycles. Data analysis of this evaluable population was performed from November 8, 2019, to March 12, 2020.InterventionsThe study treatment was capivasertib, 480 mg, orally twice daily for 4 days on and 3 days off weekly in 28-day cycles until disease progression or unacceptable toxic effect. If patients continued hormone therapy for metastatic breast cancer, the capivasertib dose was 400 mg.Main outcomes and measuresThe primary end point was the ORR (ie, complete response [CR] and partial response) according to the Response Evaluation Criteria in Solid Tumors criteria, version 1.1. Secondary end points included progression-free survival (PFS), 6-month PFS, overall survival, and safety.ResultsIn total, 35 evaluable and analyzable patients were included, of whom 30 were women (86%), and the median (range) age was 61 (32-73) years. The most prevalent cancers were breast (18 [51%]), including 15 patients with hormone receptor (HR)-positive/ERBB2-negative and 3 with triple-negative disease, and gynecologic (11 [31%]) cancers. The ORR rate was 28.6% (95% CI, 15%-46%). One patient with endometrioid endometrial adenocarcinoma achieved a CR and remained on therapy at 35.6 months. Patients with confirmed partial response had the following tumor types: 7 had HR-positive/ERBB2-negative breast cancer, 1 had uterine leiomyosarcoma, and 1 had oncocytic parotid gland carcinoma and continued receiving treatment at 28.8 months. Sixteen patients (46%) had stable disease as the best response, 2 (6%) had progressive disease, and 7 (20%) were not evaluable. With a median follow-up of 28.4 months, the overall 6-month PFS rate was 50% (95% CI, 35%-71%). Capivasertib was discontinued because of adverse events in 11 of 35 patients (31%). Grade 3 treatment-related adverse events included hyperglycemia (8 [23%]) and rash (4 [11%]). One grade 4 hyperglycemic adverse event was reported.Conclusions and relevanceThis nonrandomized trial found that, in patients with an AKT1 E17K-mutated tumor treated with capivasertib, a clinically significant ORR was achieved, including 1 CR. Clinically meaningful activity with single-agent capivasertib was demonstrated in refractory malignant neoplasms, including rare cancers.Trial registrationClinicalTrials.gov Identifier: NCT00700882.

Dataset Information

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 ^E17K-Mutant, ER-Positive Metastatic Breast Cancer.

Purpose

Patients and methods

Results

Conclusions

Publications

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with <i>AKT1</i> <sup>E17K</sup>-Mutant, ER-Positive Metastatic Breast Cancer.

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Dataset Information

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.

Purpose

Patients and methods

Results

Conclusions

Publications

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with <i>AKT1</i> <sup>E17K</sup>-Mutant, ER-Positive Metastatic Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 ^E17K-Mutant, ER-Positive Metastatic Breast Cancer.