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Original Investigation
December 30, 2020

Effect of Capivasertib in Patients With an AKT1 E17K-Mutated Tumor: NCI-MATCH Subprotocol EAY131-Y Nonrandomized Trial

Author Affiliations
  • 1Department of Medicine, Columbia University Irving Medical Center, New York, New York
  • 2Now with Winship Cancer Institute at Emory University, Atlanta, Georgia
  • 3Department of Biostatistics, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 4Department of Obstetrics and Gynecology, Washington University School of Medicine in St Louis, St Louis, Missouri
  • 5Department of Medicine, TGen/HonorHealth Research Institute, Scottsdale, Arizona
  • 6Department of Medicine, Thomas Jefferson University Health, Philadelphia, Pennsylvania
  • 7Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
  • 8Department of Biostatistics, Dana-Farber Cancer Institute–ECOG (Eastern Cooperative Oncology Group)–ACRIN (American College of Radiology Imaging Network) Biostatistics Center, Boston, Massachusetts
  • 9Division of Cancer Therapeutics and Diagnosis, Molecular Characterization and Assay Development Laboratory, Leidos, Frederick, Maryland
  • 10Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston
  • 11Department of Pathology, City of Hope National Medical Center, Duarte, California
  • 12Department of Medicine, University of Pennsylvania, Philadelphia
  • 13Department of Medicine, University of Texas Southwestern Simmons Cancer Center, Dallas
  • 14Department of Medicine, Massachusetts General Hospital, Boston
JAMA Oncol. 2021;7(2):271-278. doi:10.1001/jamaoncol.2020.6741
Key Points

Question  What is the clinical activity of capivasertib in patients with an AKT1 E17K-mutated metastatic tumor?

Findings  In this nonrandomized trial of 35 patients with an AKT1 E17K-mutated tumor treated with capivasertib, the confirmed overall response rate was 28.6%, and 1 complete response and 9 partial responses were achieved. Grade 3 treatment-related adverse events included hyperglycemia and rash, and 1 patient had a grade 4 hyperglycemic adverse event.

Meaning  The results of this trial indicate that capivasertib had a clinically significant objective response rate in patients with an AKT1 E17K-mutated metastatic tumor of various histologies, including rare cancers.

Abstract

Importance  In 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.

Objective  To assess the objective response rate (ORR) of capivasertib in patients with an AKT1 E17K-mutated tumor.

Design, Setting, and Participants  Between 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.

Interventions  The 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 Measures  The 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.

Results  In 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 Relevance  This 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 Registration  ClinicalTrials.gov Identifier: NCT00700882

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