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

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.

Figure 1.. CONSORT Diagram for NCI MATCH Subprotocol

^aReasons participants did not receive an assignment: screened outside of the subprotocol group window (n = 8), also have sequence variation excluded (n = 12), prior treatment (n = 1), and an annotation issue (n = 5). ^bReasons assigned participants were not enrolled: prior treatment (n = 2), deteriorating performance status (n = 3), inadequate organ function (n = 1), and reason unknown (n = 2).

Figure 2.. Response to Capivasertib in Patients With an AKT1 E17K-Mutated Tumor

The subprotocol EAY131-Y trial included 35 eligible, evaluable, and analyzable patients. Eight patients were screened outside of the subprotocol group window, 12 had excluded mutated tumors, 1 had previous treatment, and 5 had an annotation issue. Two patients had previous treatment, 3 had deteriorating Eastern Cooperative Oncology Group Performance Status score, 1 had inadequate organ function, and 2 had unknown reasons. A, The waterfall plot demonstrates the best percentage change from baseline in the sum of the diameters of the target lesions for patients with follow-up target lesion measurements (n = 28). The best responses labeled below the bars demonstrate the confirmed overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1: complete response (CR; n = 1), partial response (PR; n = 9), stable disease (SD; n = 16), and progressive disease (PD; n = 2). Four patients are labeled as SD because of missing follow-up scans confirming PR. One patient with hormone receptor (HR)-positive/ERBB2 (formerly HER2)-negative breast cancer (BC) missed cycle 2 measurements, and at cycle 4, the patient experienced a 74% reduction with a new lesion after cycle 4. Of the 3 evaluable patients with HR-positive/ERBB2-negative BC who continued hormone therapy along with capivasertib, 2 had a PR and 1 was a patient missing cycle 2 measurements. B, The swimmer plot of the objective responses from the start of treatment to disease progression is shown. At the time of the analysis, 2 patients continued on therapy. TNBC indicates triple-negative breast cancer. C and D, In the subprotocol EAY131-Y trial, the median progression-free survival (PFS) was 5.5 months (C) and the median overall survival (OS) was 14.5 months (D). ^aNew lesion. ^bMissing follow-up scan confirming PR. ^cHormone therapy along with capivasertib. ^dReduction with a new lesion after cycle 4.