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Ipatasertib in Patients with Tumors with AKT Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131)
Carolyn K McCourt1, Zihan Wei2, Kevin Kalinsky3
1Washington University School of Medicine, St. Louis, Missouri.
Purpose:
Activating mutations in AKT genes are rare but play an important role in the commonly dysregulated PI3K/AKT/mTOR signaling pathway in multiple cancers. NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolled patients to targeted therapies based on matching tumor genomic alterations. Subprotocol Z1K evaluated ipatasertib, a pan-AKT inhibitor, in patients with AKT1E17K-mutant metastatic tumors.
Patients And Methods:
Patients received ipatasertib 400 mg orally once daily in a 28-day cycle until progression or unacceptable toxicity. Patients with well-controlled diabetes were eligible. Patients with known KRAS, NRAS, HRAS, or BRAF mutations were excluded. Prior PI3K and mTOR inhibitors were allowed. Prior AKT inhibitors were excluded. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival, 6-month progression-free survival, and toxicity.
Results:
Thirty-five patients were enrolled, and 29 patients were included in the prespecified primary efficacy analysis. Multiple histologies were enrolled, with breast (n = 18) and gynecologic (n = 7) being the most common. The majority had >3 lines of prior therapy (19/29; 65.5%). The ORR was 24.1% (7/29; 90% confidence interval, 11.9%-40.6%) with P < 0.001 against a null rate of 5%. All responses were partial responses. The median response duration was 10.1 months (90% confidence interval, 3.7-10.8). The most common toxicities of any grade included diarrhea (n = 25), nausea (n = 13), and hyperglycemia (n = 9). Grade 3/4 toxicities observed were consistent with reported toxicities for AKT inhibition. Twelve grade 3 events occurred that were thought to be at least possibly related to treatment.
Conclusions:
The study met its primary endpoint with an ORR of 24.1% (P < 0.001), with ipatasertib demonstrating clinically significant activity in heavily pretreated patients with various tumors harboring AKT1E17K mutations. See related commentary by Dahmer Tiecher and Schram, p. 4863.
Insights
Ipatasertib showed significant activity in patients with AKT1E17K mutant metastatic tumors, meeting the primary endpoint. This pan-AKT inhibitor demonstrated clinical benefit in heavily pretreated individuals across various cancer types.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Activating mutations in AKT genes are rare but crucial in the PI3K/AKT/mTOR pathway.
- NCI-MATCH (EAY131) is a tumor-agnostic trial matching therapies to genomic alterations.
- Subprotocol Z1K focused on ipatasertib for AKT1E17K mutant metastatic tumors.
Purpose of the Study:
- To evaluate the efficacy and safety of ipatasertib in patients with AKT1E17K mutant metastatic tumors.
- To determine the objective response rate (ORR) as the primary endpoint.
- To assess secondary endpoints including progression-free survival (PFS) and toxicity.
Main Methods:
- Patients received ipatasertib 400mg orally daily in 28-day cycles.
- Exclusion criteria included known KRAS, NRAS, HRAS, or BRAF mutations.
- Primary efficacy analysis included 29 patients; ORR was the primary endpoint.
Main Results:
- The objective response rate (ORR) was 24.1% (7/29), meeting the primary endpoint (P < 0.001).
- All responses were partial responses, with a median response duration of 10.1 months.
- Common toxicities included diarrhea, nausea, and hyperglycemia; Grade 3/4 events were consistent with AKT inhibition.
Conclusions:
- Ipatasertib demonstrated clinically significant activity in heavily pretreated patients with AKT1E17K mutant tumors.
- The study met its primary endpoint, supporting ipatasertib's role in this specific patient population.
- Further research may explore ipatasertib in combination therapies or earlier lines of treatment.
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