Ipatasertib Shows Significant Activity in Tumors With AKT1E17K Mutations

Results from the phase 2 MATCH trial (NCT06400251) show that ipatasertib demonstrated clinically significant activity in heavily pretreated patients with various tumors harboring AKT1^E17K mutations.^1,2

The total enrollment was 35 patients, 29 of whom 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 of patients had >3 lines of prior therapy (n = 19/29; 65.5%). The objective response rate (ORR) was 24.1% (n = 7/29; 90% CI, 11.9%–40.6%). %. All responses were partial responses. The median duration of response was 10.1 months (90% CI, 3.7–10.8). 

The 6-month progression-free survival rate (PFS) was 46.8% (90% CI, 30.9%–61.2%). The PFS was 5.5 months (90% CI, 3.6–12.9).

The most common adverse events (AEs) of any grade included diarrhea (n = 25), nausea (n = 13), and hyperglycemia (n = 9). Grade 3/4 AEs observed were consistent with reported AEs for AKT inhibition. Twelve grade 3 events occurred that were thought to be at least possibly related to treatment.

Serious AEs occurred in 38.24% of patients (n = 13/34). The most common serious AEs were anemia (n = 1/34), cardiac arrest (n = 1), diarrhea (n = 3/34), nausea (n = 1/34), and vomiting (n = 2/34). 

Patients received 400 mg orally once daily of ipatasertib in a 28-day cycle until progression or unacceptable toxicity. 

Patient inclusion criteria included but was not limited to having well-controlled diabetes, prior PI3K and mTOR inhibitors, and having castration-resistant prostate cancer with maintained castrate levels of testosterone.

Patient exclusion criteria included but was not limited to having known KRAS, NRAS, HRAS, or BRAF mutations; prior AKT inhibitors; hypersensitivity to ipatasertib or compounds of similar chemical or biologic composition; and a history of inflammatory bowel diseases or active diverticulitis.

The median age of patients was 63 years (range, 35–83). Of the 29 patients analyzed, 93.1% were female and 6.9% were male. Most patients were White (75.9%).

The primary end point was ORR. Secondary end points included PFS, 6-month PFS, and toxicity.

In commentary published along with the findings in Clinical Cancer Research, authors Ricardo Dahmer Tiecher, MD, and Alison M. Schram, MD, wrote, “Basket trials of AKT-mutated tumors show that pan-AKT inhibitors are active in hormone receptor–positive breast cancer. There is mounting evidence for AKT inhibition in other tumor types, although small sample sizes limit evaluation of the tumor-agnostic potential for AKT inhibition. Emerging AKT1^E17K–specific molecules may improve tolerability and efficacy.”³

REFERENCES

1.McCourt C, Wei Z, Kalinsky K et al. Ipatasertib in patients with tumors with AKT mutations: Results from the NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocol Z1K. Published and accessed December 1, 2025. Clin Cancer Res. (2025) 31 (23): 4912–4919. doi: 10.1158/1078-0432.CCR-24-3431.

2.Testing ipatasertib as potentially targeted treatment in cancers with AKT genetic changes (MATCH – Subprotocol Z1K). ClinicalTrials.gov. Updated November 20, 2025. Accessed December 2, 2025. https://clinicaltrials.gov/study/NCT06400251 

3.Dahmer Tiecher R, Schram A. Tumor-agnostic AKT inhibition: Is it time to AKT? Published December 1, 2025. Accessed December 2, 2025. Clin Cancer Res. (2025) 31 (23): 4863–4865. doi: 10.1158/1078-0432.CCR-25-2640.