Targeting mutant AKT1 has antitumor activity in a basket trial of patients with AKT1-mutant tumors.

  • Major finding: Targeting mutant AKT1 has antitumor activity in a basket trial of patients with AKT1-mutant tumors.

  • Clinical relevance: Decreases in AKT1E17K levels in cell-free DNA are linked to improved progression-free survival.

  • Impact: The oncogenic AKT1E17K mutation may be therapeutically targeted in multiple tumor types.

AKT1E17K is an oncogenic gain-of-function mutation that occurs infrequently but in diverse tumor types. To determine if AKT1E17K-positive tumors are sensitive to AKT inhibition, Hyman and colleagues tested the safety and activity of the ATP-competitive pan-AKT kinase inhibitor AZD5363 in a multicohort basket study of patients with AKT1-mutant solid tumors including estrogen receptor (ER)–positive breast cancer, triple-negative breast cancer, gynecologic cancer, lung cancer, prostate cancer, and colon cancer. A total of 58 heavily pretreated patients with AKT1-mutant tumors (90% of whom harbored the AKT1E17K mutation) were treated with AZD5363. The primary endpoint was safety, and secondary endpoints included progression-free survival (PFS) and response. The most common grade ≥3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Confirmed partial responses were observed in 4 patients with ER-positive breast cancer, 2 patients with endometrial cancer, 1 patient with cervical cancer, 1 patient with triple-negative breast cancer, and 1 patient with lung adenocarcinoma. Median PFS among heavily pretreated AKT1E17K-mutant tumors was 5.5 months in patients with ER-positive breast cancer, 6.6 months in patients with gynecologic cancer, and 4.2 months in patients with other solid tumors. Reductions in AKT1E17K levels in cell-free DNA (cfDNA) were associated with improved PFS, but responses were observed even in patients where AKT1E17K was undetectable in cfDNA. Exploratory analysis of sequencing data from pretreatment biopsies revealed that both the pattern of co-mutated genes as well as the clonality and allelic configuration of the sensitizing AKT1 mutation conditioned the depth and durability of treatment response. Specifically, co-mutation of PIK3CA/MTOR and allelic imbalance were both associated with improved PFS. Collectively, these findings indicate that AKT1E17K may be therapeutically targeted by AZD5363 in patients with diverse tumor types.

Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL, Dean EJ, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol 2017 May 10 [Epub ahead of print].

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