AKT Inhibitor Activity in AKT1-Mutant Solid Tumors
As reported by Hyman et al in the Journal of Clinical Oncology, a basket study has shown activity of an investigational ATP-competitive pan-AKT kinase inhibitor (AZD5363) in solid tumors with AKT1 E17K mutation.
Study Details
In the study, 52 patients with advanced estrogen receptor–positive breast cancer (n = 20), gynecologic cancers (n = 15), or other solid tumors (n = 17) refractory to standard therapy who had no known RAS/RAF mutations received AZD5363 at 480 mg twice daily for 4 days on/3 days off weekly in 21-day cycles. Patients had a median of five prior lines of therapy and no prior treatment with catalytic AKT inhibitors.
Responses and Biomarkers
Confirmed partial responses were observed in patients with estrogen receptor–positive breast (n = 4) and endometrial cancers (n = 2) and in those with cervical cancer, triple-negative breast cancer, and lung adenocarcinoma (n = 1 each). Unconfirmed partial responses were observed in estrogen receptor–positive breast cancer (n = 2), triple-negative breast cancer (n = 1), and anal cancer (n = 1). Median progression-free survival was 5.5 months in patients with estrogen receptor–positive breast cancer, 6.6 months in those with gynecologic cancers, and 4.2 months in those with other solid tumors.
In biomarker analyses, imbalance of the AKT1 E17K mutant allele (observed in 21 of 37 patients with samples adequate for analysis) was associated with longer progression-free survival vs absence of imbalance (median = 8.2 vs 4.1 months, hazard ratio [HR] = 0.41, P = .04); this imbalance was most frequently due to copy-neutral loss of heterozygosity with loss of the wild-type allele.
Improved progression-free survival was also associated with the presence vs absence of coincident phosphoinositide 3-kinase (PI3K) pathway hotspot mutations (median = not reached vs 4.3 months, HR = 0.21, P = .045). Persistent declines in AKT1 E17K in plasma cell-free DNA (maintained into treatment cycle 2) were associated with improved progression-free survival (median = 5.6 vs 2.6 months, HR = 0.18; P = .004) and with objective response (P = .025); all 5 patients with decline > 21 days had a response of >18 weeks. Responses were also observed in patients without detectable AKT1 E17K in pretreatment cell-free DNA.
Adverse Events
The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Drug-related serious adverse events occurred in 16%. Adverse events led to dose reduction in 34% of patients and to treatment discontinuation in 12%.
The investigators concluded: “This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.”
The study was supported by grants from the National Institutes of Health, Cycle for Survival, and Conquer Cancer Foundation of ASCO and AstraZeneca.
David M. Hyman, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
