Amultihistology basket study proved the targetability of the AKT1 E17K mutation in human cancers by treating patients with various types of cancer harboring an AKT1 E17K mutation with AZD5363, an oral pan-AKT inhibitor, according to findings published in the Journal of Clinical Oncology. 1 The PI3K/AKT pathway is one of the most frequently activated pathways across cancers and can be triggered by one of several mutations.
Although the AKT1 E17K mutation can be found in many cancer types, they nonetheless occur at a relatively low prevalence in individual tumor lineages despite being the most common AKT1 mutation. The oncogenic nature of these gain-of-function mutations means they can be targeted with an AKT inhibitor in the hopes of improving patient outcomes.
The safety and efficacy of the AKT inhibitor had previously been investigated in patients with PIK3CA-mutant estrogen receptor (ER)-positive breast cancer, HER2-positive breast cancer, or gynecologic cancers. Three of 51 patients experienced a partial response, and the optimal dose and schedule for AZD5363 was set.
In the basket study of patients with AKT1 mutations, 58 heavily pretreated patients were enrolled to receive 480 mg twice daily of AZD5363 on a 21-day cycle for 4 days followed by 3 days off, repeated weekly.
Of the enrolled patients, 52 showed expression of an E17K mutation, 2 patients had an E79K mutation, and 1 each had an F35L, T34N, or V201A mutation; one patient had an undetectable mutation. Patients were a median 59 years (range, 31-77) and had received a median of 5 treatment regimens (range, 1-14). A majority of the patients (91.4%) were female and had a WHO performance status of 1 (53.4%); the remainder had a performance status of 0.
Following enrollment, patients were divided into 3 cohorts based on the location of their primary tumor: ER-positive breast cancer (n = 20), gynecologic cancers (n = 18), and other solid tumors (n = 20) (Table).
Once treatment commenced, patient disease was assessed and analyzed at baseline, every 6 weeks for 6 months, then every 12 weeks until any occurrence of a significant change in progression or withdrawal. The primary endpoint of this study was safety; response according to RECIST v1.1 criteria and progression-free survival (PFS) were key secondary endpoints.
Partial responses were confirmed in AKT1 E17K-mutant patients, including in 4 patients with ER-positive breast cancer, 2 with endometrial cancer, and 1 patient each with cervical cancer, triple-negative breast cancer, and lung adenocarcinoma. One patient with ovarian cancer with a Q17K mutation experienced stable disease and tumor regression lasting 14 months.
In treated patients with E17K mutations, the median PFS was 5.5 months (95% CI, 2.9-6.9) for patients with ER-positive breast cancer, 6.6 months (95% CI, 1.5-8.3) for gynecologic cancers, and 4.2 months (95% CI, 2.1-12.8) for other solid tumor types. Researchers concluded that there was no apparent correlation between tumor type and response.
Grade ≥3 adverse events (AEs) were observed in 70.7% of patients, and 51.7% were deemed to have a casually related AE, as assessed by the investigator. Hyperglycemia (24.1%), diarrhea (17.2%), and maculopapular rash (15.5%) were the common grade ≥3 AEs reported. A dose reduction was necessitated in 34% of patients, with the above AEs being the leading causes. Serious AEs were experienced by 15.5% of patients, and the authors, led by David M. Hyman, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, noted that the toxicity profile was consistent with that of previous studies with AZD5363.
Prior to treatment, researchers collected and sequenced tumor samples and tumor-derived cell-free DNA (cfDNA) for retrospective and comparative analysis purposes and to see whether response could be predicted through examination of biomarkers. Interestingly, in 1 evaluable sample in which the AKT1 E17K mutation could not be confirmed in either cfDNA or archival tumor, the patient experienced rapid disease progression.
During cycle 1, a ≥50% decrease in the AKT1 E17K mutant allele in cfDNA was observed in 22 of 23 patients (95.5%) that showed no correlation with response. Observations of an ongoing decrease in mutant alleles going into cycle 2 showed an association with an increase in PFS (median PFS, 5.6 vs 2.6 months in those who did not demonstrate a decline; HR, 0.18; P = .004). Five patients experienced a clearance of AKT1 E17K mutant alleles in cfDNA lasting more than 21 days that correlated with objective responses lasting ≥18 weeks (P = .025).