AKT Inhibition in Solid Tumors With AKT1 Mutations

Abstract

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K–mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor–positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K–mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response (P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion 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.

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer

“…In most breast cancer series this is the most frequently altered potentially actionable pathway, thus these alterations are actively being pursued in trials with PI3K/AKT/ mTOR inhibitors. 2,23,24 CDH1 mutations, as expected, were almost exclusively found in invasive lobular carcinoma. CDH1 loss is pathognomonic for lobular carcinomas; the fact that we found CDH1 mutations in only 56% of patients suggests that CDH1 loss may also be mediated through non-genomic mechanisms.…”

“…Data is emerging that targeting some of these alterations, such as AKT and HER2 mutations, indeed may have antitumor efficacy. 1,2 Most proof-of-principle genomically-selected trials are conducted in the metastatic setting, while many molecular characterization efforts such as The Cancer Genome Atlas (TCGA) were performed in operable breast cancer. 3 In order to effectively design and interpret genotype-selected trials, it is critical to determine the genomic profile of patients with metastatic breast cancer (MBC), the frequency of genomic alterations as well as co-alterations, and to determine the impact of common alterations on prognosis.…”

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

“…These patients were diagnosed with one of 21 unique cancer types, the most common being breast, lung, bladder and colorectal cancer (61% of patients treated). As has been seen in other basket studies 10,11 , we identified and enrolled a number of orphan tumour types including cancers of the biliary tract, salivary gland, small bowel and vagina, as well as extramammary Paget’s disease (13% of all patients). Patients tended to be heavily pretreated with approximately half having received ≥3 prior lines of systemic therapy.…”

“…The initial generation of these studies focused on evaluating individual somatic mutations that were already clinically validated in one cancer (eg BRAF V600 in melanoma) in other tumour types 10,35 . More recently, basket studies have been used to generate initial or even practice-changing clinical data of truly novel genomic biomarkers, especially when these genomic alterations occur at low frequency across a wide distribution of cancer types 11,36,37 . SUMMIT extends this concept one step further by demonstrating for the first time how a single study can be used to simultaneously evaluate a range of individual variants in HER2 and HER3, each with varying degrees of prior biologic characterization.…”

A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers

“…are reported. Encouraging early response rates of the use of AZD5363 (6/21, 28%) with the schedules recommended in this study have been reported (25). Further efforts to improve outcomes by combining AZD5363 with fulvestrant in AKT-mutant breast cancer is ongoing.…”