Skip to main content
Premium Trial:

Request an Annual Quote

AstraZeneca's Capivasertib, Fulvestrant Combo Shows Promise in AKT1 E17K-Mutated Breast Cancer

NEW YORK – Researchers reported results from a Phase I study comparing AstraZeneca's investigational AKT inhibitor capivasertib alone or in combination with the endocrine therapy fulvestrant in AKT1 E17K-mutated, estrogen receptor-positive metastatic breast cancer patients in Clinical Cancer Research this week.

The study, led by Lillian Smyth of St. Vincent's University Hospital, found that the AKT inhibitor either alone or in combination with fulvestrant was efficacious in this molecularly defined subset of patients, including in those who had previously received fulvestrant and started progressing. The efficacy and safety of the combination regimen was "marginally better" than capivasertib monotherapy.

"Furthermore, our data provide a rationale for incorporating potentially actionable alterations in breast cancer into diagnostic testing algorithms for the early identification of these alterations in the metastatic disease course," Smyth and colleagues wrote in the paper.

The analysis was performed on 63 heavily pretreated patients. Patients had their AKT1 E17 K mutation status detected in tissue samples by local next-generation sequencing or central blood-based testing with Sysmex Inostics' OncoBEAM. Of those, 20 received capivasertib monotherapy and 43 received the capivasertib and fulvestrant combination.

In the monotherapy group, the overall response rate was 20 percent. In the combination cohort, overall response rate was 36 percent in those who received fulvestrant previously and 20 percent in patients who did not. Additional analysis revealed that patients in both the monotherapy and combination arms who received fewer than two prior lines of chemotherapy responded better to treatment than those who received more than three prior lines.

"This study demonstrates that AKT1 E17K is a clinically relevant, valid target in ER-positive breast cancer and that the AKT inhibitor capivasertib is tolerable and active as both monotherapy and in combination with fulvestrant, including in patients with prior fulvestrant resistance," the authors wrote.

In ER-positive breast cancer, the PI3K pathway is commonly activated. About 7 percent of ER-positive breast cancers induce activation of this pathway through AKT1 mutations, most commonly through AKT1 E17K. Researchers stated that this genomic subgroup may not respond as well to PI3K inhibitor therapy.

In the National Cancer Institutes' MATCH trial, capivasertib was explored in a pan-cancer fashion and yielded some encouraging signals in breast cancer patients who were hormone receptor-positive. 

In this latest study, researchers conducted exploratory biomarker analysis on plasma samples using NGS and ddPCR, which detected AKT1 E17K mutations in 33 out of 41 patients and 31 of 41 patients, respectively. Researchers reported that when there was at least a 50 percent decrease in AKT1 E17K mutant copies per mL of plasma from baseline to the start of the second cycle of treatment, patients were more likely to have improved treatment-related progression-free survival. The authors wrote that this finding suggests that plasma-based analysis may provide an "additional diagnostic opportunity" in this setting.

"With other genomic biomarkers such as PIK3CA mutations expected to become part of routine management paradigms over the coming years in breast cancer, these data have the prospect of becoming part of a rationale to incorporate other potentially actionable alterations in breast cancer, including ERBB2 and AKT1, into diagnostic testing algorithms and for the early identification of these alterations in the metastatic disease course," the authors wrote.