AZ drug matched to cancer mutation passes phase 2 test

A drug developed by AstraZeneca that targets a specific cancer mutation called AKT E17K has shown activity in a phase 2 trial involving a range of solid tumour types.

Capivasertib (AZD5363) – an orally-active AKT inhibitor – was tested in 35 patients with breast, endometrial and ovarian cancers who had already been treated with at least three prior regimens and showed a partial response rate in eight subjects (23%), with another 16 (46%) showing stable disease. More than half the patients were still alive after six-months.

Side effects “should be carefully managed,” according to an abstract of the EAY131-Y trial, which was presented at the EORTC-NCI-AACR (ENA) 2018 symposium in Dublin yesterday. The main toxicities were elevated blood sugar levels, fatigue, diarrhoea and nausea/vomiting, and skin reactions.

The trial is part of a larger study called NCI-MATCH that aims to determine whether cancer patients can be treated successfully by selecting therapies that target gene abnormalities found in their tumours, rather than by cancer type. AKT E17K is present in about 1% of all tumours and is particularly common in prostate cancer.

NCI-MATCH includes 39 subprotocols that are testing different drugs or drug combinations matched to other tumour gene abnormalities, to try to build a broader picture of the potential for personalised therapy matched to tumour profiles.

The first approvals for type-agnostic therapies have already been granted, with Merck/MSD’s Keytruda (pembrolizumab( and Bristol-Myers Squibb’s Opdivo (nivolumab) – both PD-1 checkpoint inhibitors – greenlighted for solid tumours with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) motifs, respectively.

Meanwhile, this isn’t the first clinical data for capivasertib, but adds to a growing body of evidence that the AKT class has potential.

At this year’s ASCO meeting, the results of the phase 2 PAKT trial in triple negative breast cancer (TNBC) showed that adding the drug to first-line therapy with paclitaxel resulted in significant extensions in both progression-free survival (to 4.2 from 2.9 months for paclitaxel alone) and overall survival (from 12.6 months to 19.1 months).

Drilling down into the data, the researchers found that capivasertib was only working in patients with mutations in PIK3CA, which is on the same molecular pathway as AKT and is also being targeted by experimental drugs such as Novartis’ alpelisib.

A rival AKT inhibitor from BioOncology – ipatasertib – also reported positive data at ASCO from the mid-stage LOTUS trial in first-line TNBC with similar gains seen, while ArQule also has preliminary results with its miransertib candidate and is due to provide an update at ENA later this week.

Presenting the EAY131-Y results, Dr Kevin Kalinsky of New York Presbyterian-Columbia University Irving Medical Centre said: “We determined in advance that if 16% of patients experienced this response from the treatment, it would be a signal to move the drug on to a larger trial.”

The 23% overall response rate “is a positive finding in a trial with patients whose cancers continued to grow despite previous treatments,” he added.