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DUBLIN, IRELAND-Treatment with capivasertib, a drug designed to work against a particular gene mutation found in some tumors, shows signs of being effective in a trial of 35 patients presented at the 2018 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (Abstract 001).


The phase II trial (EAY131-Y) is part of a larger study, called NCI-MATCH (EAY131), which aims to determine whether cancer patients can be treated successfully by selecting therapies that target gene abnormalities found in their tumors, rather than by cancer type.


Researchers say their results provide further evidence that the approach of tailoring treatment according to tumor genes could offer more effective treatments for individual patients in the future. The more traditional approach is to treat patients based on what has worked in the past for other patients with the same type of cancer.


The research was presented by Kevin Kalinsky, MD, Assistant Professor of Medicine, New York Presbyterian-Columbia University Irving Medical Center. "Capivasertib can be taken by mouth and it's a type of drug called an AKT inhibitor. This means it binds to a molecule called AKT that has mutated a change that plays a role in helping cancer cells grow," he explained. "In a prior phase II study, capivasertib has shown potential in treating an aggressive form of breast cancer.


"In this trial, we wanted to see if capivasertib could be used in patients with any type of cancer whose tumors have the mutation that leads the AKT molecule to become overactive and make the cancer grow."


Key Findings

Patients were selected by having the cells from their tumors tested. Each of the 35 patients in the trial was carrying the AKT mutation in the cells of their tumor. Although this mutation occurs in several different types of cancer, overall it is rare. Researchers found the mutation in 1.3 percent of patients (70 of 5548) tested centrally in the NCI-MATCH trial.


In all patients on the EAY131-Y study, the cancer had spread to other parts of the body, and most had already received three or more previous treatments. The patients were treated with capivasertib, taken by mouth twice a day, in weekly cycles of 4 days with treatment and 3 days without treatment.


Patients' tumors were measured by imaging, such as CT scans, before and after treatment. In the best confirmed responses, the tumor reduced in size in eight patients (23%), and in 16 patients (46%) the tumor did not grow but did not shrink either. In three patients (9%), the tumor grew.


Researchers observed the following side effects from the drug, saying that physicians should carefully manage these in patients being treated with capivasertib: high blood sugar, fatigue, diarrhea, nausea, vomiting, and skin rash.


"Overall, 23 percent of the patients in our trial experienced a positive response, which was defined as tumor shrinkage from before they started capivasertib," Kalinsky said. "We determined in advance that if 16 percent of patients experienced this response from the treatment, it would be a signal to move the drug on to a larger trial. This is a positive finding in a trial with patients whose cancers continued to grow despite previous treatments."


Researchers estimate that, 6 months after the treatment, the percentage of patients alive and without their tumors growing was 52 percent.


"This study is a limited but important piece of evidence. More trials are needed to learn the benefit in each tumor type and to understand why some patients did not have a response while others had a prolonged time without tumor growth," Kalinsky added.


Charles Swanton of the Francis Crick Institute, London, Scientific Co-Chair of the EORTC-NCI-AACR Symposium commented on the research. "Although we understand more than ever about the role of genes in different cancers, there is still a lack of evidence on using this knowledge to guide treatments and improve patient survival," he noted. "Outside of a trial setting, this approach is not widely available.


"This study is a small but important piece of evidence and it's part of a larger study that will help us move towards more personalized cancer treatments," Swanton concluded. "This trial approach is particularly important for those with rarer cancers where we know less about which treatments are most effective and conducting patient trials is difficult."


The larger NCI-MATCH study is ongoing with 39 subprotocols that are testing different drugs or drug combinations matched to other tumour gene abnormalities.