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NCI-MATCH Patients With AKT1-Mutated Cancers Respond Well to AstraZeneca Drug


This article had been updated to correctly note that the data reported is from Arm Y of the MATCH study. 

NEW YORK (GenomeWeb) – New data from the National Cancer Institute's MATCH trial suggests that patients with a variety of cancers that harbor a specific mutation in the AKT1 gene may benefit from the investigational AstraZeneca AKT inhibitor AZD5363.

The data, presented this week at a conference in Dublin, Ireland, that is hosted by the European Organization for Research and Treatment of Cancer, the NCI, and the American Association for Cancer Research, is the latest output from NCI-MATCH, a study launched in 2015 that is employing a molecularly-informed, pan-cancer approach to improve the understanding of tumors and treatment response. AstraZeneca's AKT inhibitor AZD5363, also called capivasertib, was studied in one out of approximately 40 arms in NCI-MATCH that explore the efficacy and safety of drugs in diverse tumor types that have a molecular abnormality in common.

The new findings follow other NCI-MATCH results that were presented this summer. At the American Society of Clinical Oncology's annual meeting researchers reported data from the first three arms of NCI-MATCH. In arm W, response to AstraZeneca's investigational FGFR inhibitor AZD4547 was studied in patients who harbored different FGFR alterations. In arm Q, researchers looked for response to Genentech's Kadcyla (trastuzumab emtansine) among patients with HER2-amplified tumors other than breast and gastric cancers. In arm I, researchers studied patients with PIK3CA-mutated tumors who received Roche's PI3K inhibitor taselisib.

The responses seen in these arms had failed to impress attendees of the meeting. As Gail Eckhardt from the University of Texas at Austin and Christopher Lieu from the University of Colorado, Denver recently pointed out in JAMA Oncology, objective response rates were low in these three arms, ranging from 0 percent to 9.5 percent, and none of the drugs reached "the prespecified threshold of notable clinical activity."

In contrast, researchers led by Kevin Kalinsky, assistant professor of medicine at the New York Presbyterian-Columbia University Irving Medical Center, presented data at the meeting in Dublin this week showing that arm Y did meet its prespecified threshold for response. Out of 35 enrolled patients with the AKT1 E17K mutation who received AZD5363, eight saw their tumors shrink.

"At least 16 percent of patients needed to have shrinkage of their cancer in order for this to be a positive arm [of NCI-MATCH,]" Kalinsky said in an interview. "And our rate was 23 percent."

The AKT1 E17K mutation was detected in 70 patients, or about one percent, of the more than 5,500 who were centrally tested for genomic alterations as part of the NCI-MATCH trial. Most of the patients enrolled in this sub-study had invasive breast cancer (51 percent) and endometrioid cancer (23 percent), but there were also patients with rare tumor types that carried this mutation.

Kalinsky noted that researchers had previously presented data from another study that suggested benefit from the drug in triple-negative breast cancer patients who had AKT1 mutations and other pathway alterations. But in this arm, only three patients had triple-negative breast cancer, while most of the breast cancer patients had hormone receptor-positive tumors, suggesting that a more diverse group of breast cancer patients might be able to derive benefit from AZD5363.

Specifically, six of the eight partial responders had hormone receptor-positive, HER2-negative breast cancer, one patient had endometrioid adenocarcinoma, and one had a rare leiomyosarcoma.

An additional 16 patients, or 46 percent, had stable disease, which means their cancer did not grow or shrink while receiving AZD5363, or may have shrunk a little but not enough to meet the threshold for a partial response. One of these patients had a parotid gland tumor, a rare form of head and neck cancer. This patient is still on therapy, according to Kalinksy, and has been receiving the AKT inhibitor without signs of cancer progression for more than a year and a half.

The researchers estimated that the six-month progression-free survival rate was 52 percent. At this time, three patients are still on the study and have been on the drug for 14, 22, and 25 months. This is notable, according to Kalinsky, particularly because all the patients in the study have metastatic or unresectable cancers, and more than 50 percent had received and progressed on three prior treatments.

Based on the prior efficacy seen in breast cancer patients with this drug, AstraZeneca is likely to focus on advancing AZD5363 in this setting first. "But where NCI-MATCH becomes helpful is that we identified patients with much less common tumors than breast cancer who seem to really respond to this," Kalinsky said. "The goal is to come together and move forward with other studies in patients with rarer tumors, such as those with leiomyosarcomas or parotid gland tumors … to see if in a larger cohort, we can see responses."

In contrast to the clear efficacy signals coming out of this arm, the oncology community was disappointed with the results from the first three arms of NCI-MATCH reported at the ASCO annual meeting. Their expectations were high, given the responses seen in the variety of cancer patients with mismatch repair deficiency or high microsatellite instability treated with the immunotherapy Keytruda (pembrolizumab) and the success of the pan-cancer strategy with the TRK inhibitor larotrectinib.

Compared to these examples, the first three NCI-MATCH arms to report out data were not a ringing endorsement of the pan-cancer strategy but presented a far more complex picture of tumor biology and heterogeneity. For example, in arm W, involving the FGFR inhibitor AZD4547, the data suggested differential responses based on whether patients had FGFR fusions, point mutations, or amplifications.

In their JAMA Oncology piece, Eckhardt and Lieu wrote that that these first NCI-MATCH results offer an opportunity for learning and to apply those lessons to reducing imprecision in precision oncology. They wrote of the need to study drug combinations that target multiple driver or resistance pathways and to make use of pre-clinical models that help elucidate these pathways and allow researchers to investigate "rational combinations" of drugs.

"There is no doubt that these MATCH results represent a well-intentioned and coordinated attempt to deploy precision medicine in oncology," Eckhardt and Lieu wrote. "These results, along with others, represent the continual evolution of imprecise cancer biology and thus should drive us toward integrative and iterative strategies that improve the outcomes for our patients."

Kalinsky also reflected that NCI-MATCH offers researchers an opportunity to learn about tumor biology, for example, how different types of alterations in the same gene can differentially impact response to the same therapy. Additionally, he noted that because study sites are open in well over a thousand cancer centers around the country, it allows researchers to collect real-world data from diverse sets of patients who otherwise may not have been able to access an investigational drug like AZD5363.

Notably, in this sub-study, two patients, despite having the AKT1 E17K mutation, still progressed on the drug, while eight were not able to be evaluated. One of the two patients who progressed had a rare sarcoma and the other estrogen receptor-positive breast cancer.

Kalinsky's team did not identify any genomic alterations that could explain why these two patients didn't respond to AZD5363. Researchers, however, have collected tissue samples from study participants for exome and RNA sequencing analysis, and plasma samples for cell-free DNA analysis, which could provide additional insights into other mechanisms of sensitivity or resistance.

In this arm, there were 27 evaluable patients because some discontinued due to disease progression or toxicities. Diarrhea, fatigue, and rash were among the most common grade 1/2 drug-related adverse events in the study. Grade 3/4 adverse events due to the drug included elevated blood sugar, rash, and diarrhea. Within the first cycle of the drug, nearly half the patients required dose adjustments.

Since AZD5363 is being giving to patients within NCI-MATCH at academic and community sites, Kalinksky cautioned that researchers need to be more aware of the side effects of the drug and manage them appropriately. "As this drug is developed, we should be increasingly aware of how to manage the blood sugar spikes or manage the rash," he noted.