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Beat AML Umbrella Trial Demonstrates Feasibility of Rapid Precision Medicine Approach

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ORLANDO – In the Beat AML umbrella trial, researchers were able to employ a rapid precision medicine approach that allowed older, previously untreated patients with acute myeloid leukemia to receive first-line treatments based on the molecular profile of their cancer. 

Across the study's various arms, those who received a precision approach lived significantly longer than those who received standard-of-care treatments. The investigators plan to further explore the efficacy of the specific biomarker-guided treatments, as well as combination approaches, with biopharmaceutical partners. 

"We know now that AML is a heterogeneous disease. It is driven by the serial acquisition of mutations that leads to interpatient heterogeneity, both in biology and clinical response," Amy Burd, a co-lead author of the Beat AML study, said at the American Society of Hematology Annual Meeting. Burd is VP of research strategy for the trial at the Leukemia & Lymphoma Society (LLS).

According to the LLS, treatments for AML have not improved much in over 40 years despite being the most lethal of blood cancers. Although in recent years targeted treatments have become available, chemotherapy remains the mainstay, which can be toxic and damage patients' bone marrow. Stem cell transplants may be an option, but that can also lead to complications. 

This year in the US, an estimated 21,400 patients will be newly diagnosed with AML, and nearly 11,000 patients will die from the cancer. Only around 25 percent of patients survive for three year or longer and may be potentially cured. Younger patients have a better shot at remission, with around 65 percent of those under 60 years of age achieving it. 

Meanwhile, the median age for AML diagnosis is 65 years old, and these older patients tend to have worse outcomes upon starting treatment and their duration of remission tends to be shorter. The five-year survival rate is below 20 percent for patients over 60 years old. 

The LLS started Beat AML in 2016 aiming to advance new precision therapies for those 60 or older and treatment naive. The US Food and Drug Administration in recent years has approved several targeted drugs for patients with mutations in genes such as FLT3, IDH1, and IDH2. Given the increasing evidence of efficacy for targeted therapies, the Beat AML investigators hypothesized that it may be possible to improve outcomes in patients by matching them to a drug based on the molecular characteristics driving their leukemia. 

In the trial, investigators employ an algorithm that matches patients to biomarker-treatment arms such that each patient has the best chance at a durable benefit. If, for example, patients have core binding factor AML associated with various well-known chromosomal rearrangements, there's data suggesting that they may be cured with chemotherapy, and in Beat AML they'll receive chemo. If they harbor an IDH1 or IDH2 mutation, they would receive a drug that targets those mutations, since there's data showing such a strategy may result in a durable benefit. 

However, since older AML patients tend to accumulate multiple mutations, the treatment matching algorithm also factors in the genomic mutation at the "root of the AML," John Byrd, the co-lead author of the Beat AML trial and a cancer researcher at the Ohio State University Comprehensive Cancer Center, explained in an interview. 

"If you think of a dandelion, if you don't pull out the root, it's going to come back," he said. With this in mind, the Beat AML trial assigns targeted therapy that can inhibit the gene mutation that's driving the dominant clone in the AML. If patients don't have a biomarker to match to a treatment arm in Beat AML, they can receive a broad-acting agent or get an investigational drug in a different trial. 

"Ultimately, all decisions are made based on what's best for the patient," LLS' Burd said. "Even if that means a study outside of the Beat AML study." 

The primary goal of the Beat AML study, however, is to try to address the lengthy turnaround times for in-depth genomic analysis that is the precursor to prescribing precision approaches. Leukemia patients, who often present with aggressive disease, are usually initiated on treatment that same day. Large next-generation sequencing panels can take weeks. 

One previous retrospective analysis in which the median time from diagnosis to treatment was eight days suggested that waiting that long for lab results before putting patients on treatment may not negatively impact their survival. The Beat AML trial prospectively tested out the feasibility of putting patients on a matched drug based on genomic profiling within a week of diagnosis. 

In Beat AML, patients had to have three types of analysis: local cytogenetics with central review, next-generation sequencing on Foundation Medicine's FoundationOne Heme, and assessment of FLT3 internal tandem duplication and tyrosine kinase domain mutations using Invivoscribe's LeukoStrat CDx. At the ASH Annual Meeting, LLS' Burd and colleagues showed that it is possible to perform these analyses in seven days, with nearly 95 percent of 395 eligible patients assigned to different cytogenetic or genomic treatment groups within Beat AML in that time frame. 

"Turning molecular tests around for big genes, such as TP53, where you have to sequence the whole gene, is a big deal," said OSU's Byrd. "Foundation has worked really hard [to do that]. It's been a team effort. Probably the most important thing for this population is to turn the test around quickly."

FoundationOne Heme analyzes hundreds of genes via DNA and RNA sequencing and is intended to be used to subtype patients with hematologic malignancies, as well as inform their prognosis and treatment strategies. When the whole panel is performed, the turnaround time is between 14 days and 21 days. But in the BeatAML study, Foundation Medicine tested patients for mutations in eight genes using this test.

If there was any doubt at the start of the study that Foundation would be able to meet the seven-day time frame, the data clearly show that the lab was able to meet it and that waiting seven days to give therapy didn't negatively impact patient outcomes. Jo-Anne Vergilio, senior director of pathology at Foundation Medicine, said that to date, the lab's median turnaround time for the eight genes is six days, and the lab has met the seven-day time frame for 95 percent of the samples.

According to LLS' Burd, the Beat AML findings show that "a delay in treatment that allows for genomic [analysis] is safe and doesn't impact the overall survival." The data suggest that it may even extend the overall survival for patients if they go on to a molecularly-informed therapy compared to the standard of care, she added. 

Out of the 394 assigned to a treatment arm with in Beat AML, 224 patients actually went on to receive a treatment within one of the biomarker substudies, while 171 patients decided to receive either standard of care, an alternative investigational therapy in another study, palliative care, or other treatment. Patients who received treatments using a precision approach within Beat AML had significantly longer median overall survival compared to those who received the standard of care, 12.8 months versus 3.9 months. However, Burd noted median overall survival was not reached for those who chose to have an investigational therapy within another trial.

The 30-day estimated death rate was 20.4 percent for those on standard-of-care treatments, and 72.6 percent for those on palliative care. In contrast, the death rate was 3.7 percent for patients receiving treatments within a Beat AML substudy and 0 percent for those receiving investigational drugs on other studies.

To OSU's Byrd, these promising data are a sign that forthcoming treatments for myeloid cancers have the potential to really change the treatment landscape. "We're at an incredible place in cancer therapy in general but in myeloid malignancies particularly, where we have tons of exciting targeted drugs that as we combine them have the potential to really have an impact," Byrd said. "We're just starting to see that." 

However, since 171 patients decided not to go on a Beat AML substudy, one oncologist wondered why that was after Burd's presentation at the meeting, and what some of their reasons were. Burd noted that Beat AML didn't track the reasons why some patients opted for alternative treatments. 

The hope within umbrella trials is to ultimately find early efficacy signals for biomarker-guided drugs in small cohorts of patients. If there are signs of activity then the drug is graduated to testing in larger trials. If the activity is lackluster, then the arm is retired. According to Burd, the investigators have closed one therapy arm looking at patients with tp53 mutations due to lack of efficacy, though she didn't specify the specific treatment. 

There are currently 11 actively recruiting arms in Beat AML. OSU's Byrd said except for the one retired substudy, all other arms have shown patient benefit and will move on to the next stage of evaluation. 

"The future direction of the trial is to build upon the response data that's already been seen with some of our drugs, and [study] combination therapies going forward," LLS' Burd added, noting that the trial will explore novel combinations with pharma partners, with the goal of getting patients to experience more durable responses. 

As the study progresses, Burd believes that Beat AML will ultimately help shift the paradigm of how AML is treated toward more precision medicine approaches. She envisions that the umbrella trial could also be a model for exploring precision medicine strategies for young AML patients, and for those with other myeloid malignancies.