Foundation Medicine recently announced a companion diagnostic partnership with Syndax Pharmaceuticals to identify AML patients with NPM1 mutations using a comprehensive genomic profiling (CGP) test based on the FoundationOne Heme platform. If approved, it could be the first NGS CDx test to detect genomic alterations in hematologic neoplasms.
NPM1 mutations are unique to AML patients and are the most frequently found genomic alteration, appearing in approximately 30 percent of newly diagnosed AML patients. There are currently no targeted treatments approved for patients with NPM1-mutated AML, and the 5-year overall survival for patients with NPM1-mutated AML is approximately 50 percent.
The partnership will include seeking regulatory approval of an assay based on the FoundationOne Heme platform, which has been used clinically for over a decade as a CGP test developed specifically for heme malignancies and was the CGP test used in the BeatAML Master Clinical Trial led by the Leukemia and Lymphoma Society.
“Blood cancers have a devastating impact on the lives of so many patients and their families,” said Ashley Yocum, executive research lead at the Leukemia & Lymphoma Society, in the Foundation Medicine partnership announcement. “Thanks to advancements in comprehensive genomic profiling, and decades of scientific research for new treatments, we are seeing a paradigm shift in how many types of blood cancer are diagnosed and treated, allowing more patients to benefit from the promise of precision medicine with access to more personalized treatment options.”
For decades, the standard of care for adult patients with acute myeloid leukemia (AML) has featured a combination approach of two chemotherapies, cytarabine and anthracycline. This approach falls short for many patients, with the NIH reporting a five-year overall survival rate of about 30 percent.
This unmet need has led to growing investment in the development of new, targeted therapies that can be used alone or in combination with standard chemotherapy to improve survival for patients with AML or those with other types of hematologic (heme) malignancies.
Response to these targeted therapies is associated with relevant biomarkers unique to each patient. There are currently six FDA-approved targeted therapies for heme malignancies that are associated with a specific biomarker today, such as for AML patients with FLT3, IDH1, or IDH2 mutations or for chronic myeloid leukemia (CML) patients with BCR-ABL fusions or PDGFRB rearrangements. In addition to these six treatment-relevant biomarkers, there are a number of additional biomarkers that, if tested for, provide information about prognosis, potential resistance, and clinical trials for which a patient may be eligible.
With a handful of approved biomarker-driven treatments, cytogenetic and single-biomarker tests or the use of hotspot panels has historically been enough — but that dynamic is changing and suggests the need for broader molecular testing, such as with CGP tests, to complement standard cytogenetic testing.
Dozens of genes are now recommended for testing in patients with heme malignancies, according to the 2022 WHO Classification, and studies have shown that genomic findings are highly frequent in patients with heme malignancies, including 90 percent of patients with AML who have somatic mutations according to a 2024 study in Blood Cancer. Mutations in these genes can be:
- Prognostic, in the setting of standard intensive chemotherapy,
- Predictive of therapy response, such as when menin inhibitors are combined with standard chemotherapy, and
- Targetable, as shown with FLT3, IDH1/2 mutations and BCR-ABL1 fusions approved to identify patients today and biomarkers such as NPM1 mutations and KMT2A rearrangements under investigation in clinical trials.
More than 40 biomarkers are being studied in clinical trials for heme cancers today, particularly in the relapsed and refractory settings where combinations of treatments may be needed to overcome drug resistance and improve remission rates.
In a recent series of presentations hosted by CancerNetwork, Ghayas Issa, medical oncologist at MD Anderson Cancer Center, said he believes routine broad molecular testing should be more common in these relapsed or refractory settings to identify new resistance variants or variants being targeted in clinical trials. For example, he said, NPM1 variants are common at diagnosis and will remain during relapse, but a new mutation in FLT3 can be acquired during treatment and change decision making.
FoundationOne Heme identifies those important NPM1 or FLT3 variants and many other biomarkers. FoundationOne Heme uses co-extraction to assess over 400 genes in DNA and 250 genes in RNA from a single sample to detect all four main classes of genomic alterations, including sensitive detection of fusions and genomic signatures like microsatellite instability and tumor mutational burden, to inform treatment decisions and enrollment in clinical trials.
Foundation Medicine has a track record of success with CDx submissions and is the global leader in approved CDx indications, with approximately 60 percent of all U.S. companion diagnostic approvals for next-generation sequencing (NGS) testing. This experience in solid tumors can be leveraged to support the ongoing CDx development for CGP testing in heme malignancies and this first announced partnership with Syndax Pharmaceuticals.
FoundationOne®Heme is a laboratory developed test that was developed and its performance characteristics determined by Foundation Medicine. FoundationOne Heme has not been cleared or approved by the U.S. Food and Drug Administration. For more information on FoundationOne Heme, please see its Technical Specifications at http://www.foundationmedicine.com.
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