NEW YORK – The clinical launch of the FoundationOne RNA test in May could potentially open new companion diagnostic market opportunities for Foundation Medicine and advance the Roche subsidiary's overarching strategy of supporting cancer patients' treatment decisions through all stages of diagnoses, according to a company executive.
The RNA sequencing-based tissue-based test, which Foundation initially launched last year for research and investigation use, detects cancer-related fusions in 318 genes in all solid tumors. Now, by making FoundationOne RNA available for clinical use, the firm hopes to partner with pharmaceutical companies that want to use it to explore new therapeutic modalities, such as antibody-drug conjugates (ADCs), bispecifics, and protein degraders that may benefit from the use of RNA expression signatures, said Dave Fabrizio, Foundation's VP of partner innovation.
Foundation's existing DNA tests, the tissue-based FoundationOne CDx and plasma-based FoundationOne Liquid CDx, have multiple companion diagnostic indications and are widely used. By comparison, FoundationOne RNA's ability to gauge gene fusions allows users to "characterize the state of [a] tumor a little bit more completely," Fabrizio said.
"DNA characterizes the genotype; those mutations are not changing in a dynamic nature," he explained. "RNA is much more dynamic, and it represents [the] biological state your tumor cells [are in] at any given point in time."
While Foundation already has an RNA-based test, FoundationOne Heme, that assay is intended for hematologic malignancies with an emphasis on fusion calling, Fabrizio noted. And although the company will pursue companion diagnostic indications with the US Food and Drug Administration for FoundationOne Heme in the future, FoundationOne RNA enables the firm to expand its fusion calling services to the solid tumor setting.
The company envisions drugmakers will want to use the test to develop more precise RNA-based therapies, such as ADCs, which are typically designed to bind to a highly expressed protein on a tumor cell and release a toxic payload that kills it. However, there are "more nuances" to be considered when understanding how well an ADC might work in the body, for example, how that toxic payload may affect the surrounding cells, Fabrizio noted.
Although it's still early days for FoundationOne RNA, the company is betting that a test that measures the RNA expression signatures within a tumor cell can provide drugmakers with a deeper mechanistic understanding of their ADCs and home in on the patients most likely to respond. To date, Foundation hasn't publicly disclosed any collaborations in which FoundationOne RNA is being used as a companion diagnostic in drug trials, but according to Fabrizio, researchers and pharmaceutical companies have expressed interest.
The company also hasn't shared data on the test's ability to predict patients' responses to ADCs or other drugs in clinical trials, although Fabrizio said the firm is currently running several studies evaluating FoundationOne RNA's capabilities in this regard. "We don't know exactly where or how [the expression signatures] will be useful, but we know it's more information," Fabrizio said.
The default strategy for many drug developers, particularly those developing ADCs, is to use immunohistochemistry staining to gauge a single protein biomarker because "usually they're targeting just one thing on the cell" with their drugs, and IHC employs well-understood technology. Despite IHC being a widely used, low-risk tool, in Fabrizio's view, using it to gauge individual biomarkers is a "myopic" strategy.
At a time when patients with certain tumor types, like non-small cell lung cancer, can be eligible for multiple FDA-approved treatments based on the biomarkers driving their tumors, using IHC, they may run out of tissue before they are fully evaluated for all their treatment options.
Recognizing that lack of tissue is often a barrier to getting precision medicines, Foundation uses a novel co-extraction methodology that reduces the tissue input burden for those seeking both RNA and DNA sequencing, according to Fabrizio. "In other words, you don't need twice as much tissue to get twice the information," he said.
In clinically launching FoundationOne RNA, Foundation is also aiming to broaden access to more complex biomarker tests that, to date, have been largely performed at research institutions. While many researchers have "made headway" in identifying RNA signatures associated with certain therapies, assessing these biomarkers usually requires whole-transcriptome sequencing, which often isn't available to patients unless they're at an academic medical center, Fabrizio noted.
However, a clinician may not need all the information provided by a whole-transcriptome sequencing test when trying to decide if a patient will respond to a particular drug. FoundationOne RNA is intended to capture "a subset of that transcriptome," he said. Instead of investigating 22,000 genes, the test is looking at 1,500 genes based on what Foundation expects to be the most biologically relevant. The firm has tried to "build a bridge between that research discovery and a clinical commercial solution," Fabrizio said.
Foundation is performing this assay in its CLIA-certified laboratory, but like it did with FoundationOne CDx, the firm plans to eventually seek marketing approval from the FDA, Fabrizio said. Clinically launching the laboratory-developed test ahead of FDA approval allows Foundation to gather the necessary clinical validity data on FoundationOne RNA through partnerships with pharmaceutical firms, institutions, and academic researchers interested in the role gene expression signatures play in drug response.
Eventually, Foundation hopes to publish the data it generates with its partners and use it to further develop the test or design clinical trials that explore additional uses, Fabrizio said. For example, FoundationOne RNA's ability to detect complex expression signatures can be harnessed for determining the molecular subtypes of certain cancers. Cancer subtyping to determine, for example, if a breast tumor is luminal A, luminal B, HER2-enriched, or basal- or normal-like can also inform treatment selection or be used to enroll patients into clinical trials.
The firm is taking a "platform-level validation" approach to FoundationOne RNA, according to Fabrizio, by first generating analytical validity evidence across all the genes that the test covers. Using the same core gene set, Foundation can then generate clinical validity evidence on the test's ability to guide treatment with specific drugs and submit that data in supplemental premarket approval applications to the FDA seeking specific CDx claims.
Beyond FoundationOne RNA, the firm is also building out use cases for its other less-established tests for therapy monitoring, FoundationOne Tracker and FoundationOne Monitor. The former is the company's clinically available tumor-informed therapy monitoring assay that measures circulating-tumor DNA as a correlate to how much disease is left in a patient's body and indicates how well a patient's cancer is responding to treatment. FoundationOne Monitor is the "next evolution" of the firm's therapy monitoring strategy, a tumor-naive test intended for patients who do not have a recent tissue biopsy or can't provide a tissue sample.
Foundation's biopharma partners are using FoundationOne Monitor, which gauges ctDNA in blood, in retrospective and prospective clinical trials to understand how patients respond to different therapies and explore how the test results complement imaging data, Fabrizio said.
The newer tests like FoundationOne RNA, Tracker, and Monitor, alongside its more established tests like FoundationOne CDx, Liquid CDx, and Heme, fall under the firm's overarching aim of ensuring cancer patients have an assay available to support every stage and scenario they may encounter, even if they have minimal tissue for testing or stopped responding to treatment.
As the patient receives treatment, for example, the company's therapy monitoring tests can measure response, but if the drug isn't working, a clinician can use FoundationOne CDx, FoundationOne Liquid CDx, or FoundationOne RNA to go back to the drawing board and determine if another therapy may work better. The "idea is to provide as many shots on goal as possible for the patient," Fabrizio said.