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Researchers Laud First Prospective Evidence of Functional Precision Medicine Benefit

Blood samples

NEW YORK – Since a group of Austrian researchers published results in Cancer Discovery a few weeks ago showing that a functional precision medicine approach improved patients' survival, discussions have rippled through the field about the study's implications for personalized cancer medicine and how, logistically, researchers in other health systems might replicate the work.

The EXALT-1 prospective trial, short for Extended Analysis for Leukemia/Lymphoma Treatment, demonstrated that testing patients' samples for drug response ex-vivo and then treating them accordingly could improve survival for those with blood cancers, such as acute myeloid leukemia, acute lymphoblastic leukemia, and B-cell and T-cell non-Hodgkin lymphomas.

The trial design, in theory, was not all that different from a genomically matched umbrella trial such as NCI-MATCH, I-PREDICT, or the lung cancer-specific National Lung Matrix Trial. Consenting patients received genomic testing, followed by individualized treatment based on the results. In EXALT-1, however, therapy selection didn't rely on genomic sequencing results, but rather on information gleaned from directly treating patients' samples with a series of drugs ex vivo.

If live tumor samples — representing a model of tumors inside patients' bodies — shrink when exposed to a drug ex vivo, the idea goes, there may be a decent rationale for treating the patient with the same drug.

"Functional precision medicine assays represent a shortcut that bypasses a large proportion of the mechanistic understanding," explained Philipp Staber, who led the EXALT-1 trial and is a physician scientist and directs the lymphoma program at the University of Vienna. "These assays directly screen for functional compounds [and] provide a direct, quick, and individual drug selection for a specific cancer sample."

In other words, with functional testing, it isn't essential to understand the exact biological reason why a patient's cancer is responding to a drug; seeing the patients' cancer cells respond is enough to inform therapy decisions. 

EXALT-1 enrolled 143 patients with relapsed or refractory blood cancers after a median of three prior lines of treatment. Investigators ran these patients' fresh samples — biopsies, bone marrow aspirations, or peripheral blood samples — through an ex vivo functional precision medicine assay to determine if their cancer cells showed responses to 139 drugs. A molecular tumor board involving pharmacists, hematologist oncologists, biologists, pathologists, and specialists from laboratory medicine reviewed the functional testing results and generated treatment recommendations for each patient.

Of 56 advanced blood cancer patients who received recommended treatments, 54 percent experienced a meaningful benefit from the approach, which the researchers defined as significantly longer progression-free survival times than prior treatments. The median progression-free survival ratio — calculated as the time patients spent on matched treatment without progression divided by their time without progression on prior treatment — was 3.4. "This indicates that their individual progression-free survival on [functional precision medicine]-guided treatment more than tripled when compared to their most recent individualized response time," Staber and colleagues wrote in the Cancer Discovery paper.

After a year receiving matched therapies, moreover, 23 percent of patients still hadn't experienced disease progression, whereas the same had been true of just five percent of these patients on their previous treatments.

In the National Lung Matrix Trial, for comparison, in 15 out of 19 cohorts in that molecularly matched study there were either zero or single-digit response rates.

"Compared to other precision medicine trials, this is quite remarkable," Staber said in a web-based discussion with members of the Society for Functional Precision Medicine this week, highlighting the durable responses that he and his colleagues observed in EXALT-1.

Pharmacoscopy approach

The functional ex vivo testing approach, dubbed "pharmacoscopy," was used to screen patients' samples for drug responses. After staining the cancer cells and suspending them in wells containing different drugs, the test uses single-cell imaging via immunofluorescence paired with automated microscopy and machine-learning analysis to see which drugs led to cytotoxicity and reduced the fraction of cancer cells in the sample material.

The technologies in the ex vivo assay aren't particularly novel and are "used in many academic centers worldwide," Staber said. But they aren't routinely used to personalize treatment decisions for patients in an n-of-1 fashion because the approach hasn't demonstrated feasibility or survival benefit in prospective studies.

That may soon change. "This [Cancer Discovery] paper will become a classic because it is one of the first, if not the first, to be published to actually do this prospectively with the intent of demonstrating patient benefit," said Anthony Letai of the Dana-Farber Cancer Institute and president of the Society for Functional Precision Medicine, during a discussion of the EXALT-1 results. "All of us, myself included, have to publish more of this, but I think this is a superb start."

After EXALT-1, Staber and his team are now conducting a highly anticipated randomized study dubbed EXALT-2, in which 150 patients with aggressive hematologic cancers are randomized to three cohorts, and matched to treatment via comprehensive genomic profiling with Foundation Medicine's FoundationOneHeme or using the ex vivo functional assay approach, or given physician's choice of treatment. Researchers will compare patients' progression-free survival times across these cohorts.

Advantages, challenges

Proponents of the functional precision medicine approach believe it could get around the limited benefit seen with genomically matched precision oncology, and a number of groups are working on validating this.

"Genomics are important and have been helping us to deepen our molecular understanding of disease mechanisms, [but] the translation of these insights into effective treatments remains challenging," Staber said. While targeting driver mutations with available drugs can provide significant benefit among certain populations, the approach to date hasn't benefitted the majority of cancer patients. A low proportion of patients ultimately match to a therapy arm in precision medicine umbrella trials after genomic sequencing.

For example, published data from the NCI MATCH trial last year showed that just 12 percent of approximately 5,500 sequenced cancer patients received treatment based on molecular tumor markers.

In theory, because the utility of functional testing doesn't rely on a patient having an established molecular biomarker, the number of patients matched with a drug via ex vivo response testing could be much higher, if not universal.

Seeing the commercial opportunity in this approach, several functional precision medicine firms have sprung up in recent years hoping to validate these tests and market them as superior to genomically informed precision medicine. The testing approach used in the EXALT-1 trial, for example, sparked a spinout company from the Austrian Academy of Sciences, dubbed Allcyte, which was then acquired by Exscientia this past June.

Massachusetts Institute of Technology spinout Travera is another player in the space that aims to commercialize a broadly predictive biomarker that measures cell mass to predict drug efficacy.

"In theory, we should be able to run this assay for every drug, and in practice, we're finding out that that's exactly right," Clifford Reid, CEO of Travera, recently said about the approach. Reid, who spent much of his career in the commercial genomics space and was formerly CEO of sequencing technology firm Complete Genomics, moved to Travera when he realized the limits of genomically matched treatment approaches and is now an active member of the Society for Functional Precision Medicine.

Other firms are seizing the approach in new ways. SEngine, for example, is working on commercializing its high-throughput drug screening PARIS test as a diagnostic tool using patient-derived three-dimensional organoids. Notable Labs, meanwhile, uses functional precision medicine assays to in-license and repurpose failed targeted drugs for functional biomarker-defined patient populations.  

All these firms see tremendous potential in guiding cancer treatment with functional assays — be it in the place of genomic sequencing or via a combination of both approaches. Several of these firms have validated their tests in large-scale studies to the extent that they have shown their tests can predict drug responses with high sensitivity. Some of the firms have even prospectively validated the predictive capabilities of their approaches.

But showing that the drugs predicted to work by these functional assays are actually allowing patients to live longer will be key to the future success of this approach. And toward that end, there are still logistical hurdles to overcome.

"The Holy Grail for functional precision medicine approaches would be to really personalize treatment, to get to an N-of-1 therapy, and this is structurally quite challenging," Staber said.

First, researchers and commercial firms running these validation studies must have access to the hundreds of drugs they will test on patients' tissue or blood samples.

In Vienna, Austria, where EXALT-1 took place, this is not a major challenge, Staber explained, since the pharmaceutical companies offered two-month supplies of their drugs for free, and then, the insurance companies covered the off-label treatments for benefitting patients. This type of coverage-with-evidence schema is not common across health systems around the globe.

"This may be [possible] due to our insurance system in here in Austria," Staber acknowledged. "Maybe we are living on a cloud."

Additionally, in a discussion following his presentation to the Society for Functional Precision Medicine, several US-based researchers raised concerns about CLIA certification for the functional laboratory tests or needing an investigational device exemption from the US Food and Drug Administration to perform a clinical trial. The documentation and regulatory processes involved can be a challenge for studying new approaches like this.

Finally, the requirement that patient samples remain fresh and "living" during the functional testing procedure to maintain strong correlation with patients' drug responses places logistical challenges on functional precision medicine on the whole. While next-generation sequencing of formalin-fixed paraffin-embedded tissue samples can be done over the course of several weeks, fresh tissue needs to be tested shortly after biopsy.

The approach, wrote Staber and colleagues in Cancer Discovery, is "based on the collection of viable cells, the procurement of which requires an intimate interplay between different hospital departments, such as surgery, pathology, and laboratory."

Because Staber, as well as the firm Exscientia, envision a future in which a central lab can run patient samples and generate treatment recommendations on a commercial scale, the hope is that "real-time biopsy becomes common for personalized approaches [and] this hurdle can be expected to vanish gradually."

In the EXALT-1 trial, Staber said, the turnaround time from biopsy to treatment recommendation was five days, but "in well-optimized settings, [the approach in EXALT-1] or similar functional approaches can offer reports between 36 and 96 hours post sampling." However, turnaround times may be more of an issue outside of Austria, on a global scale.

Beyond the logistical barriers of obtaining the drugs, certifying tests, and transporting fresh samples, there is pervasive belief across much of the field, based on earlier failed studies using a limited roster of drugs and older technologies, that functional testing doesn't work. Researchers and commercial firms will need to contend with this.

"Too often, if you try to broach the topic of functional precision medicine, you often get a very uninformed response to the effect of, 'Well, we tried that and it doesn't work,'" Letai said in a discussion of the EXALT-1 study implications. "[But that was] 20-to-30 years ago when there was nothing but cisplatin and there were these chemo sensitivity in vitro assays that didn't work well enough for clinical use … and guess what? Everything has gotten better since then. Let's give it another try."