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Ex Vivo Drug Screening Identifies Personalized Treatments for Most Pediatric Cancer Patients in Trial


NEW YORK – A prospective study of First Ascent Biomedical's ex vivo drug screening platform plus genomic profiling has demonstrated the feasibility of the functional precision medicine approach to guide treatment of relapsed or refractory pediatric cancers.

The trial included 25 pediatric or adolescent patients with relapsed or refractory solid tumors or hematological cancers, and 19 patients received treatment recommendations based on their drug sensitivity testing and genomic profiling, also called functional precision medicine (FPM). First Ascent conducted the trial of its drug testing platform, dubbed xDRIVE, in collaboration with Nicklaus Children's Hospital in Miami and Florida International University. The results were published this month in Nature Medicine.

The study participants represented a range of solid and blood cancers, including osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, glioblastoma, medulloblastoma, neuroblastoma, astrocytoma, and Wilms tumor. Three-quarters of patients in the trial had a solid tumor, and one-quarter had a hematological malignancy.

The researchers noted this was the first trial to evaluate an FPM approach in pediatric solid and hematological cancers. They pointed to two recent studies of this approach in Europe, but both were in adult hematological cancers. Both of those studies showed the method provided clinical benefit for those patients.

"When we look at early-stage disease, most cancers have treatment options available, but that starts to become much more challenging when we get to the advanced disease," said Noah Berlow, cofounder and chief technology officer at Beaverton, Oregon-based First Ascent and an author of the latest study. "If a patient has been through multiple lines of therapy, they generally exhaust standard of care and will end up with few treatment options available [at later stages]. This is exceptionally true in pediatric cancers where there's also very often few, if any, clinical trials available, so the need for treatments in pediatrics is really pronounced."

Clinical outcomes

In the trial, patients provided tumor samples for genomic and drug sensitivity testing. Genomic analysis was conducted at the University of California, San Francisco's Clinical Cancer Genomics Lab using its next-generation sequencing-based UCSF500 cancer gene panel, which screens for mutations in more than 500 genes. Drug sensitivity testing, meanwhile, was performed on cells derived from patients' tumor samples at First Ascent's lab.

The trial's functional precision medicine tumor board (FPMTB) made treatment recommendations for 19 patients who had both genomic profiling and drug sensitivity testing results. Of the 14 patients who received therapeutic recommendations from the FPMTB, six received a functional precision medicine-guided treatment and the others received a non-FPM guided treatment of their physician's choice.

Five of the six patients who received an FPM-guided treatment achieved an objective response of partial response or better, and the one remaining patient achieved stable disease. Only one of the non-FPM treatment patients, however, achieved an objective response.

The researchers also evaluated patients' progression-free survival. Because the study population was small and heterogenous, the researchers evaluated progression-free survival against the individual patient's prior line of therapy. In the FPM-guided cohort, progression-free survival was longer on the FPM treatment than their previous treatment. The FPM group also had a longer progression-free survival on treatment than the non-FPM group.

They highlighted one "exceptional responder" in the FPM group, a patient with acute myeloid leukemia who received Novartis' Rydapt (midostaurin) due to the identification of an FLT3-ITD mutation. Drug sensitivity testing further found that Rydapt had the highest efficacy compared to other treatments such as Bayer's Nexavar (sorafenib) and Takeda's Iclusig (ponatinib). The sensitivity testing also showed that the patient only needed two types of chemotherapy, as opposed to three, which reduced toxicity. It also found that the steroids the patient was receiving were contributing to acute proliferation of cells, and the patient was taken off of that treatment.

The patient achieved a complete response on the FPM treatment plan, which also increased the durability of their second bone marrow transplant. This patient remains cancer free after more than two years, which is twice the progression-free survival of their first bone marrow transplant, the researchers wrote.

The researchers concluded that these data suggest FPM-guided treatment leads to better outcomes than physician's choice treatment in pediatric patients with cancer.

"The most important takeaway is that it works, that we can do this," said Diana Azzam, cofounder and scientific adviser to First Ascent and senior author of the study. "It's highly resource intensive, but it can be done. We have these technologies in the lab [and] we want to start implementing them in the clinic, and it has to be a huge collaborative effort between the physicians and wanting to use these tools and technologies that researchers have developed."

Feasibility testing

As part of the study, the researchers were also evaluating the feasibility of an FPM approach that combines genomic profiling and First Ascent's xDRIVE platform.

From the original group of 24 patients enrolled in the trial, drug sensitivity testing was successfully performed for 21 patients and genomic profiling was successfully performed for 20 patients. Two patients had insufficient sample size for both drug sensitivity testing and genomic profiling, and one patient had unsuccessful drug sensitivity testing. However, the researchers noted that they originally expected 60 percent of enrolled patients to have results from both tests and ended up having results for 76 percent of enrolled patients.

The drug sensitivity testing platform tested up to 125 drugs approved by the US Food and Drug Administration as a monotherapy or combination therapies on patient-derived tumor cultures. The drugs tested included ones that were still being investigated in late-stage clinical trials or non-cancer agents that have been investigated for potential repurposing as anticancer treatments.

The platform assigned drug sensitivity scores and half-maximum inhibitory concentration values to determine which drugs may be effective. Drugs were ranked by drug sensitivity score and only recommended to the FPMTB if the inhibitory concentration values were less than or equal to the maximum clinically achievable plasma concentration of the drug found to be safe and effective in clinical trials.

The turnaround time for drug sensitivity testing in the trial was nine days for hematological cancers and 10 days for solid tumors. Turnaround time for genomic profiling was much longer, they said, 26.5 days for the UCSF500 test. Once the drug sensitivity results were returned, the FPMTB convened to discuss treatments and would modify their choices, if necessary, when genomics results were available.

"The [drug sensitivity testing] turnaround time is well within the two-week window that enables real-world clinical use to support decision-making," Berlow said.

Berlow said the First Ascent team has worked to optimize the drug sensitivity testing process and can now return results three days after the tumor cultures have been processed.

Berlow noted that the genomic profiling in this study was slower than average, which is usually around two weeks for panels from large diagnostics firms. The goal, he said, is to get both results returned in less than two weeks, which is considered the optimal time frame to support clinical decision-making without waiting too long to start treatment.

The interdisciplinary FPMTB included the treating physicians, pharmacists, hematology or oncology nurses, precision medicine specialists, and clinical research coordinators from Nicklaus Children's Hospital, along with translational researchers from Florida International University. The FPMTB met biweekly, and soon after patient results were received, Azzam said.

The researchers also found that drug sensitivity testing returned actionable treatment recommendations for 84 percent of patients. Among the 20 patients who had results from both drug sensitivity testing and genomic profiling, the researchers noted that only 25 percent had an actionable treatment recommendation based on genomic profiling alone.

Next steps

With this feasibility trial completed, Azzam said the team is aiming to conduct a larger randomized trial to continue moving the FPM platform toward clinical use. The first step, she said, is to obtain CLIA certification for its lab, which the firm is currently working on.

Berlow said once the CLIA certification is obtained, the goal will be to scale the lab's operations to meet the potential future demand for FPM testing.

"If we look at where genomics is today in the US, about 200,000 to 250,000 tests are provided annually because the need is that great," he said. "Ultimately, we foresee a similar need for functional precision medicine, if we can really show the improvement in outcomes. It's going to be a matter of reaching that level of scale as well, but all of that starts with CLIA."

Once granted CLIA certification, First Ascent aims to begin a randomized trial in this pediatric patient population around the end of this year, Azzam said. The design of that trial will likely compare the FPM-guided treatment to physician's choice of treatment to assess prospectively whether FPM improves outcomes.

The firm also has two other ongoing clinical trials of this FPM approach: one evaluating the same combination of drug sensitivity testing and genomic profiling in adult cancers and the other exploring the FPM approach as a way to address disparities for Black and Hispanic pediatric cancer patients.

Berlow added that the First Ascent team is looking to integrate artificial intelligence into the xDRIVE platform to provide new insights on novel drug combinations and improve the platform's ability to interpret all the data generated from drug sensitivity testing and genomic profiling.

"We want a better understanding of the relationships between the drug response we're seeing in patients and the underlying molecular characteristics," he said. "Right now, interpretation of the genome remains a challenge, but if we look at it from the lens of combining FPM data and analyzing it through artificial intelligence, that can give us a lot of new insights."

Finally, the team is also experimenting with doing drug sensitivity testing on smaller tumor samples, like core needle or fine needle biopsies. Initial results have shown success in testing drugs on the smaller biopsies, Azzam said, which would help improve the method's accessibility.

Azzam said the longer-term goal is to get First Ascent's platform approved by the FDA for clinical use, taking a similar path as other cancer diagnostics. She noted that the team is working with the agency to understand what data is needed to support such an application.

Because FPM is a new approach, the team is also working to ensure insurance coverage for this testing, she added.

"We're working really hard on making sure we implement studies that show not only that we can use this test to improve outcomes, but also we can use this test to save costs and reduce the trial and error that usually happens when choosing treatment," Azzam said.