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Biocept to Refocus CNSide Assay Plans After FDA Feedback Suggests Targeting Narrower Indications

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NEW YORK – Biocept is continuing to amass new data on its CNSide cancer metastasis assay in the hopes of capturing the interest of oncologists after the US Food and Drug Administration rejected the liquid biopsy firm's first bid to garner breakthrough designation, according to a recent filing with the US Securities and Exchange Commission.

Reflecting on new data presented at the San Antonio Breast Cancer Symposium earlier this month, Michael Dugan, Biocept's chief medical officer, said he believes oncologists are still intrigued by the concept of the CNSide test as a reservoir for a variety of clinical insights. At the meeting, researchers presented results from a study showing the test, which isolates and analyses circulating tumor cells and cell-free DNA from cerebral spinal fluid, could not only detect the presence of cancer in the brain or central nervous system but could also identify actionable biomarker information in the form of HER2 overexpression.

Despite that, it has become clear the regulatory agency needs Biocept to demonstrate how the assay would improve care in specific use cases to merit a breakthrough device designation. This may present a potentially steeper path than what the firm was hoping for when it launched CNSide earlier this year for diagnosing cancers that have metastasized to the central nervous system.

"At the time, we saw the breakthrough device filing as a way to get the attention of pharma early and get into a pipeline that would be very advantageous to us," Dugan said in an interview. The company was seeking breakthrough device designation for CNSide in a broad context, as both a monitoring tool and to guide therapeutic decision-making.

However, the process of garnering the designation became more challenging for the company when the FDA wanted more data regarding specific indications of use for the test. "We had gone in a rather broad [direction]," he said. "And [the agency] wanted to see it more split out, as well as more data to support each [indication]."

The feedback has been helpful, according to Dugan, and has driven Biocept to develop a more specific path forward, starting with a trial to demonstrate the test's superiority over current cytology technologies in monitoring therapy response for patients with leptomeningeal disease, a more advanced spread of cancer cells to the central nervous system than single brain metastatic lesions.

The company, with its steering committee led by Northwestern University neuro-oncologist Priya Kumthekar, has developed a protocol for a study that will involve patients who can have multiple lumbar punctures, or who have an intrathecal catheter that can be drawn from repeatedly. The study will follow those patients over the course of their initial treatment and assess whether Biocept's test can detect a substantial change in the number of tumor cells in the CSF corresponding to therapy response. This would then support an initial submission to the FDA.

Following this, Dugan said, the firm aims to gather and publish more data on the CNSide assay's ability to detect specific molecular therapeutic targets. Chief amongst those is HER2, he said, which was the subject of the company's poster presentation at SABCS.

"What we found, much to our surprise, is that [HER2 is] much more common in … circulating tumor cells in the CSF than might be imagined, even in patients who were negative on their initial tumor [biopsies]," he said.

Discussing the company's presentation during the conference, Eudocia Lee, director of clinical research in neuro-oncology at Dana-Farber Cancer Institute, suggested that neuro-oncologists see a real unmet need for better tools to assess patients with CNS metastasis and leptomeningeal disease, or LMD.

Current CSF cytology technologies have limited sensitivity "with perhaps a false-negative rate of around 30 percent," she said. But based on early results, experts like Lee believe liquid biopsy technologies could offer new opportunities to track response and detect actionable markers.

According to Lee, Biocept's investigators used CNSide on specimens from 77 breast cancer patients with suspected LMD, quantifying tumor cell numbers and using FISH to assess HER2 status.

In 57 of 77 samples, or 74 percent of the cohort, the company was able to detect the presence of metastatic tumor cells and give a count of their recovered number. Among those 57 patients, 32 demonstrated HER2 amplification by FISH.

Further studies will be needed to establish clinical utility, but the early data do seem to represent sensitivity and applicability beyond what can be achieved with CSF cytology, Lee said.

According to Dugan, Biocept has also seen HER2 amplification in CNS circulating tumor cells across a variety of other tumor types, including in patients with metastatic gastroesophageal junction tumors, metastatic colon cancer, metastatic head and neck cancer, and lung cancer.

"Almost any tumor type could potentially have at least a low level of HER2 expression, particularly as a mechanism of resistance," Dugan said, citing emerging data presented at the SABCS meeting from new antibody drug conjugates that may offer significant benefits to metastatic patients, even with low expression of the biomarker. For example, analysis from the DESTINY-Breast03 Phase III trial found that trastuzumab deruxtecan demonstrated a higher progression-free survival and objective response rate overall but especially in patients with stable brain metastases compared to alternative drugs.

In Dugan's view, this potentially opens up broader uses for CSF-based testing, particularly in patients who have advanced to leptomeningeal disease. "We can help those patients because we can identify targets for therapy that they might not have been able to consider before," he said.

Lee said that prior studies comparing resected brain metastatic tissue to primary tumor samples have found that HER2 positivity seems to be detected in the CNS about 15 percent of the time.

"What we don't know yet is what the correlation is" between HER2 in primary tumors and in brain metastases and circulating tumor cells, she said. Part of the anticipated value of better CSF assays, she added, is that they could provide "a way to assess [this] with something less invasive than a craniotomy."

However, she added, it's still unknown whether patients who are HER2-positive by CSF testing will respond to HER2-directed therapy as would be expected of those with HER2-positive tumor tissue.

According to Dugan, breast cancer, where about 5 percent of patients might be expected to progress to LMD, is low-hanging fruit in terms of indications for the CNSide assay. But patients with other tumor types can also develop this advanced form of CNS metastasis, even though they may not be regularly identified.

In such cases, oncologists may see that a patient isn't doing well and send them to hospice, when there could, potentially, be a life-extending, alternate option.

"We've seen patients who live more than a year, or two or three years, with appropriate treatment," Dugan said. "If people just know there's a way to go after these cells, identify them, and give a directed therapy, you're going to see a revolution in the next few years."

During her presentation, Lee highlighted the fact that patients with brain metastases and LMD have historically been excluded from targeted drug trials and encouraged her colleagues to do their part to remedy this.

For Dugan, the fact that Biocept has seen biomarkers like HER2 present in CNS CTCs in patients whose initial tumors were negative is a further indication of how useful an assay like CNSide could be to recruit patients for such trials and improve their chance of success.

"The studies being done right now … are looking at metastatic brain tumors that are amenable to surgical resection … characterizing them with whole-genome sequencing and so forth to try to find targets of therapy," he said. "But the thing is, they're missing a lot of patients that are not amenable to surgical biopsy and relying just on the primary tumor data as a way to guide therapy, knowing full well that there's genetic heterogeneity, but they're not really able to evaluate it."

At least one attendee at SABCS expressed frustration at not being able to treat more of their patients with targeted therapy and was intrigued by the possibility that cancer cells from non-HER2 tumor subtypes may start expressing HER2 after they metastasize to the brain, opening up the possibility of targeted treatment.

In the meantime, if Biocept is successful in advancing CNSide for therapy response monitoring, widespread implementation would likely require fundamental changes to how patients are sampled.

"It's not standard of care to sample the CSF unless you have a suspicion of LMD … because the existing technology is so poor it doesn't really work that well," Dugan acknowledged. "A lot of the cells are lost in processing, and they don't preserve the cells or capture the cells in any directed manner with conventional cytopathology techniques."

For CNSide's utility to become more established, oncologists would have to be willing to perform lumbar punctures more frequently than they do now, Dugan said. If so, the potential benefits would have to outweigh the risks of additional procedures.

Finally, based on conversations with radiation oncologists, Dugan believes there is one other potential niche for CNSide: guiding decision-making regarding radiotherapy strategies.

Clinicians currently suspect that a proportion of patients with multiple brain metastases may have undiagnosed LMD, and a tool that facilitates this diagnosis could enable more personalized care. "They'd like to avoid whole brain radiation and do stereotactic radiation, which is more focused and has less side effects [for non-LMD cases], if they can," Dugan said.

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