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Biodesix's Proteomic Method for Predicting Immunotherapy Response Advancing Toward Market

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NEW YORK — As part of its plans to grow its presence in the lung cancer space, Biodesix shared new data last week supporting the ability of its Primary Immune Response assay to identify non-small cell lung cancer patients who are likely to respond to immune checkpoint inhibitors and those at risk for adverse events.

Biodesix's serum-based proteomic test measures a pre-treatment immune profile that it said can inform therapeutic decisions with ICI. The Boulder, Colorado-based firm will perform PIR within its CLIA-certified, CAP-accredited laboratory and plans to market it as a test for guiding immunotherapy decisions for late-stage NSCLC patients.

Although Biodesix hasn't yet publicized a commercial launch date for the test, at the American Association for Cancer Research's virtual annual meeting last week, the test was featured in several studies led by Young Kwang Chae, associate professor of medicine at Northwestern University Feinberg School of Medicine.

In one study, Chae and his team explored the ability of available mass spectrometry-based serum proteomics signatures, including the signature underlying PIR, to predict cancer patients' outcomes on ICI. They identified PIR and other classifier algorithms published in the literature and reported at medical meetings as of Nov. 18, 2020, and reviewed their reported ability to determine which advanced lung and melanoma patients would have favorable or unfavorable outcomes on ICI.

Currently, PD-L1 expression is one of the main tumor and immune biomarkers oncologists use to predict whether their patients are likely to respond to ICI, but it isn't as precise as many would like. Recognizing this, Chae's group hypothesized that these mass spectrometry-based serum proteomics signatures may be able to better characterize patients' immune responses to treatment.

"We wanted to tell who will be the [best] responders [by] looking at progression-free survival and overall survival, as only 30 percent of lung cancer patients respond to ICI," Chae said.

Analyzing the compiled data from these prior studies and presentations, the researchers found that mass spectrometry-based serum proteomic signatures, like PIR, were able to predict survival outcomes independently of PD-L1 expression levels for patients receiving ICI alone or combined with chemotherapy as a first-line treatment. Moreover, patients with unfavorable predictive markers had worse prognoses on ICI monotherapy compared to ICI with chemotherapy.

Based on this exercise, Chae and his group concluded in an abstract that mass spectrometry-based serum proteomic tests could "reliably identify patients expected to have a worse prognosis." In addition, the data suggested that these tests could be useful in identifying which patients with a worse prognosis could benefit from more aggressive front-line treatment with ICI and chemotherapy.

In a second study reported by Chae's group at AACR, the researchers used a serum-based proteomic signature, namely PIR, to explore the associations between immunotherapy treatment and immune-related adverse events in NSCLC patients.

Immune-related adverse events caused by ICI manifest in a range of side effects that resemble autoimmune responses and can affect almost every organ in the body. "The million-dollar question is, [which] patients will get severe immune toxicity, because we don't want to give therapy to patients who suffer from fatal side effects," Chae said.

Chae's team collected data from 38 NSCLC patients who had a baseline PIR test within one week of beginning immunotherapy. Based on the PIR results, patients were deemed either "sensitive" or "not sensitive." The researchers then compared between the groups the length of time between when patients started therapy to their first episode of an immune-related adverse event, as well as the frequency and severity of these adverse events.

In the study, 21 patients, or 55 percent, experienced one or more immune-related adverse events. They also saw a total of 33 immune-related adverse events, with the majority classified as grade 1 (18) or grade 2 (11).

The PIR-sensitive group showed longer periods free of immune-related adverse events, with a median time to first adverse event of 54 weeks. In comparison, the median time to first immune-related adverse event was 9.5 weeks in the cohort deemed "not sensitive" by PIR.

Based on these results, Chae and his colleague concluded that PIR-sensitive patients are more likely to tolerate immunotherapy longer without developing immune-related adverse events. "It implies the potential value of the baseline PIR test in predicting the development of [immune-related adverse events] and selecting subsets of patients who need close monitoring with immunotherapy," they wrote in their abstract.

Following these initial investigations, Chae said his team will need to perform larger studies to validate PIR's ability to predict which patients are likely to experience toxicities to ICI.

"Because there hasn't been any precedent of host-proteomic signal [linked] to toxicity, we're still exploring whether we can predict, with a baseline blood test, the toxicity in addition to the immune response and how tightly they are correlated," Chae said.

Matthew Ellis, director of the Baylor College of Medicine's Lester and Sue Smith Breast Center, who was not involved in these studies, pointed out that cancer researchers face several issues when using mass spectrometry to guide immunotherapy use, including understanding the nature of the body's immune response to tumors, the tumor's metabolomics, and the tumor's impact on the patient's overall therapy response. 

While Ellis noted that Chae's team is applying a different "yet entirely valid approach" with Biodesix's PIR assay and using proteomics to solve clinical problems, identifying the presence or absence of driver oncogenes can be "tricky" in his view.

"They're working with blood … but you [also] need to focus on the tumor and its microenvironment," Ellis said. "Essentially, with proteogenomics, it starts with the genomics, since the information flows from the corrupted genome to the proteome, [and] you need both pieces of information."

However, Chae noted that if clinicians only look at the tumor, they will not be able to predict how the patient's immune system will react to the treatment. He believes that Biodesix's PIR assay can provide critical insights in this regard by characterizing the host's overall immune status prior to receiving therapy.

Kieran O'Kane, chief commercial officer of Biodesix, said that the studies presented at AACR will help the firm commercialize the PIR assay for predicting immunotherapy response and toxicities. He added that PIR differs from the firm's VeriStrat assay — which uses mass spectrometry to monitor disease aggressiveness — because it is specifically designed to interrogate a patient's immune response to immunotherapy.

"The technology we're using has significantly evolved since we developed the VeriStrat test, as we're able to take a deeper look into the proteome," O'Kane said. "There's better resolution from the [MALDI-time of flight mass spectrometry] instruments, and our methods have developed significantly in terms of the algorithms we applied to improve the resolution of the instrument."

As part of the envisioned workflow for PIR, Biodesix will send its proprietary blood collection device — a cassette with blood separation paper — to oncologists to collect "a few droplets of blood" during a patient's initial lung cancer diagnosis, O'Kane said.

"Since you're not shipping liquid blood, it stabilizes the sample and makes it less susceptible to environmental influences," he explained.

After processing the cassette on the test in its Colorado lab, Biodesix will generate a test report and send it back to the physician to use in patient care. The firm is continuing to study PIR's capabilities and patients' results can also be used in observational trials, according to O'Kane.

While O'Kane declined to provide specifics about the assay's turnaround time, he anticipates that the test will have a roughly similar turnaround time to the VeriStrat assay's 36-hour workflow.

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