NEW YORK- Following the co-launch last month of its ctDx Lung targeted next-generation sequencing (NGS) liquid biopsy assay with the Laboratory Corporation of America, Resolution Bioscience is now engaged in discussions with HMOs and other private payors to secure commercial coverage for the test.
While Kirkland, Washington-based Resolution has not publicly disclosed details about current negotiations, the firm noted that it has secured coverage for about 100 million lives in the US between Medicare, Medicare Advantage, and major private payors.
According to Resolution CEO Mark Li, the Centers for Medicare and Medicaid Services agreed to cover ctDx Lung earlier this year based on the published results of an ongoing prospective trial led by researchers at Memorial Sloan Kettering Cancer Center (MSK).
Resolution believes ctDx Lung can help guide oncologist decisions to administer targeted therapies for patients that have been diagnosed with a recurrent, relapsed, refractory, metastatic, or advanced non-small cell lung cancer (NSCLC).
Using extracted cell-free DNA (cfDNA) from a patient's blood sample, Resolution's assay uses its patented hybrid-capture NGS technology to hybridize 40-base-pair probes to the fragments, perform primer extension, further bind the probes to the ctDNA fragments, and increase capture rate. Resolution then uses proprietary bioinformatics to analyze the captured fragments for mutations, including novel fusions and gene deletions.
Clinicians interested in using Resolution's assay to guide NSCLC therapy can order it through LabCorp's Integrated Oncology Division via the firm's website or with their local LabCorp representative. After the doctor submits a patient's blood sample in a collection kit, it is sent to Resolution's CLIA-certified lab. Resolution can return a patient's clinical report through LabCorp's delivery network in about a week.
Li said that ctDx Lung covers all NSCLC mutations that have US Food and Drug Administration-approved therapies and includes biomarkers that have shown promise in clinical trials. While Resolution has several larger research panels for biomarker discovery, Li noted that the firm thought it would be more appropriate to provide information that can "guide medical decisions … today."
CMS coverage
Resolution began initial discussions with CMS in in late 2019, followed by official Medicare Part B and Medicare Advantage coverage in February.
Li said that ctDx Lung is covered for Medicare patients with stages III through IV NSCLC, in accordance with MolDx Local Coverage Determination (LCD) 39043. The decision covers plasma-based genomic profiling for all solid tumors besides those in the central nervous system. The coverage decision is identical to CMS's prior decision issued for Guardant Health's Guardant360 CDx NGS assay.
Medicare examined several studies published by Resolution and its collaborators to determine the test's clinical utility before deciding to cover the assay, Li said. The major pieces of evidence that convinced the US national health insurance program included the initial results of the large-scale ongoing prospective study led by MSK to demonstrate the clinical utility of liquid biopsy.
In the initial small-scale 2018 study, published in the Journal of the National Cancer Institute, the researchers used Resolution's assay to analyze potentially useful mutations in blood samples from 210 patients. The group reported that the clinical response rate between the somatic mutations found in blood and tissue was nearly 97 percent when uncovering oncogenic driver gene mutations.
Based on the study's promising results, the researchers extended the project to 2021 and have since continued collecting NSCLC samples from patients in a large-scale trial, which Li said currently has enrolled more than 1,100 patients. Additional aims of the ongoing study include discovering new fusions, longitudinal monitoring of changes in mutational allele frequency over time as an indication of response or progression, and understanding the influence on sensitivity when the patient is either on or off therapy.
"When a patient is on therapy and responding clinically, the tumor signal in the blood may be limited … and a lower signal means higher sensitivity requirements for the assay," Li explained. "Additionally, there may be differences in tumor signal strength with systemic versus targeted therapies."
Medicare also considered results from validation studies that Resolution performed with Dana-Farber Cancer Institute (DFCI) researchers. In one retrospective study, DFCI and Resolution compared ctDx Lung to Guardant360 by evaluating their ability to detect fusion-positive NSCLCs from blood samples. The team found that Resolution's test identified six more oncogenic fusions than Guardant's test and tended to report higher allele frequency percentages in fusions.
Resolution also presented data to Medicare from the DFCI's nationwide Study of Plasma NGS for Assessment, Characterization, and Evaluation of Patients with ALK Resistance, or SPACEWALK, trial. The team sequenced ctDNA from patients' blood samples to identify genetic changes that contribute to drug resistance and that could be used to guide treatment decisions.
Both Resolution and LabCorp are receiving a single reimbursement from Medicare for the ctDx Lung assay, but Li declined to disclose additional financial details.
With the CMS reimbursement in hand, Resolution now aims to achieve full US private payor coverage for the test.
"We have Medicare [Part B] and Medicare Advantage coverage, and now we're talking to a variety of private payors to extend that coverage to commercial patients," Li said. "While we've not disclosed anything publicly, we've secured decisions … and right now we have about 100 million lives covered."
Resolution has also pursued a unique proprietary lab analysis code issued by the American Medical Association for the test, which Li argued is crucial to the firm's plan for its current negotiations with private payors and HMOs.
"A lot of other liquid biopsy firms are using the 81479 CPT code, which is the generic unlisted molecular pathology code … [and] makes it difficult for private payors to evaluate the efficacy of their test," Li explained. "We feel [that] it is important for payors to be able to perform benefit analysis by test, which is hampered if you bill under the generic code."
While Resolution currently offers ctDx Lung as a laboratory-developed test, the firm has said in the past that it would like to eventually kit the test for users. Li noted that his team is speaking with several pharmaceutical partners about leveraging the assay as a companion diagnostic to support therapeutics but declined to provide additional details.
NSCLC Competitors
Other firms are aiming to capture a slice of the late-stage NSCLC testing market with their own liquid biopsy assays for companion diagnostics. In addition to the initial draft LCD coverage last year, Guardant received FDA approval in August for a companion diagnostic indication for Guardant360 to identify NSCLC patients with epidermal growth factor receptor alterations who may benefit from treatment with osimertinib (AstraZeneca's Tagrisso)
Foundation Medicine partnered with Takeda Pharmaceuticals USA last month to develop companion diagnostics for Takeda's lung cancer portfolio. The group will use Foundation's recently FDA-approved NGS FoundationOne Liquid CDx assay, which covers more than 300 cancer-related genes, to identify patients eligible for mobocertinib or brigantine (Takeda's Alunbrig).
However, Li argued that Resolution's platform, which uses patented molecular biology, allows the firm to annotate the cfDNA "in ways that technology by other companies do not offer." Resolution's molecular biology informs the company's bioinformatics and allows for increased information capture, which Li said his team leverages to make more accurate variant calls.
Pointing out that both Foundation Medicine and Guardant Health have published data using larger, 120-base-pair capture baits or probes, Li claimed that Resolution's much smaller capture probes offer higher capture rates.
"Smaller probes increase the probability that the entire probe will hybridize to the short, 150-165 bp cfDNA fragment, and our proprietary molecular biology produces very high on-target rates, even with such short probes," Li said. "Additionally, our probes are directional and extend across the rest of the fragment and in doing so, are able to discover de novo novel fusions and mutations."
However, Geoff Oxnard, VP, global medical lead, liquid franchise at Foundation Medicine pointed out that bait design is just one component of an assay's development.
"Our test was developed to obtained high confidence, high sensitivity results from the regions it targets, and allows for the detection of novel fusions across all types of solid tumors," Oxnard said in an email.
"Liquid biopsies are complex diagnostics that play a critical role in patient care, [and] to ensure that patients are getting the best care, a test needs validation, coverage and fast turn-around time," a Guardant spokesperson said in an email. "Without these test attributes, patients may not be receiving optimal care …. [and] the Guardant360 CDx delivers against all of these dimensions."
Resolution is also the only liquid biopsy firm to so far identify its data from a 2017 American Association for Cancer Research AstraZeneca-sponsored presentation, which included results of a "bakeoff" evaluation between four companies' NGS liquid biopsy tests. Li argued that Resolution's test had the highest PPV and lowest false positive rate of the four assays at the bakeoff.
Serena Guzman, VP of commercial at of LabCorp Oncology Hub, said that ctDx Lung sits firmly within LabCorp's focus on diagnostic and drug development activities in oncology. While certain research is done in house at LabCorp, the firm works with partners like Resolution that have "promising technologies" to make an impact on improving patient care.
"Studies have shown that [ctDx Lung] will help the doctor select the most effective, targeted treatment for their patients," Guzman said in an email. "It is convenient, effective, accessible, and most importantly will help more patients get the treatment that is likely to provide a positive response to their disease."