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Reduced misdiagnosis

By Katie Pfaff

Staff Writer

Integrated Diagnostics Inc. (Indidx) has raised the bar on lung cancer detection with publication of study results regarding its Xpresys Lung 2 (XL2) liquid biopsy test for early stage disease. The differential diagnostic test has been confirmed to provide accurate distinction between benign and malignant nodules, possibly avoiding unnecessary biopsy or surgery in early suspect nodules. The study was published online Feb. 26, 2018, in CHEST, the journal of the American College of Chest Physicians.

"Xpresys Lung is designed to 'rule out' out patients who have benign nodules," Albert Luderer, CEO, Indidx, told BioWorld MedTech. "When combined with standard-of-care clinical risk factors, the test calculates whether the patient's nodule is likely benign, or not, and it does this with a high degree of statistical accuracy. XL2 offers objective molecular evidence of the status of the lung nodule within the context of the standard-of-care nodule patient work-up. The test is run prior to making the decision to proceed with an invasive diagnostic procedure. Used in this fashion, XL2 is capable of ruling out cancer in the majority of benign nodule patients."

Protein to rule out cancer

The study, "Assessment of plasma proteomics biomarker's ability to distinguish benign from malignant lung nodules: results of the PANOPTIC (PulmonAry NOdule Plasma proTeomIc Classifier) trial," used multiple reaction monitoring mass spectrometry to measure plasma proteins LG3BP and C163A which are linked to lung cancer. In cases of malignancy, LG3BP is increased, and C163A is decreased. "Indidx pioneered the liquid biopsy approach to lung nodules based on proteomic, or protein, analyses of blood plasma samples from hundreds of patients with nodules," said Luderer. "This research resulted in the discovery of several lung cancer-associated changes in a patient's plasma proteome."

The prospective, 33-center observational study included 685 patients with lung nodules measuring between 8 mm and 30 mm. Pretest probability of malignancy was set at 50 percent or less. 178 participants deemed low to moderate risk of malignancy were assessed (pCA ≤50 percent) and found to have a 16 percent incidence of cancer. Within that group, XL2 was able to detect between benign and malignant tissue with 97 percent sensitivity (CI 82 percent to 100 percent), 44 percent specificity (CI 36 percent to 52 percent) and 98 percent negative predictive value (CI 92 percent to 100 percent). When compared to gold standard diagnostics such as a doctor's estimated chance of cancer (p<0.001), positron emission tomography, and validated risk models, XL2's performance was superior.

Avoiding unnecessary treatment

"From a performance standpoint, the key trial result was that if the test were used, 40 percent of invasive procedures on benign nodules would be avoided," said Luderer." In addition, the proportion of malignant nodules incorrectly sent to observation would be reduced from the clinical trial observed 45 percent to 3 percent. These results are in the subgroup of patients who present with low to moderate risk." The most recent study was conducted as validation for Seattle-based Indidx's earlier research, which indicated the protein changes could be used to detect early stage lung cancer and exclude patients with benign nodules.

Both studies focused exclusively on "stage 1A lung nodules," said study co-authors Paul Kearney and Steven Springmeyer. "This is incredibly important as these are the lung nodules that are the hardest to assess. We integrated clinical risk factors and found that the proteomic signal was additive to the clinical risk factors. So in a real sense, XL2 is providing physicians with a molecular insight that they have never had before."

XL2 incorporates the methods of several clinical elements used in diagnosis, including size of the nodules, age of the patient and protein levels.

Nodules are difficult to diagnose

Lung nodules are problematic for physicians and patients since they are difficult to diagnose and biopsy by invasive surgery carries risks and high costs. Most often nodules are benign.

"The inability to correctly identify benign lung nodule patients drove XL2 development," said Luderer. "There are in excess of a million nodule patients per year in the U.S. with nodules from about 8 to 30 millimeters in diameter. This size range of nodules is considered to encompass the most difficult diagnosis for pulmonologists. Most of these patients are benign; however, despite advances in imaging technologies, the diagnostic precision for identifying cancer has not materially improved over the past decades. When you combine the clinical guesswork with the risks of needle or surgical biopsy in the lung – a vital organ – it quickly becomes a very difficult situation for the patient and physician.

"The fear of lung cancer also affects clinical judgment since to miss a cancer especially at an early stage of its history, limits future successful therapeutic intervention. The best radiologic factor is the size of the nodule with smaller nodules being more often benign. But cancerous nodules start small, and you don't want to be watching while it becomes too late to cure the cancer with surgical removal." About 36 percent of patients with benign nodules incorrectly undergo diagnostic procedures or surgery, according to peer-review literature, he said.

Indidx will continue its efforts toward commercial launch, including a planned financing round. The firm licensed the intellectual property, which served as basis for the test, from the Institute for Systems Biology and Caltech.

San Diego-based Biocept Inc. presented a poster at AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic in San Diego, which reported including Thermo Fisher's Quantstudio5 (QS5) real-time PCR instrument into Biocept's Target Selector ctDNA lung cancer assays leads to better detection of lung cancer mutations. The company shared that data from 3,000 samples tested with its liquid biopsy assays for BRAF, EGFR and KRAS mutations indicated single mutant copy detection on the QS5 platform with greater than 99 percent sensitivity and greater than 99 percent specificity. (See BioWorld MedTech, Jan. 10, 2018.) China-based Amoy Diagnostics Co. Ltd. won CFDA approval for its epidermal growth factor receptor (EGFR) mutation detection kit for non-small-cell lung cancer in late January. The companion diagnostic test is designed to assess probability of effectiveness with EGFR TKI (tyrosine kinase inhibitor)-based non-small-cell lung cancer therapies. Amoydx reported the real-time polymerase chain reaction test allows for quick and reliable mutation coverage to identify 41 EGFR mutations in exons 18-21, L858R, exon 19 deletions, and T790M. The test, which looks for EGFR mutations among circulating tumor derived fragmented DNA (ctDNA) in plasma from patients with advanced or metastatic NSCLC, uses the company's super-amplification-refractory mutation system (ARMS) technology. Amoydx earlier collaborated with Merck KGaA to create a liquid biopsy test for metastatic colorectal cancer in China using the super-ARMS technology in July 2016. The test will roll out in China first, with commercialization in Argentina, India, Mexico, Taiwan, Hong Kong, Brazil and Russia next year. (See BioWorld MedTech, Jan. 26, 2018.)

Published  March 12, 2018

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