SEATTLE—In late February, Integrated Diagnostics announced the online publication of full results of a large prospective clinical trial validating its Xpresys Lung 2 (XL2) diagnostic in Chest, the peer-reviewed official medical journal of the American College of Chest Physicians, entitled “Assessment of Plasma Proteomics Biomarker’s Ability to Distinguish Benign From Malignant Lung Nodules: Results of the PANOPTIC (PulmonAry NOdule Plasma proTeomIc Classifier) trial.”
“Integrated Diagnostics pioneered the liquid biopsy approach to lung nodules based on proteomic (protein) analyses of blood plasma samples from hundreds of patients with nodules,” said Integrated Diagnostics CEO Dr. Albert Luderer. “This research resulted in the discovery of several lung cancer-associated changes in a patient’s plasma proteome.” The original findings were published in Science Translational Medicine and the Journal of Thoracic Oncology, and collectively demonstrated that specific protein changes could be detected in early-stage lung cancer and utilized to exclude cancer in patients with benign nodules.
XL2 measures levels of two proteins in the blood plasma sample. These proteins’ relative abundance differs in a benign nodule patient as compared to a patient with a malignant nodule. The liquid biopsy blood sample is first separated to provide plasma for analysis. The patient’s plasma is then processed through sophisticated liquid chromatographic columns to remove high abundant (non-diagnostically significant) proteins.
“The remaining low abundant proteins are then further processed to yield peptide fragments of the whole protein molecules,” says Steven Springmeyer, chief medical officer of Integrated Diagnostics. “The sample is joined with standards and controls and then analyzed on state-of-art multiple reaction monitoring LC-MS (triple quad). The peptide signature peaks for the two proteins are identified and the data entered into the integrated calculations to generate the test report.”
“XL2's development strategy was planned from the beginning of the company. Our goal was to develop a test that could rule out lung cancer, thereby helping reduce unnecessary invasive procedures, improve patient outcomes, reduce complications and lessen the cost to the healthcare system,” Springmeyer continues. “Our technical approach deployed systems biology experimentation coupled with the ability to measure hundreds of proteins simultaneously. This allowed a non-biased study of changes associated with the evolution of a pathologic condition such as lung cancer.
“We continued to research the proteins that had been identified from our earlier lung cancer work with the intention to improve the diagnostic performance of our original product, Xpresys Lung 1. Once the PANOPTIC clinical trial results were available, we were able to validate the discovery work that created Xpresys Lung 2 with samples from our first prospective study. This work was followed by validation utilizing the PANOPTIC prospective study.”
The clinical validation represents the performance of the second-generation diagnostic test of Integrated Diagnostic’s original published work. XL2 combines five standard-of-care clinical factors such as patient age and nodule size in combination with the measurement of two proteins into a single risk assessment. The validation study confirmed the high accuracy of XL2 in identifying benign nodules in patients with a pretest probability of malignancy of 50 percent and less.
“For the second-generation test, we were able to determine the two proteins (from the original 11 proteins) that provided the most information in the intended-use population. We found that the measurement of these two proteins combined with five clinical factors ... produced remarkably high diagnostic performance,” Springmeyer notes. “It was reassuring to find that the resultant integration of the proteins and clinical factors was diagnostically synergistic rather than merely additive.”
State-of-art instrumentation used multiple reaction monitoring mass spectrometry to measure the relative abundance of two plasma proteins, LG3BP and C163A. These proteins were integrated into a ratio that is associated with the malignant condition—LG3BP is elevated and C163A is diminished.
Co-authors of the PANOPTIC study Dr. Paul Kearney and Springmeyer said, “to establish a high level of evidence, we conducted two prospective studies, one for discovery and the other for validation, that focused only on Stage 1A lung nodules. 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 reportedly demonstrated a sensitivity of 97 percent, a specificity of 44 percent and a negative predictive value of 98 percent in distinguishing benign from malignant nodules. When XL2 performance was contrasted to other standard-of-care diagnostic modalities performed on these patients, the classifier performed better than all other modalities including positron emission tomography (PET), validated lung nodule risk models and physician estimated cancer probability.
“The PANOPTIC trial is providing a number of ‘firsts’. This is the first time physician estimates of the probability of cancer were collected and compared to the final diagnosis of a lung nodule. The physician estimates were significantly better than existing calculators, but they often didn’t follow their estimates, perhaps because they lacked confidence in their estimates,” Springmeyer tells DDNews.
“A major highlight of PANOPTIC is that XL2 can achieve a very high predictive value (98 percent) when a nodule is benign,” he continues. “This should translate into a high degree of confidence to observe the benign nodules with further CT scans rather than proceeding with unnecessary procedures. 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. In addition, the proportion of malignant nodules incorrectly sent to observation would be reduced from the clinical trial observed 45 percent to 3 percent.
“When XL2 is launched, this will be the first commercial application of a proteomic diagnostic test for pulmonary nodules. This is a platform technology that has the potential to be applied to many other medical areas with unmet needs for diagnosis, clinical assessments or disease staging.”