This story has been updated to reflect the sensitivity and specificity data for the test the Wistar Institute presented at CHEST 2016.
NEW YORK (GenomeWeb) – As a gene expression classifier test for lung nodules heads toward the clinic, the organizations developing the test — the Wistar Institute and OncoCyte — are revealing more about the path they've taken and what it took to get where they are.
This week, Louise Showe, scientific director at the Wistar Institute, presented data from a 600-person study on the test at the American College of Chest Physicians 2016 meeting in Los Angeles. Meanwhile, Alameda, California-based OncoCyte told GenomeWeb more about its plans to commercialize the test and put it on the market by the second quarter of 2017.
"We had quite nice results," Showe told GenomeWeb, after presenting at the CHEST conference. "It's probably not the end [of our investigation], but it shows that the path we decided to pursue was a reasonable one."
The data suggest that the blood-based gene signature test plus algorithm, which now runs on the NanoString Technologies nCounter platform, is able to distinguish malignant from benign lung growths, and provide preliminary stratification of patients by nodule size and thus cancer risk.
Looking at 610 samples, the study demonstrated a sensitivity of 90 percent and specificity of 46 percent for the test, the organizations said in a statement. Specificity changed as a function of nodule size, with smaller nodules having higher specificity; for smaller nodules less than 10 mm in size, sensitivity stayed the same and specificity increased to 54 percent. "Including nodule size in the classifier algorithm increased the diagnostic test's accuracy significantly," OncoCyte said in a statement. At CHEST, Showe presented data showing that using both biomarker and nodule size data for all samples gave sensitivity of 90 percent and specificity of 62 percent.
"It's very good news," OncoCyte CEO William Annett told GenomeWeb. The firm acquired worldwide exclusive rights to the test from Wistar in January. "This would be a confirmatory test — post-screening but pre-biopsy."
Currently, screening of smokers and ex-smokers at high risk for lung cancer is done with low-dose computed tomography scans. These scans are great at finding nodules, but terrible at finding malignancies. "If there's anything in your lung, it's going to show, but there's no specificity," Annett said. In general, only about 4 percent of nodules are malignant. "It's got a 96 percent false positive rate. You have to follow up with everyone, because you don't know. That leads to a great deal of over treatment and follow-on CT scans," which expose patients to radiation, he said.
But he expects the number of CT scans for patients at risk of lung cancer to only increase, due to new screening recommendations from the US Preventive Services Task Force that came out in 2013. "[CT scan-based screening] isn't at the level you see as with mammograms or colonoscopy, but over time it will get up there, and they're increasing quickly."
With lots of nodules being found and most of them being benign, the prevailing practice has been to wait until they got bigger in diameter before going in for a biopsy. But that doesn't help doctors catch tumors earlier, when chances of survival are higher.
About 12 years ago, the Wistar Institute decided to look into whether they could develop a test to find lung cancer earlier. The early funding came from grants from the Pennsylvania Department of Health, heavily supported by money from the landmark tobacco settlements of 1998, Showe noted. As part of a larger grant, Wistar got around $300,000 from 2004 to 2008 to start out. The first studies were done with peripheral blood mononuclear cells (PBMCs).
In those studies, Showe and her colleagues demonstrated the feasibility of making a blood-based test, using Illumina microarrays as a discovery platform. As a scientist, Showe said she was interested in getting it to work, but wasn't sure if the clinicians would climb on board.
"Initially, the pulmonologists were really skeptical that this could ever possibly work," she said, recalling an interaction when first starting out. Several experts gathered to discuss whether one could use blood as a surrogate for detecting tumor. "One of the panel members said he thought a pimple would have a bigger effect on the immune system [than a tumor]. That made me think there would be a lot of resistance. But by the end, they were very supportive of us," she said.
A few years ago, as Wistar looked to translate its findings, Showe decided to make two key transitions.
"We didn't want to continue working with PBMCs. It was too difficult to collect samples soon after blood was taken. We wanted to develop something that could be collected even in a clinician's office," said Showe. Wistar chose to migrate to the Paxgene whole-blood collection tube. "Switching to Paxgene simplified collection and let us get many more samples than we were getting," she said.
The other migration was away from Illumina microarrays and onto the NanoString nCpunter gene expression analyzer platform. While there were several reasons for this change, Showe highlighted two: "It requires very little manipulation of the sample being tested and had already been [US Food and Drug Administration]-approved for a diagnostic for breast cancer recurrence." Like the Wistar test, NanoString's Prosigna breast cancer test is a gene expression classifier aided by an algorithm.
In 2012, Wistar received another grant from the Pennsylvania DOH, $991,062 over two years to fund the study. "That enabled us to do the sample collection we did."
By 2013, the institute had signed on with OncoCyte to begin developing the test, and in 2015 they expanded their agreement. Earlier this year, they finally signed the licensing agreement.
Annett said the deal includes standard terms such as an upfront payment, maintenance fees, and milestone and royalty payments. Among the disclosed terms is the range of royalty payments: 3 percent to 5 percent, subject to reduction for stacking. Milestones include the first IDE filing or equivalent regulatory filing, or any sublicense and first sale of a licensed LDT product.
Meantime, OncoCyte is ramping up its efforts, having set a target to launch a CLIA-certified laboratory developed test in the spring of 2017.
"We are taking the project to the next phase by carrying out our own study based on Wistar's encouraging findings and expect to complete our study later this year," Annett said. "Wistar's finding that nodule size data combined with biomarker results significantly increases the accuracy of the diagnostic test is an important development, and we will be evaluating nodule size and the test's performance in our study and algorithm."
OncoCyte is collecting samples from patients at 30 sites, Annett said. They're halfway to their target of about 300 and expect to be finished with collection by December, although they have not announced a principal investigator.
"We need to see if we get the same results as Wistar," he said. "If we can, we're in the commercially attractive range for sensitivity and specificity."
Annett said there's some debate among physicians as to what that range is, exactly. "Sensitivity has to be at least 90 percent, we don't want false negatives," he said. For specificity, the bar is lower, since the current standard of care offers basically none. "Anything over 35 to 40 percent would be commercially viable and of use to physicians. If it's lower, I doubt you would get much take-up."
The firm is also in the process of certifying its lab with the state of California and nabbing a CLIA certification. If they get it, OncoCyte will need yet another study to validate the test in the lab.
But even that won't mark the end of the studies they'll need. "After we launch, reimbursement for diagnostics is something you have to be meticulous about. We'll need clinical utility studies after launch to show insurance companies, payors that physicians actually change practice and do use fewer biopsies," Annett said.
The firm also hasn't disclosed an expected cost for the test. "We're using the NanoString platform, so it's not inexpensive. We have to have our own CLIA lab, our own staff, reagents, machines," Annett said. Price will likely be based on the value provided, he added. "Payors can save significant amounts of money from avoiding biopsies and side effects and hospitalizations. It's a cost-effective procedure," he said.
If OncoCyte is successful in meeting its deadline, it will mark the end of a chapter for Showe. "Our intent was to make something that wouldn't only be applicable in large academic centers, but something which could be useful in more remote areas or even be collected in a clinician's office. It's been 12 years since we started this, so I think we have certainly at this point, [and] met those goals," she said.
But Showe plans to push her research further with the aim of developing a test that could determine whether or not patients will have a recurrence of the disease. "One thing we're working on is to see whether we can develop a blood test and gene expression profile to have some idea of which patients are likely to have a better outcome or worse outcome. If we had a good enough test, the clinician could decide when doing lung surgery whether to include additional therapy."