By Turna Ray
Following publication of positive validation studies in The Lancet showing that its gene-expression assay can assess whether early-stage lung cancer patients are at high risk of death during a five-year window after surgery, test developer Pinpoint Genomics believes it is in good standing to start reimbursement discussions with payors.
Researchers led by Michael Mann and David Jablons from the University of California, San Francisco, published data from two retrospective investigations in The Lancet demonstrating that Pinpoint Genomics' multi-gene expression test "reliably identified" early-stage, non-squamous, non-small cell lung cancer patients at heightened risk of succumbing to their disease in the years after they'd had cancerous tumors surgically removed. One of the studies discussed in the paper was a blinded investigation of more than 400 stage I non-squamous NSCLC patients treated at Kaiser Permanente Northern California Hospitals. A second trial studied more than 1,000 stage I through stage III non-squamous NSCLC patients treated at cancer centers within the China Clinical Trials Consortium.
The test was developed based on technology licensed from UCSF, and Mann, Jablons, and other authors on the paper serve as consultants for the firm.
Researchers involved in the development of the Pinpoint Dx Lung Assay believe that these robust findings from two clinical trials are sufficient to start reimbursement discussions with payors. The Pinpoint Dx Lung Assay, which gauges the expression of 14 genes, was launched in the US market in concert with The Lancet article. As reported by PGx Reporter sister publication GenomeWeb Daily News, the test carries a list price of nearly $4,000.
"Given the definitive, unprecedented nature of the large-scale validation of the prognostic significance of the assay, we don't anticipate the need for any additional studies for reimbursement," Mann, director of UCSF's Cardiothoracic Translational Research Laboratory, told PGx Reporter this week.
Additionally, "the fact that one of the studies was done by Kaiser is very likely to encourage the widespread use of the test in their system," he said.
Payors will likely consider the medical need for a test like the Pinpoint Dx Lung Assay that can may help oncologists better discern which early-stage NSCLC patients need adjuvant chemotherapy treatment. Between 30 percent and 50 percent of early-stage NSCLC patients experience disease recurrence, which "almost always leads to death" in a five-year period, Mann said. The early-stage NSCLC patient population has a high rate of occult metastasis, which is when cancer cells are found in the sputum but imaging tests or bronchoscopies fail to find a tumor. Furthermore, many stage II patients forgo chemotherapy after the surgical resection of their tumors, hoping to avoid treatment-related toxicities.
"Despite the high rate of occult metastasis and the proven survival benefit of adjuvant platinum-based chemotherapy in stage II-III disease, no data lend support to the use of adjuvant treatment in patients with stage IA tumors as defined by conventional criteria," Johannes Kratz of UCSF and colleagues wrote in The Lancet article. "A more precise staging test," such as the Pinpoint Dx Lung Assay, would allow doctors to identify patients "who meet clinicopathological criteria for stage I disease, but who … have a worse than expected prognosis," such as those at high risk for occult metastasis.
NSCLC comprises 85 percent of all lung cancer cases, making it the most common form of the disease. Mann estimated that each year there are between 40,000 and 50,000 early-stage NSCLC patients in the US who undergo resection to remove a tumor.
In the Kaiser cohort, Kratz et al. reported that the Pinpoint Dx Lung Assay was able to accurately assess that 71 percent of low-risk patients, 58 percent of intermediate-risk patients, and 49 percent of high risk patients were alive after five years. In this cohort, when researchers adjusted for age, sex, smoking history, and tumor size greater than 4 cm, the high-risk and intermediate groupings based on results from the gene-expression test, as well as age and sex, were statistically significant predictors of mortality.
Similarly, in the Chinese cohort, the gene expression test gauged that 74 percent, 57 percent, and 45 percent of low risk, intermediate risk, and high risk patients, respectively, were alive after five years. "The success of this assay in an ethnically distinct cohort might be among the strongest pieces of available evidence that fundamental genetic elements of non-squamous NSCLC biology exist that characterize the disease, genetic elements that do not depend on nor show the particular genetic make-up of a training cohort from which an assay is derived," the authors wrote in the paper.
The researchers are currently planning a prospective study in which patients with stage I non-squamous NSCLC will be tested with the Pinpoint Dx Lung Assay, and then those patients identified at high risk of death will be randomized to either an observation arm or receive adjuvant chemotherapy. Observation is currently the standard medical practice for gauging if a patient's cancer will return.
"Although the National Comprehensive Cancer Network's guidelines already recommend adjuvant chemotherapy for stage I patients who have tumor characteristics that are believed to put them at high risk of mortality, only one of those seven characteristics has ever been associated with prospective data documenting a survival benefit from chemotherapy (and those data represent a post-hoc analysis from just one study)," Mann said in an e-mail. "Furthermore, those seven characteristics have never been validated to accurately identify the highest risk stage I patients."
In The Lancet paper, Kratz et al. reported that the molecular risk categories from the Pinpoint assay outperformed standard clinical risk factors in assessing mortality in lung cancer patients after surgery. "The assay improved prognostic accuracy beyond NCCN criteria for stage I high-risk tumors, and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages," the study authors wrote.
The planned prospective study "will therefore provide unprecedented documentation of the benefit of adjuvant chemotherapy for the truly highest risk stage I patients," Mann said.
According to Mann, ongoing research is also needed to further define treatment approaches that will improve outcomes for early-stage lung cancer patients that the Pinpoint Dx Lung Assay deems to be at intermediate risk of death. In an effort to provide the most detailed prognostic data for lung cancer patients, the researchers decided not to dichotomize the risk categories into just high and low risk.
"One benefit of discriminating early-stage patients at intermediate versus low risk is that they may at least comply more rigorously with post-operative surveillance regimens so that recurrences can be detected earlier when they may be somewhat easier to treat, or even instigate more aggressive surveillance," Mann said.
Pinpoint Genomics was founded in late 2007 to support the development and commercialization of promising UCSF technologies that could help doctors deliver personalized treatment decision to early-stage lung cancer patients. The Pinpoint Dx Lung Assay was developed based on research led by Jablons, a professor in thoracic oncology at UCSF.
Pinpoint Genomics licensed this technology from UCSF and further developed the test. The assay analyzes tumor samples for the expression of 11 cancer-related target genes – BAG1, BRCA1, CDC6, CDK2API, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR, WNT3A – and 3 reference genes – ESD, TBP, YAP1.
Pinpoint Genomics is not the only group developing a gene expression signature to predict NSCLC prognosis. Indeed, a 2010 review referenced in The Lancet paper identified 16 such studies at the time. However, while the authors acknowledge that several of these signatures "successfully predicted higher-than-expected mortality after resection of early-stage disease," many of these tests haven't been validated in large-scale studies in the community setting. In addition, these tests require snap-frozen tissue samples while the Pinpoint assay runs on formalin-fixed, paraffin-embedded tissue. These factors have restricted the adoption of these earlier tests since it has been difficult to reproduce test results and such studies would be costly to run, according to the study authors.
Another advantage for Pinpoint is that it doesn't face competition from the leading player in the oncology prognostic testing market, Genomic Health, which markets Oncotype DX cancer recurrence tests for early-stage breast cancer and colon cancer but has not yet entered the lung cancer space.
According to Mann, Pinpoint Genomics has no ties to Genomic Health. Still, the nascent company can certainly benefit from emulating Genomic Health's business model, which has proven one of the most profitable in the molecular diagnostics industry — largely due to the firm's success in securing reimbursement for its tests.
Like the Oncotype DX tests, the Pinpoint Dx Lung Assay runs on a quantitative, real-time PCR-based platform and analyzes formalin-fixed paraffin-embedded tissue samples —factors that have proven beneficial in broadly commercializing Genomic Health's assays.
Also similar to Genomic Health, Pinpoint is launching its lung cancer test as a laboratory-developed test. "There are no immediate plans to seek [US Food and Drug Administration] approval" for the Pinpoint Dx Lung Assay, Mann said.
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