Breaking NGS Ground

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Laboratory workers prepare to run a diagnostic test on Thermo Fisher Scientific’s Ion Torent NGS platform.

Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

CMS Final Coverage Determination Promotes Sequencing-Based Testing for Advanced Cancer

Developers of next-generation sequencing (NGS)-based diagnostics breathed a sigh of relief in March, after months of clashing with the Centers for Medicare & Medicaid Services (CMS) over NGS testing reimbursement for Medicare and Medicare Advantage patients with advanced cancer.

CMS rattled test developers in November with a draft National Coverage Determination (NCD) that limited Medicare coverage to FDA-approved NGS panels for the most advanced oncology patients. Diagnostic companies argued that numerous clinical applications of NGS within oncology are not directly related to therapy selection, and that NGS-based testing is used in numerous other areas outside of oncology.


“The concern among the broader industry was that this could actually nip in the bud all of the interesting developments in clinical diagnostics based on NGS before it’s even really starting to flourish,” Charles Mathews, principal with ClearView Healthcare Partners, a global strategy consulting firm serving the life sciences sector, told Clinical OMICs.

However, when CMS issued its final NCD on March 16, test developers’ fears turned mostly to cheers. The final coverage determination expanded eligibility for Medicare reimbursement by adding coverage for patients with Stage III metastatic, recurrent, relapsed, or refractory cancers, in addition to the Stage IV relapsed or refractory cancers included in the draft NCD. The final NCD also included repeat testing when a new primary cancer diagnosis is made by the treating physician and the patient meets other clinical criteria. As outlined in the draft NCD, it removed coverage with evidence development for tests not authorized by the FDA.

The action by CMS followed a concurrent FDA review of Foundation Medicine’s FoundationOne CDx comprehensive genomic profiling assay through the agencies’ Parallel Review Program. FoundationOne CDx is designed to detect substitutions, insertion and deletion alterations (indels), and copy number alterations in 324 genes and select gene rearrangements. The test also detects genomic signatures, including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens.


Source: Foundation Medicine

“As the FDA moves toward biomarker driven drug approvals that are tumor agnostic, like pembrolizumab [Merck & Co.’s cancer immunotherapy Keytruda] with MSI, having a test that is FDA approved, is mapped to a broad range of companion diagnostics, interrogates the entire cancer genome and provides TMB and MSI scores on every patient report, could have a dramatic impact on clinical care,” said Gary Martucci, senior vice president, reimbursement and payer strategies at Foundation Medicine.

FoundationOne CDx became commercially available on March 30 at a list price of $5,800. For Medicare beneficiaries meeting NCD criteria, there is currently no anticipated co-pay or deductible amounts. CMS coverage also includes beneficiaries that are enrolled in Medicare Advantage plans. Depending on a member’s plan, they may be subject to a co-pay or deductible. But for those patients, some may be eligible for Foundation Medicine’s FoundationAccess program to assist with out-of-pocket expenses, Martuccis noted.


Foundation Medicine’s FoundationOne CDx won FDA approval and a CMS NCD late last year via the agencies’ parallel review program.

Automatic Approvals

FoundationOne CDx is among four NGS cancer tests that received FDA approval or clearance as an in vitro companion diagnostic, and thus automatically approved for coverage under the final NCD. The other three:

Foundation Medicine’s FoundationFocus CDxBRCA, designed to detect tumor BRCA1 and BRCA2 mutations, germline and somatic, in ovarian cancer. CDxBRCA has FDA approval as a companion diagnostic assay for Clovis Oncology’s Rubraca (rucaparib), a poly ADP-ribose polymerase (PARP) inhibitor indicated for advanced ovarian cancer.

Illumina’s Praxis Extended RAS Panel, approved for use with the company’s MiSeqDx System to help clinicians identify patients eligible for treatment of metastatic colorectal cancer with Amgen’s Vectibix (panitumumab).

Thermo Fisher Scientific’s Oncomine Dx Target Test, designed to detect 368 variants in 23 cancer-associated genes clinically associated with non-small cell lung cancer (NSCLC)—three biomarkers validated for selection of relevant targeted therapies (EGFR, ROS1, or BRAF), and 20 additional genes relevant for NSCLC pathogenesis, analytically validated for variant detection from NSCLC tissue.

Joydeep Goswami, Ph.D., president of Clinical NGS and Oncology for Thermo Fisher, said the final NCD increased by 58% the number of U.S. lives covered for Oncomine Dx Target Test by adding CMS’ 58.9 million lives. The balance of the 160 million lives covered for the test, Goswami said, is covered by commercial payers that include Cigna, Aetna, UnitedHealthcare, Independence Blue Cross, and Humana.

“The potential for greater usage of Oncomine Dx Target Test is substantial given that the average age of NSCLC diagnosis in the United States is 70, with two-thirds of those diagnosed being of Medicare age,” Goswami said. “Additionally, we expect this CMS decision to encourage the development of more NGS-based tests and greater adoption of these tests by labs to help patients. We are also hopeful that the FDA will continue to streamline requirements to help these tests to get to market faster and more cost-effectively.”

The FDA on April 12 approved two final guidance documents designed to advance NGS test development. One allows developers to rely on clinical evidence from FDA-recognized public databases to support clinical claims for their tests. The other offers recommendations for designing, developing, and validating NGS-based tests, and explains what the FDA would seek in premarket submissions.


A clinical lab scientist at Cancer Genetics, Inc. processes a non-small cell-lung cancer sample for testing using Thermo Fisher Scientific’s Oncomine Dx Target Test.

Looking Toward Expansion

Regulatory streamlining, Goswami added, should rapidly expand the pool of NGS-based FDA approved tests to include liquid biopsy and immuno-oncology-based tests. In January, Thermo Fisher launched the Oncomine Pan-Cancer Cell-Free Assay for liquid biopsy analysis, and the Oncomine Tumor Mutation Load Assay for immuno-oncology analysis. Last year, the company launched the Oncomine Immune Response Research Assay, Immune Repertoire Assay Plus, TCR beta, and Oncomine Myeloid Research Assay.

Oncomine Dx Target Test is designed for marketing overseas—it expects to launch the test in Europe and parts of Asia in the second half of 2018—and to eventually incorporate indications beyond NSCLC. Some of the 46 genes on the test’s panel are being studied by pharmacetuical companies for drugs in their development pipelines.The company aims to develop companion diagnostics for Agios Pharmaceuticals’ Phase III candidate ivosidenib (AG-120), aimed at identifying isocitrate dehydrogenase 1 (IDH1) mutations in patients with cholangiocarcinoma, and develop CDx for Blueprint Medicines’ Phase I BLU-667, designed to identify RET fusions in NSCLC patients.

The FDA has also granted marketing authorization to Memorial Sloan Kettering Cancer Center (MSK) for another advanced cancer NGS test. MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) is a 468-gene panel designed to detect gene mutations and other critical genetic aberrations in rare and common cancers. In November, MSK-IMPACT became the first tumor-profiling laboratory-developed test (LDT) to win FDA approval. The single-site assay, performed at MSK, carries no CDx indication.

As in the past, coverage determinations for NGS-based diagnostic LDTs performed in CLIA-certified laboratories for Medicare patients with advanced cancer will continue to be made by local Medicare Administrative Contractors or MACs.


Thermo Fisher made a splash with FDA approval last year with its Oncomine Dx Target Test. Now it plans to expand use of the test beyond NSCLC and to market the test overseas.

Among companies with MAC-approved LDTs is Caris Life Sciences, which won coverage in 2016 for its flagship NGS offering, MI Tumor Seek; MI stands for “Molecular Intelligence.” MI Tumor Seek is an in vitro diagnostic (IVD) NGS assay designed to provide physicians with clinically actionable information on 592 genes including, MSI, TMB, EGFR, ERBB2, KRAS, NRAS, BRCA, and BRAF. The $3,500 test has been ordered by more 10,000 oncologists in 81 countries, and about 40 biopharmas the company said.

Caris also offers 13 additional FDA approved/cleared assays, and an additional 23 FDA-registered IVDs through MI Profile, which uses a comprehensive genomic profiling-plus approach that assesses DNA, RNA, and proteins.

“The result of the [final NCD] decision is going to be a pretty significant expansion and acceptance by the provider community,” said David Spetzler, Ph.D., Caris’ president and CSO. “When you have events like FDA approval for Foundation Medicine and CMS ratifying payment, that’s going to make the entire community more comfortable ordering these types of tests. I think we’ll also naturally see a significant increase in the number of providers that start to perform this type of testing, to ensure that there is adequate access for every patient in our country.”


Thermo Fisher made a splash with FDA approval last year with its Oncomine Dx Target Test. Now it plans to expand use of the test beyond NSCLC and to market the test overseas.

‘A Lot More’ FDA Engagement

Spetzler said that he expected the final NCD “is going to promote a lot more engagement with the FDA” for diagnostic developers. Caris has a pre-submission with the FDA for MICDx, a combined DNA-RNA assay the company is developing, with the goal of improving detection of translocations that will inform decisions on therapy selection.

“We’ll see a very significant increase in the number of applications to the FDA, whether it be clearance or approval, in order to ensure coverage for these types of tests,” Spetzler noted. “Certainly, that’s our intention and plan. We’ve engaged with the FDA already, and I believe that other providers will do the same thing.”

AdvaMedDx, a division of the Advanced Medical Technology Association representing diagnostics manufacturers, is “very hopeful and encouraged about the final NCD and its potential for expanding coverage for these types of tests to patients with advanced cancer,” Executive Director Susan Van Meter said. “We’re certainly seeing positive movement in the direction of ensuring patient access, but this is really the beginning.”

CMS’ focus on tying NGS test coverage to therapy selection means that diagnostics companies whose tests could show significant value, but are not companion diagnostics, will likely struggle with how their tests fit into coverage under Medicare. Mathews said ClearView Healthcare Partners is working with one such developer seeking to market a cancer–recurrence monitoring assay.

“The good news is, now it’s not exclusively prohibited by the policy. But now we’re back to, how can you convince the local MAC that there’s value in that particular application of sequencing?” said Mathews, whose firm has offices in Newton, MA; New York; and San Francisco. “In general, having this pathway is better than not having this pathway, but it leaves open questions about how to bring forward assays that are not specifically focused on therapy selection or in oncology specifically.”

Whatever ways those are resolved, Mathews added, “the final NCD has now established a recognizable and repeatable pathway for others that are interested in this space. That is really exciting for those of us that work in the space, because one issue people have had is the big overhang from investors all the way down through innovators, who have been saying, ‘If we went and did this, and we built this big product, would anybody ever pay for it?’ Now, there’s a very clear pathway saying, ‘If it fits the criteria of the policy, if we are able to get not an FDA approval but now clearance for it, then Medicare at least will pay for it.’”




































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This article was originally published in the May/June 2018 issue of Clinical OMICs. For more content like this and details on how to get a free subscription, go to www.clinicalomics.com.

 

 

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