David S. Klimstra, MD
The use of next-generation sequencing (NGS) to diagnose cancers and guide therapy decisions is expanding as more therapies are linked to genomic abnormalities. But advances in molecular testing face headwinds in the near term as clinicians struggle to manage the wealth of data produced by tests and payers balk at covering expensive assays backed by sparse evidence for improved outcomes.
The debate over the future of testing centers on broad-spectrum panels that evaluate tumor tissue for dozens or hundreds of genes at once, as opposed to standard in vitro diagnostics that test for a single aberration such as HER2, to predict response to trastuzumab (Herceptin) in breast cancer, and EGFR, to guide the use of tyrosine kinase inhibitors for lung cancer. Spurred by a 2013 US Supreme Court decision that genes are not patentable, along with the plunging cost of sequencing and the convenience of using 1 tissue sample to check for multiple abnormalities, private labs, academic hospitals, and cancer centers have developed panels that examine as many as 500 genes at once in the last 5 years.
The growing significance of NGS was illustrated in December 2017 by the first FDA approval of a large panel, Foundation Medicine’s FoundationOne CDx (F1CDx), which detects mutations in 324 genes and 2 genomic signatures in any tumor type. CMS conducted a parallel review that led to a proposal for limited Medicare coverage of the test.
Last year, the FDA also granted authorization for MSK-IMPACT, a 468-gene assay developed by Memorial Sloan Kettering Cancer Center (MSK) in New York, New York. The decision created a new pathway for regulatory analysis of large gene testing panels (FIGURE). The authorization could promote test adoption and cooperation with pharmaceutical companies, possibly payer coverage as well, while potentially paving the way for future approvals of other similar products.
Figure. FDA's Approach to NGS Tumor-Profiling Tests
However, the federal review process also underscores the hurdles that laboratories face as they seek broader acceptance of their products. Although testing companies and oncologists have applauded CMS for addressing the question of NGS coverage, many have also expressed dismay at the accompanying restrictions. Under the draft policy, CMS would only pay for tests that are FDA approved or cleared or are being used in National Cancer Institute-sponsored trials and would not cover retesting using the same test, among other limitations.1
A decision is due February 28, 2018.
The policy specifically mentions 5 tests that the FDA has approved so far (TABLE). Additionally, the draft identifies the patient population elgible for test coverage as those who have recurrent, metastatic, or advanced stage IV cancer.1
Table. FDA-Approved NGS Tumor-Profiling Tests
“What it would basically do is deny payment for the vast majority of assays currently being offered, unless they follow our lead and obtain FDA clearance. Even then, it’s a rather restrictive subset of cancer types that would be covered,” said David S. Klimstra, MD, chair of the Department of Pathology at MSK. He said he is also concerned that CMS’ proposed policy would essentially expand FDA authority over the assays without the usual congressional oversight. Such assays are currently considered laboratory-developed tests (LDTs) that do not need FDA approval.
“The draft policy is also only directed toward next-generation sequencing assays,” Klimstra noted. “CMS would continue to support existing payment structures for single-gene assays, which are less broad-spectrum, less tissueefficient, and less sensitive, but it would refuse to pay for the best assays out there. In a sense, that is a clear step backward.”
Rising Demand for Panel Testing
The dominant technologies for molecular marker testing include immunohistochemistry, fluorescence in situ hybridization, and NGS methods. Use of all of these types of assays is increasing due to the expansion of targeted therapies, but the number of multigene NGS tests ordered annually appears to be rising particularly quickly. NGS assays represented 27% of molecular tests in the National Institutes of Health’s Genetic Testing Registry in February 2016, up from 10% 2 years earlier.2
Panels of at least 5 genes accounted for 16% of NGS tests. In addition, the number of oncology genetic tests of all types in the registry had jumped 153% over 12 months.