Earlier this year, the FDA announced two guidances to help drive the development of novel technology (1). The first guidance, “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics”, provides public databases that can be used as clinical validation of novel NGS platforms. The second guidance, “Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS) – Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases”, provides recommendations on how to design and validate NGS tests which will be used to diagnose patients with genetic diseases.
During this Point/Counterpoint sessions at ASCO 2018, panelists Howard A Burris, MD, Sarah Cannon Research Institute, and Leonard B Saltz, MD, Memorial Sloan Kettering Cancer Center, discussed whether or not next-generation sequencing is right for every patient. This session, moderated by Peter Yu, MD, Palo Alto Medical Foundation, highlighted both the benefits of NGS sequencing (finding effective FDA approved therapies, the ability to enroll patients on trials, the ability to determine novel mechanisms of resistance) but also acknowledged that we are still in the preliminary stages of this technology (variable analytic validity and clinical validity, discordant results between different NGS platforms, reimbursement issues). Both presenters reviewed data highlighting some of the successful precision medicine approaches (Pembrolizumab for patients with Mismatch Repair Deficiency3) as well as some of the trials which highlighted major challenges in precision medicine (MOSCATO-14).
Dr. Burris also presented data from a survey of 200+ community oncologists, and posed the question “If your loved one was diagnosed with a relapsed or recurrent cancer, would you want their tumor molecularly profiled”? He received 166 responses: 164 (98.8%) said Yes, and 2 (1.2%) said No. As one presenter noted, “This is not a debate” anymore about whether or not NGS can be helpful and whether or not oncologists can order the test – the FDA has approved an NGS assay and CMS has issued a national coverage determination (NCD) on NGS. Rather, additional key questions still need to be answered. Per Dr. Saltz: “1. For an approved NGS assay, can it be used for any tumor type? 2. If CMS has paid for one approved NGS assay, will CMS pay for the same patient to have an analysis performed by a different approved NGS assay? 3. Can an approved NGS assay be used solely to look for eligibility for clinical trials of targeted agents?” Tougher questions will include, for a “targetable” finding, what is “good enough to be worth it”, as in finding a targetable mutation in 1 in 2, 1 in 10, 1 in 100, etc, and what will we define as “good enough clinical benefit to be worth it”, with respect to disease response and control.
In conclusion, Saltz stated, “with NGS, as with so many aspects of cancer care, we must strive to maintain a balance between optimism and realism, without which it is easy for our patients and their families to build up expectations that far exceed what we can deliver”.
Moderated by: Peter Yu, MD, Palo Alto Medical Foundation
Presented by: Howard A Burris, MD, Sarah Cannon Research Institute, and Leonard B Saltz, MD, Memorial Sloan Kettering Cancer Center,
Written by: Jason Zhu, MD, Fellow, Division of Hematology and Oncology, Duke University Medical Center at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA
1. Wetterstrand KA. DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program (GSP) Available at www.genome.gov/sequencingcostsdata.
2. Commissioner, Office of the. “Press Announcements - FDA Finalizes Guidances to Accelerate the Development of Reliable, Beneficial next Generation Sequencing-Based Tests.” US Food and Drug Administration Home Page, Center for Biologics Evaluation and Research, www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm604462.htm.
3. Le DT, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. doi: 10.1126/science.aan6733. Epub 2017 Jun 8. PubMed PMID: 28596308; PubMed Central PMCID: PMC5576142.
4. Massard C, Soria JC. High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial. Cancer Discov. 2017 Jun;7(6):586-595. doi: 10.1158/2159-8290.CD-16-1396. Epub 2017 Apr 1. PubMed PMID: 28365644.