The Approved RET-Fusion NGS‑based Companion Diagnotic Test for Pralsetinib

The Approved RET-Fusion NGS‑based Companion Diagnotic Test for Pralsetinib

An interview with Scott Fogerty, Associate Director, Diagnostic Partnering, on Thermo Fisher Scientific’s NGS-Based Companion Diagnostic for RET Fusion-Positive Non-Small Cell Lung Cancer

The U.S. Food and Drug Administration (FDA) recently granted premarket approval to Thermo Fisher Scientific’s Oncomine Dx Target Test as a companion diagnostic (CDx) to identify RET* fusion-positive, metastatic non-small cell lung cancer (NSCLC) patients who are candidates for GAVRETO™ (pralsetinib, a tyrosine kinase inhibitor).1-3 The test reports result on 23 genes, including EGFR, BRAF, RET, and ROS1 as companion diagnostics; a full list can be found in the Physician Insert for this test (see Reference 3, especially item 5).

At least 10 ng of DNA and RNA is extracted from NSCLC formalin-fixed paraffin-embedded (FFPE) samples, processed with Oncomine Dx Target Test on the Ion PGM Dx system, and a report is generated with approved targeted therapies (e.g., RET positive results for GAVRETO) for review by healthcare providers for patient treatment decisions.

Oncomine Dx Target Test was initially approved in 2017 as the first targeted next-generation sequencing (NGS)-based Companion Diagnostic (CDx) for three companion diagnostics makers with FDA‑approved therapies in NSCLC. The recent approval is the first and only FDA-approval of a RET companion diagnostic for a targeted therapy.2

We contacted Thermo Fisher Scientific to follow up on this precision diagnostic kit, especially for its use with GAVRETO. Scott Fogerty agreed to address a few questions on the kit and system.

Q. Thank you for agreeing to address questions regarding Oncomine and GAVRETO. Can we please start with the history of the Thermo Fisher Scientific with this assay? What kicked it off, what has kept the focus during development?

A. We started our Oncomine companion diagnostics program in 2015 with the signing of the first NGS companion diagnostic partnership with Pfizer and Novartis for targeted therapies in NSCLC. This CDx development program was a bit unusual, since both drugs were already approved for use in cancer patients. The approach helped de-risk our development efforts as we did not have to worry about the chance the drugs would fail during development. That effort led to the submission and approval of Oncomine Dx Target Test by the FDA in 2017 as the first NGS companion diagnostic test for multiple therapies. Since then, we have signed more than 10 pharmaceutical CDx partnerships supporting new drugs or new cancer indications that are currently in development. More importantly, we have expanded the approval of Oncomine Dx Target Test in other regions around the world, including EU, Japan, Korea, and Israel, where the test is now reimbursed as well as commercially available.

Q. Can you discuss the history with BluePrint Medicines, starting from before the agreement struck in 2017?

A. We always want to get involved as early as possible in joint CDx and drug development programs since the pairing is obviously tied together. We started our first CDx discussions on GAVRETO (then BLU-667) in late 2015, well before BluePrint entered the clinic with the drug in early 2017. They had conducted a pilot study with preclinical samples using the Oncomine Focus Assay, our RUO panel that was the antecedent leading to the Oncomine Dx Target Test, and compared the results detecting RET fusions with other NGS platforms available at the time. BluePrint was encouraged by the results but needed time to work through the dose escalation study in NSCLC patients due to uncertainty about a new drug’s safety and efficacy going into Phase I clinical studies. In Phase I oncology clinical studies, rather than testing the drug in healthy individuals, sick patients are treated through dose escalation. This means there can be early clinical evidence the drug is working in the intent to treatment patient population. At the same time, we, Thermo Fisher, were also seeking FDA approval of our test. With the approval of Oncomine Dx Target Test in 2017 and early Phase I signs showing GAVRETO was safe and patients were responding, we entered the CDx partnership in October of 2017.

“We always want to get involved as early as possible in joint CDx and drug development programs since the pairing is obviously tied together”

Q. Can you provide some insight on the approval process for this assay application?

A. The submission and approval process with the FDA for companion diagnostics involves a substantial number of rigorous laboratory studies guided by the code of federal regulations governing in vitro diagnostic tests. These studies include early test feasibility, analytical validation and clinical validation studies to demonstrate the robust performance of the IVD test, including sensitivity, reproducibility, and accuracy using tumor biopsy samples obtained from the patients enrolled in drug registration clinical trials.

Q. How was the signature for this assay developed? That is, were the components and sequences developed de novo? Or were leads in the literature or in laboratory the basis for this assay?

A. Gene fusions are proving to be important driver mutations in NSCLC and other cancer indications. Their clinical relevance has been demonstrated in many publications, preclinical and clinical studies as well as numerous clinical trials. As such, Thermo Fisher Oncomine panels, including Oncomine Dx Target Test, deliver results for a range of gene fusions, including the RET gene, for solid tumor samples.

Q. Regarding assay approval and designation as a companion diagnostic, how were the number of participants determined for the premarket approval (PMA) trial? Was the number based on using the signature to find potential responders to power the statistics?

A. For the development of companion diagnostics, clinical study samples come from our pharmaceutical partner’s clinical trial cohorts. The number of samples is determined by the trial sample size, which is designed by the pharmaceutical company’s clinical statisticians to demonstrate the efficacy of the drug in the treatment population with a high level of statistical confidence.

Q. Obtaining FFPE biopsy samples from lung tissue can be challenging. We had previously discussed using circulating nucleic acid for NSCLC assays and noted that Oncomine has applications for liquid biopsy samples. Could you please comment on the state of the work for this application for NSCLC – in your labs or elsewhere (see, e.g., Reference 5)?

A. As they say in oncology, “tissue is the issue.” This can be especially true not only in NSCLC but in clinical trials, where the new drug being developed may be third or fourth in line to be used in patients who have developed resistance to previous established treatments. These patients may be too sick to undergo a tumor biopsy procedure, so being able to detect cancer driver mutations in a blood draw offers obvious advantages.

We have a number of Oncomine assays for liquid biopsy applications that work with circulating total nucleic acid (DNA and RNA), including cfTNA non-small cell lung, breast and colon cancer assays, and also a cfTNA pan-cancer assay. What we are really excited about is our latest Oncomine test, the Oncomine Precision Assay (OPA), which is a dual use FFPE and liquid biopsy test, using the same panel, that is run on our new Genexus System. More importantly, the Genexus System provides a rapid turnaround time to deliver the test results within one to two days after the patient sample arrives at the testing laboratory. While the current assay is research only (RUO), we plan to take Oncomine Precision Assay on Genexus through FDA approval. We also have two new pharmaceutical CDx partnerships underway featuring the Oncomine Precision Assay.

Q. Could you comment on the potential for this assay as a broad-based screening tool? Or do you foresee other products being derived from the Oncomine Dx Target Test that may be a cost-effective screen that can be performed in a doctor’s office (e.g., a rapid panel test)?

A. As the first NGS platform approved as a CDx, the Oncomine Dx Target Test workflow requires a highly skilled and trained operator, and it is designed to be run in CAP/CLIA certified laboratory setting. The workflow generally takes about four to five days to provide the test report. As I mentioned previously, our second generation CDx system, the Oncomine Precision Assay and Genexus System, was designed to simplify the complexity of the operator workflow through an automated design. The new system literally only requires 10 minutes of operator hands-on time and results can be achieved in as little as one day. Since the new system has built-in expertise, testing can be run by a medical technician once it is FDA-approved, bringing NGS testing closer to patients in the local community settings, where cancer patients are treated.

Another advantage of the Genexus System is the test reagents are stored and stable in the instrument and the new chip design has four channels so you can test one to a few samples at a time and not use an entire chip or reagent kit. The tool will one day enable more cost-effective NGS testing, since this mirrors how cancer patients present and are diagnosed in local communities across the country.

Q. Is Thermo Fisher Scientific conducting any pharmacovigilance or working on any follow-up studies?

A. Yes, this is required for IVD products; we have post-market surveillance plans for all our CDx programs.

Q. Did Thermo Fisher Scientific file a request to CMS for a decision on coverage (local or national)? If so, what is the status of that request and the case for reimbursement?

A. Thermo Fisher has filed for both local and national coverage determination. Without reimbursement, it is difficult for a test to gain utilization since the patient or the pharmaceutical partner would have to pay for it. Oncomine Dx Target test is covered by CMS nationally with a reimbursed price of $1950 in 2020. As importantly, unlike other NGS platform CDx tests, it is also reimbursed by over 40 commercial payors in the U.S.

Q. What is the road map for this assay? Do you foresee applications beyond NSCLC for precision medicine indications?

A. Our focus has been on NSCLC as many of our pharmaceutical partners have been actively developing drugs for this indication. NSCLC is a driver as the largest commercial market, however, many pharmaceutical and biotech companies are now also focusing on rare cancer indications (e.g., cholangiocarcinoma), and we do have a couple of CDx programs for these types of cancer indications.

In addition to our strong CDx program pipeline in NSCLC, we are actively engaged with the pharmaceutical industry to align on their emerging targeted therapy and immunotherapy pipelines to support genomic biomarker proof-ofconcept clinical studies and full-blown CDx programs through to submission and approval. We are very optimistic about the important role we can play in the practice of precision medicine; it all begins with the test to guide Patient treatment – that is, which therapy should be used with which patient. To that end, we are already in discussions with pharmaceutical colleagues regarding the development of our next generation CDx system – Oncomine Precision Assay run on the Genexus System – for use across a range of cancer indications.

JPM: Thank you, Scott.

Scott FogertyScott Fogerty – Interim Global Director Diagnostic Partnering Thermo Fisher Scientific Scott is a biopharmaceutical industry veteran with over twenty years of experience in product development, biomanufacturing, strategic marketing and business development. Mr. Fogerty has master’s degree from the University of Central Florida specializing in developmental genetics. Scott began his career as a molecular biology R&D scientist with Pharmacia and then held positions at Covance, Johnson & Johnson, Affymetrix and Thermo Fisher supporting biopharmaceutical development, translational biomarker and companion diagnostic programs from early development through to global commercialization.



* RET stands for “rearranged during transfection”

  1. GAVRETO is a potent and selective once-daily oral therapy designed to target RET fusions and mutations, and was approved based on data from the ongoing Phase 1/2 ARROW clinical trial in patients with RET fusion-positive NSCLC with or without prior therapy, see FDA approves pralsetinib for lung cancer with RET gene fusions,
  2. FDA Approves First NGS-Based Companion Diagnostic for RET Fusion-Positive Non-Small Cell Lung Cancer CDx approval expands clinical utility of Oncomine Dx Target Test to identify candidates for GAVRETO,; see also Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients with Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors (ARROW),
  3. For Information on Oncomine Dx Target Test, see:
    1. Test Kit:
    2. Physician Insert: OncomineTM Dx Target Test:
    3. Ion PGM™ Dx System,
    4. Summary of safety and effectiveness data (SSED):
    5. Physician Insert: OncomineTM Dx Target Test:
    6. For Oncomine Dx Test Clinical Trial, see, e.g., Lung Cancer Next Generation Sequencing Using the Oncomine Comprehensive Assay (LU-NGS-2):
    7. Premarket Approval for Oncomine Dx Test and Letter:,

See also:

Oncomine Cell-Free Assays

    1. Liquid Biopsy Clinical Research,
    2. Lung cfDNA Assay,;
    3. Lung Cell-Free Total Nucleic Acid Research Assay,

Clinical feasibility of NGS liquid biopsy analysis in NSCLC patients, Eirini Papadopoulou et al., PLoS One. 2019; 14(12): e0226853, or doi: 10.1371/journal.pone.0226853