By Deborah Borfitz

May 7, 2024 | In oncology, it is well appreciated that time is life. Diagnostics are therefore valuable not just to determine the disease state of patients but how best to treat them, says Jane Li, senior director of oncology, pharma, and CRO partnerships related to clinical sequencing at Thermo Fisher Scientific. 

Biomarkers of cancer are now a mainstay of therapeutic decision-making and the speed it takes to identify them can be a life-or-death matter, she says, referencing the 24-hour turnaround time of the company’s flagship Ion Torrent Genexus System. The turnkey next-generation sequencing (NGS) solution, introduced in 2019, has become the centerpiece of Thermo Fisher’s new companion diagnostic (CDx) development. 

It is no wonder. The wait time for results from NGS tests is typically two to three weeks, says Li. 

NGS-based in vitro diagnostic (IVD) testing has been expanding rapidly over the last five years to become the preferred CDx for many drugs, Li continues. Thermo Fisher is the leading player in this space, which it shares with genomic testing lab Foundation Medicine. 

A 2015 partnership with Novartis and Pfizer marked the start of NGS-based CDx at Thermo Fisher, resulting two years later in the first and only such distributed test receiving approval by the U.S. Food and Drug Administration (FDA)—the Oncomine Dx Target Test that simultaneously evaluates 23 genes associated with non-small cell lung cancer. The test currently has regulatory approval in 19 countries for 18 targeted therapies, she reports. 

Thermo Fisher has always competed on technology, notes Li. In the early days, it distinguished itself by having the most tissue-saving NGS in the industry—a huge advantage when it comes to lung cancer where tumor biopsy samples are very tiny. While other NGS technologies were experiencing failure rates as high as 30%, the demonstrated success rate of the Ion Torrent technology was over 90%. 

Thermo Fisher’s first NGS CDx, Oncomine Dx Target Test, was run on formalin-fixed, paraffin-embedded tissue samples using Thermo Fisher's Ion PGM Dx System. Two years ago, the company announced new CDx development using Oncomine Dx Express Test for both tissue and liquid biopsy on the newer Genexus System that has been “the gamechanger when it comes to turnaround time.” 

CDx Specialties

Outside of the NGS-based CDx work being done by Li and her colleagues, other divisions of Thermo Fisher are developing additional types of CDx tests involving a comprehensive collection of different technologies, she says. These include ones focused on traditional Sanger sequencing and the polymerase chain reaction (PCR) methods. 

Sanger sequencing is utilized by the transplant division where human leukocyte antigen (HLA) testing was conventionally done to match organ and tissue transplant recipients with compatible donors, says Li. But in the past few years, pharma companies have started developing oncology drugs targeting patients testing positive for specific HLA biomarkers. In late 2020, Thermo Fisher had the first HLA-based CDx approved by the FDA for a melanoma therapy. 

Most recently, with the acquisition of protein-based technologies and capabilities, Thermo Fisher has also been exploring the use of protein analysis to support pharma clinical trials and CDx purposes, says Li. Interest in the discovery of protein signatures correlating with drug response has been growing alongside NGS-based approaches.  

CDx has seen significant evolution in the past two decades. Immunohistochemistry (IHC), the standard companion diagnostic technique, has existed for over two decades now, she adds. The first HER2 therapy for breast cancer was an IHC CDx that used a chemical dye to stain the overexpressed proteins. These days, IHC remains the standard for protein-based CDx. A panel of proteins are being targeted by IHC CDx tests being produced by Roche (formerly Ventana) and Agilent (formerly Dako). 

For molecular targets, PCR has traditionally been the standard CDx in the past two decades, says Li. Leading players for PCR-based CDx are QIAGEN and Roche Diagnostics. 

Another longtime staple in the CDx arsenal are tests based on fluorescence in situ hybridization (FISH), which are useful for looking at genetic abnormalities. But over the past decade, single-gene PCR CDx and FISH CDx have been steadily displaced by NGS with its ability to cast a wide net of many diverse genomic alterations across different variant classes all at once from one single specimen, she says. 

Smooth Sailing

From a regulatory standpoint, the CDx approval process has been consistently smooth even in the U.S. and Japan where contemporaneous submission and approval of any new drug and its companion diagnostic is required. Elsewhere, including Korea and Australia, regulatory guidance is published for joint CDx and drug development, says Li, but “it is not black and white.” 

“In Japan, typically we will go together with the pharma team to PMDA [Pharmaceuticals and Medical Devices Agency] meetings... [to] talk about the drug schedule and... the CDx,” she says. With the FDA, the Center for Drug Evaluation and Research (CDER) works in parallel with the Center for Devices and Radiological Health (CDRH) on co-development projects. 

Thermo Fisher has been through the FDA approval process for seven new drugs over the last five years and close to 20 over the same period in Japan, all without complication, she reports. In the beginning, Thermo Fisher’s CDx partnerships were related to a primary CDx for a new drug, says Li. Today, the portfolio is an even mix of primary and follow-on CDx tests. 

The follow-on variety is for drugs that have already been approved, but in concert with a different CDx, sometimes a PCR-based companion diagnostic, she says. For commercial purposes, pharma companies want to add an NGS-based CDx solution to increase patient testing access. 

In other cases, a drug-CDx combo has been approved with a single site central lab in the U.S. and drugmakers—again, for commercial purposes—want to make in-country CDx testing solutions available elsewhere to expand patient access to local testing and timely treatment. One of Thermo Fisher’s advantages over other models is that it makes companion diagnostics intended for distribution in many laboratories in any country, she notes. 

Since the clinical trial assay used in support of the drug approval was different, a bridging study is done to demonstrate that the clinical efficacy observed by patient selection with the primary CDx is maintained when using the new CDx. Regulatory processes for follow-on studies, and the execution of them, follow different rules that can be country specific, says Li.  

Reimbursement Matters

In general, the development and approval of companion diagnostics follow a very similar path country to country, says Li. What differs from one place to the next are reimbursement practices around CDx. 

 In the U.S., for example, the Centers for Medicare & Medicaid Services has a national coverage policy for NGS CDx that provides clear path to obtain reimbursement coverage and pricing roughly 12 to 18 months after approval by the FDA, Li says. The price ranges from $1,500 to $3,000, depending on the panel size. 

In Japan, reimbursement gets approved by the Ministry of Health, Labour and Welfare based on the stacking number of CDx approvals, she explains. “With every new CDx approval, reimbursement price would increase, so the pricing can be somewhere between $500 to $2,000 for NGS CDx.” The entire process only takes about three months following PMDA approval, and this is why NGS CDx adoption can ramp up quickly in Japan. 

What’s Ahead

The U.S. regulatory environment for companion diagnostics appears poised for change. Last summer, the FDA launched a pilot program that allows some precision oncology drugs to be approved without a CDx and will post assay performance metrics online. The idea is to reduce risks associated with using laboratory developed tests to identify cancer biomarkers but also improve patient access to clinical trials since centralized testing is associated with delays.  

The European In Vitro Diagnostic Medical Device Regulation went into effect in 2022, significantly upgrading government policy in that part of the world, but “we are seeing a delay in execution and a long queue of applications at notified [bodies],” Li says. Across the stakeholder landscape, there needs to be “holistic consideration” of how IVDs get approved and reimbursed as well as how physicians are educated on use of the devices. 

As suggested by presentations made at the recent American Association for Cancer Research in San Diego, says Li, new ways of identifying and thinking about biomarkers are emerging. A lot of attention was paid to technologies for single cell sequencing, multiplex IHC, spatial biology, and the use of artificial intelligence to identify biomarker signatures. Her hunch, she adds, is that future CDx will be less about single technologies than the integration of molecular and protein data.