Knocking Down Barriers to Precision Oncology with Companion Diagnostics

More than 25 years ago, the FDA approved the first companion diagnostic assay. Still in use today, the HercepTest^TM marked a before and after in precision oncology, allowing the approximately 20% of women with HER2 positive breast cancer to receive targeted therapies. Since then, research and development in companion diagnostics has grown exponentially.

“Today there are more than 60 companion diagnostics approved by the FDA, most of these in the field of oncology,” said Christoph Majewski, PhD, VP, and Lifecycle Leader for Personalized Healthcare Solutions at Roche Diagnostics, a division that specializes in the development of companion diagnostics. “Most drugs that are out there today will help a fraction of the patients that receive them; identifying the fraction that will respond to these drugs is incredibly important.”

Companion diagnostics can play a key role in improving patient screening and stratification, which in turn can have a huge impact on their survival and quality of life. Their use in routine clinical practice can cut down healthcare costs by ensuring that only patients who are likely to respond to a targeted drug receive it. For pharmaceutical companies, developing targeted drugs in parallel with a companion test has also been shown to reduce R&D costs by increasing the success rate of clinical trials.

Despite the outstanding growth seen in the past two decades, there is still room for improvement. As our understanding of the complex molecular and physiological processes driving cancer grows, limitations of current diagnostic technologies become apparent. For instance, most companion tests in the market today target a single biomarker, and therefore, lack the ability to tackle the vast heterogeneity seen across patients and within individual tumors. These constraints contribute to the fact that, even today, many patients who receive targeted treatments fail to respond to them.

To realize the full potential of companion diagnostics, academic researchers and the pharmaceutical industry will need to work together to not just tackle technological challenges, but also navigate the regulatory landscape and support the effective implementation of these diagnostic tests in routine clinical practice. Most importantly, said Majewski, “It will not be a one-size-fits-all solution.”

The gold standard of companion tests

Immunohistochemistry (IHC) was behind the first wave of companion diagnostics that entered the market in the late 1990s and remained the dominant technology until just a decade ago. However, the technique presents certain limitations in terms of reproducibility and sample variability, which can be compounded by the fact that results need to be interpreted by a trained pathologist and may lead to subjective outcomes.

One application where these tests need to see improvements is checkpoint inhibitor immunotherapy. The latest estimates show that, of all patients with advanced or metastatic cancer who are eligible to be treated with checkpoint inhibitors, only 20% will respond to the treatment. In this context, IHC is a common method used to determine expression of programmed death-ligand 1 (PD-L1), a checkpoint inhibitor targeted by immunotherapies such as pembrolizumab, nivolumab, and atezolizumab. However, the antibodies used in these tests today are not able to recognize all forms of the protein, including its glycosylated state, which can result in false negatives, said Gérard Milano, PhD, scientific director of the Nice Cancer Center in France.

Milano is a strong believer that, in addition to improving existing technology, there is a need for more comprehensive diagnostics that consider the heterogeneity and complexity of tumor biomarkers. For instance, biopsy samples used to detect PD-L1 may not be representative of the entire tumor, which is leading researchers to increasingly look at the tumor microenvironment and circulating tumor DNA to better screen patients.

As scientists strive to address these limitations, Milano expects IHC to remain a strong contender in the diagnostics market: “If we can continue improving immunohistochemistry technology, it will remain the preferred analytical tool for companion diagnostics as it is affordable and easy to perform.”

Molecular profiling enters the toolbox

Over time, molecular diagnostic techniques like polymerase chain reaction (PCR) and next-generation sequencing (NGS) have entered the realm of companion diagnostics. These techniques have advanced to the point of being sensitive enough to measure small amounts of circulating tumor DNA from a blood sample, which has led to an increase in their popularity over the years.

In particular, NGS has massively contributed to a better understanding of genetic drivers of disease across a variety of tumor types. However, its application as a companion diagnostic can be limited by high costs and long turnaround times.

“Next-generation sequencing is used primarily in oncology diagnostics today as a screening tool to try to capture as much data as possible,” said Richard Watts, vice president of business development, companion diagnostics, at QIAGEN, a provider of molecular diagnostics. He noted that while NGS can provide vast amounts of information, techniques such as PCR can answer more concrete clinical questions and provide some advantages regarding sensitivity. In addition, performing NGS testing can be quite a complex undertaking, whereas PCR technology has become widely available, especially after the COVID-19 pandemic. These factors have contributed to PCR-based assays becoming the largest category of companion diagnostics on the market today.

The fast turnaround time of PCR assays is also a major draw. Watts highlighted QIAGEN’s near-patient testing platform, QIAstat-Dx, which can get results back within an hour, and without the need for trained technicians, enabling physicians to follow patients over the course of their treatment journey. He added that digital PCR platforms can also provide exceptional sensitivity for diagnostic applications such as liquid biopsy testing. “For example, many lung cancer patients are EGFR positive. When they are given EGFR-targeted therapies we know there is a particular mutation of resistance that is going to eventually occur. In this case, monitoring the patient with a digital PCR test is ideal because it’s very sensitive, fast, and cost-effective.”

Ultimately, choosing the right technology to develop a companion diagnostic test will depend on multiple factors. According to Majewski, there are two main drivers when it comes to the best choice of technology for a given companion diagnostic: the biomarker being targeted and the turnaround time. When it comes to biomarkers that are overexpressed in a tumor, such as HER2 in breast cancer, a tissue-based diagnostic may be the optimal solution to get results quickly, typically in a few days. For HER2 or hormone receptor negative breast cancers, however, an NGS test could provide more information about potential mutations that could be driving the disease, but in a real-world setting it may take two to three weeks to get results back to the patient.

“Getting a patient on the right drug as quickly as possible is very important,” said Majewski. “If a doctor has a cancer patient in an advanced stage and cannot have results back in a short time, the patient will need to be treated with chemotherapy, meaning that many patients who would be eligible for targeted therapy won’t get the best possible treatment for their specific tumor.”

A growing role for artificial intelligence

The advent of computational biology and artificial intelligence (AI) is already having a major impact on the development of companion diagnostics. For instance, AI assistants that help pathologists analyze samples and interpret the results have been introduced. Majewski sees particular promise in algorithms that can perform tasks that may be difficult for a pathologist, such as quantifying multiple biomarkers within a sample and evaluating how frequently they appear in healthy cells versus tumor cells.

The growing capabilities of AI technology will also support the integration of multiple modalities of companion diagnostics to create ever-improving scoring systems, even going beyond tumor biomarkers, to determine the best course of treatment for a patient. “We cannot neglect the importance of the patient’s pharmacogenetics if we want to optimize cancer treatment,” said Milano. He drew attention to the example set by France, where it is mandatory to test patients for dihydropyrimidine dehydrogenase deficiency before undergoing chemotherapy with fluoropyrimidine agents as the condition can put patients at high risk of experiencing adverse events and even death.

Altogether, advances in AI and computational biology are set to drastically change the companion diagnostics landscape, which will undergo considerable acceleration at both the academic research and commercial development levels. “The notion of speed is completely changing with the arrival of artificial intelligence,” said Milano.

Navigating the regulatory landscape

The successful commercialization of companion diagnostics requires developers to meet the evidence requirements set by regulators across different regions. “The regulations can be complex to navigate because all the technologies used in these assays are very different,” said Richard Sullivan, PhD, professor of cancer and global health at King’s College London and director of the Institute of Cancer Policy. “Authorities are struggling at the moment with keeping up with the speed of technology development. It took a few years to work out what was the gold standard for HER2-positive breast cancer, for example.”

Both in Europe and the U.S., companion diagnostics are currently classified as high-risk in vitro diagnostic medical devices. This means that the tests have to be thoroughly validated. As a result, their development needs to start well in advance of clinical trials.

“One of the key challenges is that this process needs to be highly synchronized,” said Majewski. “When a drug hits the market with a restricted label that requires a companion diagnostic, we need to have a companion diagnostic ready to launch the same day.”

Because of this, the developers of the companion diagnostics need to make sure the development of both the drug and its companion diagnostic are tightly aligned. This also requires that agencies overseeing the drug and companion test coordinate with each other to ensure a synchronized launch. Regulators in Europe can stand to improve in this area by following the example set by the U.S., noted Majewski.

In the EU, there have been recent changes in the regulatory landscape with the In Vitro Diagnostic Medical Devices Regulation (IVDR) entering into force. These regulations have made a significant impact on the requirements for a companion diagnostic to receive and maintain a marketing authorization, and may lead to additional costs and longer timelines in the development process. “The introduction of the new requirements in Europe with the IVDR regulation creates new challenges in terms of the speed at which we can move,” said Watts.

Working towards a brighter future

Going forward, Majewski expects biomarker-based diagnostics to become standard in cancer treatment. As the number of targeted treatments available to cancer patients continues increasing, so will the need for companion tests to accurately screen a wide range of tumors, supported by ongoing advances in their sensitivity and throughput.

Milano foresees that proteomics, and in particular spatial proteomics techniques, will take an increasingly important place in the development of companion diagnostics. To ensure success in a clinical setting, he believes that academic researchers and the pharmaceutical industry will have to work closely to achieve a higher standardization of diagnostic tests across all technological modalities.

“If we want the correct use and implementation of these tests, commercialization is the solution to achieve the largest benefit possible for the patient,” said Milano. He pointed to the example of Oncotype DX tests for breast cancer, a real-time PCR test that evaluates the expression of 21 genes, which is now widely used by physicians to determine the best course of action for breast cancer patients.

Looking into the future, Watts envisions companion diagnostics expanding beyond oncology. “We have learned a lot from the work that we have done in oncology regarding bringing new drugs to market,” he said. “Now, we are starting to apply that to other fields like neurodegenerative disease, inflammation, and autoimmune disease.”

Finally, a key factor to ensure the broad adoption of companion diagnostics will be facilitating their use in a clinical setting. “I expect a move towards more near-patient testing, where diagnostics are available to physicians and information transfer is accelerated,” said Watts. “I also expect to see more simplicity in the devices being developed, enabling users to perform more complex diagnostic procedures in a straightforward way.”

Clara Rodríguez Fernández is a science journalist specializing in biotechnology, medicine, deeptech, and startup innovation. She previously worked as a reporter at Sifted and editor at Labiotech, and she holds a MRes degree in bioengineering from Imperial College London.