Companion Diagnostics in Precision Medicine: An In-Depth Review and Future Trends

1. What Are Companion Diagnostics?

Companion diagnostics are fast becoming an essential component of targeted therapeutic strategies. This section describes companion diagnostics (CDx), their utility in clinical medicine, and their evolution in recent decades.

1.1 Why Are Companion Diagnostics Needed, and How Are they Helpful for Patients and Therapies?

The CDx market is projected to generate $10 billion in global revenue by 2026.¹ This marks a significant leap from the first approval in 1998 - indicating a steady demand for these diagnostic products.

Companion diagnostics are most often in vitro diagnostic (IVD) devices required to aid in the selection of the corresponding therapeutic drug. In other words, a CDx improves a drug/biologic safety and efficacy rate by screening appropriate patients for the treatment. While not mandated, regulators, such as the U.S. Food and Drug Administration (FDA)² and the European Medicines Agency (EMA),³ recommend that the corresponding IVD and its associated drug be developed concurrently as the full scope of the drug and the IVD are interdependent on each other.

The first approved companion diagnostic was the immunohistochemistry (IHC) test HercepTest,⁴ which was approved by the FDA in parallel with trastuzumab (Herceptin)^5,6 in 1998 for the detection of HER2 protein in breast cancer patients. Since then, globally approved CDx technologies have expanded to include in situ hybridization, gene sequencing, and polymerase chain reaction.^{7, 8} 

A CDx provides patient stratification by predicting responders that would most benefit from the corresponding therapeutic treatment, thereby improving the drug/biologic objective response rate.

Due to the heterogeneous nature of tumors, blanket treatment based solely on cancer type is not equally effective for all patients, hence, a biomarker-specific treatment has been demonstrated to be more effective. Determining HER2 status in breast cancer patients, for instance, helps identify those who may respond to targeted treatment with trastuzumab. At the same time, diagnostics such as Ki-67 IHC MIB-1 assay⁹ can identify breast cancer patients responsive to Ki-67 biomarker-related treatment. Therefore, a CDx gives vital information on the targeted biomarker so that a precise and specific treatment can be provided to the patients.

1.2 How Does a Companion Diagnostic Relate to IVD and IHC?

By definition, an IVD is a reagent, instrument, or system that can be used for diagnosis. These devices are non-invasive, meaning these products do not contact/penetrate the human body¹⁰ and can be used in sample collection (e.g., blood collection tube), sample preparation (e.g., DNA isolation kit), or to examine samples taken from the human body (e.g., IHC). As mentioned before, CDx devices are frequently IVDs. Specific to CDx, the clinical performance, or utility, is assessed in relation to the companion therapeutic. 

Using IHC, true identification of a biomarker is only possible by a well-designed scoring system validated by appropriate controls.¹¹ With a well-designed IHC assay, the robust design of an accurate CDx means results in a clinical setting will improve, leading to a well-structured and effective therapeutic regimen.

1.3 What Are the Primary Uses of Companion Diagnostics, and How Does a Companion Diagnostic Inform/Interact with Cancer Diagnosis and Treatment?

Companion diagnostics are primarily used to help identify the most suitable therapeutic treatment for patients. The main goal of a CDx is to accurately differentiate between patients who will respond to a drug treatment and those who will not. For example, the identification of overexpression in PD-L1 protein can help inform the healthcare professional to use a therapeutic that would specifically engage in regulating the PD-L1 expression, thereby more efficiently managing the treatment regimen by potentially reducing adverse effects, improving survival rate, and may also lower the financial burden on patients.

1.4 The Role of a Companion Diagnostic in Precision/Personalized Medicine

When considering the role of companion diagnostics in precision medicine (also known as personalized medicine), it’s important to first understand what precision medicine entails. True to its name, precision medicine is medical care tailored to optimize therapeutic benefits for a precise group of patients.

It is well known that individual therapeutic experiences can vary significantly. The use of a CDx allows for a more comprehensive picture of the individual and goes some way to attaining personalized treatment. This approach of personalized treatment may limit a patient’s likelihood of side effects related to an unsuitable therapeutic drug for a specific disease indication. For example, it has been demonstrated that patients expressing wild-type genotypes may have adverse health effects if treated for gene mutation-related disease.¹²

Since the first FDA approval in the late 1990s, around 50-60 CDx devices have been approved/cleared in the USA,^13,14 with an average of less than 1 CDx approval per year⁶ up to 2010, increasing to around 3 CDx approvals/year from 2011-2024.

The impact of CDx on improving patient care in the last 25 years, especially in oncology, has been significant, and with the advent of new technologies, including multiplexing, artificial intelligence, and spatial profiling, the CDx landscape is expected to expand even further and contribute to better-personalized treatments.

1.5 What Are the Differences Between a Companion Diagnostic and a Complementary Diagnostic?

A CDx is required to be used for testing for a specific disease indication, after which the corresponding therapeutic drug may be prescribed to the patient. A complementary diagnostic (CoDx) test aids in making an informed benefit–risk decision about the use of the therapeutic product, where the difference in benefit–risk is clinically meaningful. Complementary IVD information is included in the therapeutic product labeling (per the FDA). There are no formal regulations related to complementary diagnostics in either the US or the European Union (EU); however, the FDA has defined the term, which is in contrast to its EU counterpart, where there is no formal definition for a CoDx.^15,16

A CoDx is generally used when the paired drug is effective for a disease indication, irrespective of the biomarker status. However, a CoDx can predict whether a treatment group may benefit from a particular therapeutic regimen. For example, the CoDx of the IHC PD-L1 assay can inform clinicians whether OPDIVO would be effective for non-small cell lung cancer (NSCLC) and melanoma patients, helping to determine whether monotherapy or combination therapy is more appropriate. The first complementary diagnostic was Pharm Dx’s clone 28-8 PD-L1 identification assay for NSCLC patients, approved in 2015 for use with the therapeutic nivolumab (OPVIDO).¹²

Since the initial PD-L1 IHC assay approval in 2015, several CoDx have been approved¹² by the FDA (including PCR¹⁷ and radioimaging¹⁸ complementary diagnostics), while more than 55 CDx have been approved (including IHC, ISH, and NGS ) by the FDA since the initial CDx approval. As described in Table 1, CDx and CoDX are similar in nature but have subtle differences when used in a clinical setting.

Table 1. Differences between companion and complementary diagnostic

Similarly, as Figure 1 suggests from the regulatory perspective, it is not necessary to deny patients a therapeutic treatment if the complementary assay results are negative.

2. Companion Diagnostic Testing Overview

CDx testing has improved overall disease management. This section provides an overview of CDx testing and modalities developed over time.

2.1 Why Does the Advent of Companion Diagnostics Matter to Patients?

Before the development of CDx, the efficacy of drugs, particularly in the areas of hematology and oncology, ranged from 50-60%.¹⁹ However, with the advent of CDx, the success rate more than doubled for CDx-aided therapeutics,²⁰ in some cases, while in other instances, the drug efficacy increased to more than 90%,²¹ marking a significant improvement in patient management. The ability of CDx to predict responders has certainly improved patient selection, increased survival rates, and elevated overall quality of life.

2.2 Process of Testing Patients for Biomarker Analytes

A novel CDx is typically developed in the preclinical and clinical trial stages along with its therapeutic partner. The diagnostic’s analytical and clinical studies analyze the attributes of the IVD including its pathophysiological compatibility with the tested patient cohort.

Once both the device and drug are approved, the patient is tested for the analyte. Based on the results, patients are either included or excluded from the drug treatment regimen. For example, a PD-L1 CDx using IHC has been is approved for use with atezolizumab in NSCLC patients with PD-L1 tumor cell staining cut-off ≥50%. This means that only those patients will be selected for the treatment whose tumor cell staining for PD-L1 is ≥50%.²²

2.3 Companion Diagnostic Testing Modalities

Currently, more than 160 FDA-approved combinational therapies are being used with companion diagnostics across different diagnostic platforms.²³ While many CDx assays are primarily used in oncology, recent assays such as AAV5 DetectCDx and POMC/PCSK1/LEPR CDx have also been getting approval in hematology. Table 2 shows the breakdown of CDx assays by diagnostic technologies.²³

Table 2. CDx technology breakdown

HER2 CDx continues to be important for identifying HER2 protein levels in patients treated with Herceptin (trastuzumab). This CDx-drug co-development provided a template not only for the pharmaceutical and diagnostic companies for the product co-development but also for the regulatory agencies globally on developing a framework for these types of approvals and ensuring the safety and efficacy of these products for the targeted population. The most commonly used predictive assays are for the analysis of biomarkers such as HER2, EGFR, and PD-L1.²⁴

3. How Are Companion Diagnostics Developed?

The development of a novel CDx is a complex process that typically requires coordination between the diagnostic company and a pharmaceutical partner. This section details the CDx development life cycle and touches upon the regulatory features in the leading drug-diagnostic markets.

3.1 Why Do Pharmaceutical Companies Need a Companion Diagnostic?

The development of a CDx has proved to be beneficial for pharmaceutical companies as it leads to higher response rates for the corresponding drug treatment as the CDx aids in identifying the patient population that has a higher probability of benefiting from the drug.

3.2 Assay Feasibility to Commercialization

Developing a novel CDx includes selecting a biomarker, verifying the device to ensure it achieves the analytical performances desired, and validating the device's clinical utility for its intended use. Once the validation is complete, the drug-diagnostic safety and efficacy documents are submitted to the appropriate parties, such as a health authority (Figure 2). If the approving agency/ies provides product approval, the CDx, along with its companion therapeutic, is ready for product launch and commercialization.

3.3 Global Regulatory Approval Process

The US first established the pathway as the FDA approved the first CDx in 1998, followed by the EMA approval of the same diagnostic in Europe in 2000.²⁵ In China, the first approved CDx (SuperARMS) by NMPA in China was in 2018- a PCR assay to detect EGFR mutation in lung cancer patients eligible for the treatment with the therapeutic Iressa.^7,26 In the EU, with the implementation of the stringent in vitro diagnostic regulation (IVDR) (2017/746), which replaced the previous IVDD (98/79/EC), the term “companion diagnostics” was introduced formally into European IVD regulations, although it was already very well established in the industry.²⁴ Table 3 mentions the CDx regulatory trend in leading diagnostic markets.

Table 3. Salient regulatory features in different regions

*The FDA has initiated the task of down-classifying some CDx from class III (high-risk) to class II (moderate-risk) to ease the approval process²⁷

3.4 Companion Diagnostic Reimbursement

Ideally, the CDx reimbursement policy should be unambiguous to optimize patient benefits. However, this policy remains unclear in many regions. For example, in Belgium, the NSCLC treatment drug Xalkori (crizotinib) was approved for reimbursement in 2013, while its CDx was approved later in 2018. To correct the discrepancy, in 2019, the Belgian authorities decided to reimburse the drug and diagnostic together as a package rather than individually.²⁸ Similarly, in the EU, reimbursement policies vary by country;²⁹ some have a joint reimbursement policy, while others have separate policies for the drug and the diagnostic. After CDx launch- to better inform reimbursement policy and provide unambiguous clear product-specific information- the diagnostic companies should educate the end-users about the clinical utility of the product via peer-reviewed manuscripts, social media, conferences, educational webinars, or training sales and marketing associates who can help create awareness within the healthcare community on how to use the product optimally and create brand-awareness backed by robust scientific data, which may also inform the health technology assessment (HTA) of the regulators as well.

4. What Is the Future of Companion Diagnostics?

The drug-diagnostic ecosystem is poised for growth, aiding clinicians in making informed decisions. This section explores developing technologies such as spatial biology, multiplexing, and artificial intelligence (AI) and how these novel techniques can potentially improve treatment methodologies.

4.1 Multiplex and Spatial Stains

Although single protein identification via chromogenic IHC has been a reliable technique,^30,31 a single molecule analysis cannot fully reveal the pathophysiological status of a disease. Hence, it is vital to understand the in situ spatial molecular interplay between several proteins responsible for regulating the cellular microenvironment. The CDx assay has improved the overall response rate, yet this rate for some disease indications remains low due to a single biomarker detection. For example, in a clinical trial, the pembrolizumab response rate in NSCLC patients was 41% (the response rate was 20.6% before using the PD-L1 CDx).³² This response rate, although improved by the application of CDx testing, is still lower than may be desired; each patient is different physiologically, and dependence solely on one biomarker may not yield optimal results for each unique case. Hence, multiplex spatial immunofluorescence and IHC techniques (representative multiplex images shown in Figure 3) are hypothesized to improve the therapeutic response rate by building a more comprehensive picture of a case.³³

For Research Use Only, Not For Use in Diagnostic Procedures

While designing such assays, established good practices in design should always be followed. For example, fluorophores for each biomarker should be selected so that the spectral ranges do not intermix and dilute the intended biomarker fluorogenic/chromogenic signaling. To date, no multiplexing IHC-CDx for multiple biomarker detection has been approved, but with the continuous improvement in chromogenic and immunofluorescence IHC technologies, the potential of having such products approved in clinical practice to be used as a CDx looks conceivable.

4.2 Potential Limitations with Pathologist Manual Reads

Traditionally, pathologists review tissue specimens on glass slides by using bright field microscopy. However, with the adoption of digital pathology (DP)³⁴ and hybrid working practices (option of working from the laboratory and remotely from the home office), there has been a demand for a quicker turnaround time for diagnosis by a pathologist. Manual microscopy requires physically transporting slides to the pathologist’s site (academic center/hospital), which can be time-consuming. Also, consulting with a pathologist located at a distant location can take significant working hours to achieve a timely case diagnosis. In contrast, DP allows for case diagnosis consultations by digitally sharing the whole-slide images with pathologists simultaneously, eliminating the need to physically distribute slides and reducing diagnostic turnaround times.

While manual microscopy with glass slides is still the preferred method, it is slowly being replaced by DP, which uses digitized whole-slide images instead of conventional glass slides.

4.3 Digital Pathology and AI to Aid Pathologists

DP is gaining momentum in the scientific community as more pathologists become proficient with DP whole slide imaging system.³⁵ Some studies have also demonstrated that the average case read time for case diagnosis was reduced in comparison to manual microscopy.^36,37 In 2017, the first digital pathology whole slide imaging (WSI) system was granted a de novo by the FDA.^38,39 Since then, four more WSI systems have been cleared by the FDA,^40,41,42,43 suggesting a growing recognition of DP’s clinical utility. Novel technologies such as artificial intelligence (AI) and machine learning (ML) are now being used to develop algorithms that may assist a pathologist in disease diagnosis, prognostic/predictive biomarkers screening/reading, saving time to analyze challenging cases, and reducing inter-observer variability.⁴⁴

Al/ML algorithms-based studies have successfully demonstrated the identification of biomarkers such as PD-L1 and Ki-67.^44,45 Paige prostate, in 2021, became the first AI-assisted software granted a de novo by the FDA. The product was subsequently CE marked⁴⁶ in 2022 to assist a pathologist, if required, in the accurate detection of prostate cancer.⁴⁷

While stakeholders need to navigate through technology-related challenges, including standardizing algorithm validation, training algorithms with large data sets, and avoiding AI hallucinations, the future looks promising for integrating AI algorithms into routine clinical practice for disease diagnosis.

4.4 What Is Leica Biosystems Doing to Enable the Future of Companion Diagnostics?

At Leica Biosystems, we’re committed to improving patient lives by developing cutting-edge diagnostic products. Leica Biosystems has long had a presence on the CDx market- BOND Oracle HER2 IHC system⁴⁸ was approved by the FDA as a CDx for trastuzumab in 2012.⁴⁹ More recently, we have expanded our DP portfolio, where two out of five FDA-approved/cleared diagnostic systems- including the Aperio AT2 DX System⁴¹ and Aperio GT 450 DX⁴² - are from Leica Biosystems. We are proud to be the first global entity to get clearance for the native DICOM image-compliant whole slide image scanning system (GT 450 DX is cleared for SVS and DICOM⁴²).

To meet the growing demand for precision medicine, Leica Biosystems has established the Center for Enabling Precision Medicine in Newcastle (UK).⁵⁰ This facility focuses on developing CDx and is actively collaborating with pharmaceutical partners. Recognizing the value of multiplexing and AI, Leica Biosystems is at the forefront of developing these novel technologies.⁵¹ The company has collaborated with leading experts and organizations^{52, 51} to apply these techniques (Figure 4) to produce high-quality diagnostics to improve patient care.

Products shown may not be approved/cleared/available as an IVD in all regions- check product-specific webpages for product-specific information

5. Conclusion: Increasing Role of Companion Diagnostics in Precision Medicine and Leica Biosystems Commitment to Promote Patient Care

The value of companion diagnostics in improving treatment regimens is undeniable, as evidenced by the growing interest from healthcare companies, providers, and regulatory authorities. Leica Biosystems plans to enrich its CDx portfolio by incorporating cutting-edge technologies such as AI, DP, and multiplexing to improve patient lives.