Jan Trøst Jørgensen is Director and Advisor at the Dx-Rx Institute (Fredensborg, Denmark). He has more than 35 years of experience in research and development from academia as well as pharmaceutical, biotech and diagnostic companies, such as Novartis (Basel Switzerland), Novo Nordisk (Bagsværd, Denmark) and Dako/Agilent (Copenhagen, Denmark). Within the past 20 years, his focus has been on drug–diagnostic co-development projects in oncology. Jørgensen is a strong supporter of a more individualized pharmacotherapy, and he has published a number of scientific papers on companion diagnostics and drug–diagnostic co-development. In recent years, he has also worked as editor and co-author on books and special focus editions for scientific journals and is currently a member of several editorial boards.
Predictive biomarkers have been shown to play an important role in the ongoing effort to individualize pharmacotherapy approaches. Within the past couple of decades, a number of new biomarker assays have been developed, which are linked to specific drugs. Largely, these companion diagnostic (CDx) assays are used with a number of targeted oncological and hematological drugs, developed utilizing the drug–diagnostic co-development model [1,2]. The CDx assays often identify, directly or indirectly, the target for these drugs, and without such an assay, most of them will lose their value [2,3].
The concepts of precision medicine and personal medicine date back to the 1990s when genetic information began to have an impact on the development of new drugs and their use (4). In an article published in the Oncologist in 1999, the current approach of “one-size-fits-all” pharmacotherapy was questioned and it was stressed that even the best drugs were effective in 50% to 70% of patients only . In this context, disease heterogeneity and the genetic variability was mentioned as factors that might have a negative impact on treatment outcome. Furthermore, it was emphasized that an understanding of this variability might facilitate an improved treatment outcome for the individual patient. The authors also discussed the use of diagnostic tests that could inform the treating physicians of who would benefit from a specific drug and who was at risk of developing serious side effects. The description of the predictive diagnostic tests given in the Oncologist article is very close to how we perceive CDx today, which has only recently been defined by regulators in the EU, the USA, and countries worldwide [4,6,7].
The goal of individualized pharmacotherapy has been on the agenda of health care providers for decades, and one of the key elements in this effort has been the principles of rational use of drugs or rational pharmacotherapy. The essence of these principles was that the individual patients should receive medications appropriate to their clinical needs in order to optimize the benefit and minimize the harm [8). Already in the 1960s, these principles were translated into; “the right drug for the right patient in the right dose at the right time.” When we discuss precision medicine and personal medicine today, we still often use the same different “rights” to describe the concept. However, there is one major difference when we compare then with now, and that is the increase in our molecular understanding of the pathophysiology and the mechanisms of action of drugs, which is essential to the implementation of individualized pharmacotherapy and precision medicine .
Companion diagnostics: a definition
In 2014, the FDA issued a regulatory guidance document where they defined a CDx assay as an in vitro diagnostic (IVD) device that provides information that is essential for the safe and effective use of a corresponding therapeutic product . In relation to this definition, the FDA further outlined, where a CDx assay could be essential: I) to identify patients who are most likely to benefit from the therapeutic product; II) to identify patients likely to be at increased risk of serious adverse reactions as a result of treatment with the therapeutic product; III) to monitor response to treatment with the therapeutic product for the purpose of adjusting treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness. As a fourth item, the FDA state that a CDx assay identifies patients in the population for whom the therapeutic product has been adequately studied, and found safe and effective, i.e. there is insufficient information about the safety and effectiveness of the therapeutic product in any other populations. In this final item, the FDA emphasize that data on clinical outcome cannot be extrapolated to any other patient population than the one defined by the CDx assay, and thereby address off-label prescription. As a CDx assay is essential for the safe and effective use of the corresponding therapeutic product means that testing is mandatory and it is part of the labeling for the drug, which it is meant to guide .
With the development of the monoclonal antibody trastuzumab (Herceptin) for treat of metastatic breast cancer a new era began in drug development . Not only was it a scientific and medical achievement, but it also paved the way for the drug-diagnostic codevelopment model in which a predictive biomarker test is developed in parallel to the drug [1,4]. In September 1998, the FDA simultaneous granted approval of trastuzumab and the immunohistochemical (IHC) assay, HercepTest (Dako/Agilent). This assay is used to detect overexpression of the HER2 receptor in the tumor tissue, which is a prerequisite for treatment with trastuzumab and other HER2 inhibitors. The simultaneous approval of trastuzumab and HercepTest makes sense, as the assay is an important tool for selecting the patients who might benefit from the drug. HercepTest became the first regulatory-approved CDx assay, and is today also approved by the FDA for use with pertuzumab (Perjeta) and trastuzumab emtansin (Kadcyla) .
Other companion diagnostic assays
Since the approval of the HercepTest, the number of CDx assays has steadily increased and at the beginning of 2021, the total number of approved assays have reached 44 [10,11]. One of the most recent approvals is for the IHC assay, VENTANA ALK (D5F3) CDx Assay (Roche Diagnostics), which can now be used as CDx for the kinase inhibitor lorlatinib (Lorviqua) in the treatment of ALK-positive non-small cell lung cancer. The analytical platforms used with the different CDx assays are diverse. Until 2011, IHC and in situ hybridization (ISH) were the dominating technologies, when the first CDx assay based on the polymerase chain reaction (PCR) technology was approved, namely the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). This is an assay used for detection of the BRAF V600E mutation in patients with melanoma, who might be candidates for treatment with vemurafenib (Zelboraf) [10,11]. Within the last five years, next generation sequencing (NGS) has made its entrance as a CDx platform. The first assay based on this technology to be approved by the FDA was the FoundationFocus CDxBRCA Assay (Foundation Medicine), which is an assay for detection of BRCA1 and BRCA2 mutations in tumor tissue from patients with ovarian cancer, who might be candidates for treatment with the PARP inhibitor rucaparib (Rubraca). Currently, seven NGS based assays have been approved by the FDA as CDx. Today, PCR and NGS based assays make up more than 50% of all FDA-approved CDx assays underlining the current focus on genomic markers . Table 1 lists the combination of drugs and biomarker for the CDx assays that have obtained FDA-approval up until April 2021 .
The role of regulators
Before a CDx assay can be used in the clinic, it must be analytically and clinically validated and the clinical utility sufficiently documented. As this type of assay plays an important role as a treatment decision tool, an insufficient accuracy and robustness could possess risks to the patients. In the USA, the FDA classify CDx assays as high-risk medical devices, Class III, and they are thus subject to high- level regulatory control. Before such an assay can be used in the clinic, the analytical and clinical documentation must be reviewed and approved by the FDA, often through the submission of a Premarket Market Application [1,7,11]. In the EU, we have had a somewhat different attitude to this so far and here, CDx assays are low risk medical devices, which can be used in the clinic without any direct regulatory approval. For the same reason, it is difficult to get an overview of the CDx assays, which are on the market in the EU today. However, in May 2022, the new In Vito Diagnostic Regulation (IVDR) will come into force and this will change the situation . Consequently, a CDx assay can no longer be brought to the market and used in the clinic without a direct regulatory approval. Furthermore, as in the United States, this type of assay will now be classified as high-risk medical devices (Class C). It is not only the new CDx assays that have to live up to the requirements in the IVDR but also the existing assays, so the transition phase is expected to be challenging for a number of IVD companies.
Although the use of genetic biomarkers and targeted drugs has improved the outcome for a number of cancer diseases, there is a growing recognition that it is not enough simply to focus on genomics alone. In order to better understand the complex nature of oncological and hematological diseases, we need to have a better knowledge of the changes taking place at the protein level in order to bridge the gap between cancer genotype and phenotype. Increased attention is now paid to proteogenomics research combining the disciplines of proteomics and genomics .
With our increasing knowledge of molecular medicine, the use of predictive biomarkers has steadily increased, and especially within the hematological and oncological disease area, a number of targeted drugs have now a CDx assay linked to their use. Without such an assay, most of these drugs will lose their value. Moving forwards, CDx assays will continue to play an important role in our efforts to realize precision medicine.
Table 1. Drugs and biomarkers for the FDA-approved CDx assays .
|Alectinib, Brigatinib, Ceritinib, Crizotinib, Lorlatinib||ALK/ALK|
|Binimetinib, Cobimetinib, Dabrafenib, Encorafenib, Trametinib, Vemurafenib,||BRAF|
|Niraparib, Olaparib, Rucaparib, Talazoparib||BRCA1/BRCA2|
|Afatinib, Cetuximab, Dacomitinib, Erlotinib, Gefitinib, Osimertinib, Panitumumab||EGFR/EGFR|
|Trastuzumab, Pertuzumab, Trastuzumab emtansine||HER2/HER2|
|Atezolizumab, Cemiplimab, Nivolumab, Pembrolizumab||PD-L1|
|Cetuximab, Panitumumab||RAS (KRAS/NRAS)|
|Deferasirox||Software for MRI|
- Jørgensen JT, Hersom M. Clinical and regulatory aspects of companion diagnostic development in oncology. Pharmacol. Ther. 103(6), 999–1008 (2018).
- Jørgensen JT. Predictive biomarkers and clinical evidence. Basic Clin. Pharmacol. Toxicol. 128(5), 642–648 (2021).
- Jørgensen JT. Clinical application of companion diagnostics. Trends Mol Med. 21(7), 405–407 (2015).
- Jørgensen JT. Twenty years with personalized medicine: past, present, and future of individualized pharmacotherapy. 24(7), 432–440 (2019).
- Langreth R, Waldholz M. New era of personalized medicine: targeting drugs for each unique genetic profile. 4(5), 426–427 (1999).
- Regulation (EU) 2017/746 of the European Parliament and of the council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU. Official Journal of the European Union. 176–132 (2017).
- FDA guidance document: guidance for industry and Food and Drug Administration Staff. In Vitro companion diagnostic devices https://www.fda.gov/media/81309/download
- Klett CJ, Moseley EC. The right drug for the right patient. Consult. Psychol. 29(6), 546–551 (1965).
- Hayes DF. HER2 and breast cancer – a phenomenal success story. Engl. J. Med. 381(13), 1284–1286 (2019).
- FDA List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools
- Jørgensen JT. The current landscape of the FDA approved companion diagnostics. Oncol. doi: 10.1016/j.tranon.2021.101063 (2021) (Epub ahead of print).
- Rodriguez H, Zenklusen JC, Staudt LM et al. The next horizon in precision oncology: proteogenomics to inform cancer diagnosis and treatment. Cell 138(7), 1661–1670 (2021).