Improving Cancer Biomarker Testing and Cancer Diagnosis for Sustainable Healthcare

Investing in the future Improving cancer biomarker testing and cancer diagnosis for sustainable healthcare

A White Paper, by the following contributors: Antonella Cardone, Director, European Cancer Patient Coalition (ECPC); Professor Jesus Garcia-Foncillas, MD, PHD, Director, Oncohealth Institute and University Hospital “Fundacion Jimenez Diaz” Autonomous University of Madrid, Spain; Dr Lydia Makaroff, CEO, Fight Bladder Cancer, UK, and Vice-President, World Bladder Cancer Patient Coalition, Belgium; Dr Pietro Presti, MBA, PHD, Vice-President European Cancer Patient Coalition (ECPC); Dr Albrecht Stenzinger, MD, Pathologist, Institute of Pathology, University Hospital Heidelberg, Germany; Professor Gilles Vassal, Pediatric Oncologist and Director of Clinical Research at Gustave Roussy, Villejuif, France

The development of this White Paper was funded by Bayer. Editorial control is retained by the authors. MAC-VIT-ALL-0011-1

Local Approval Number: MA-LAR-BE-0067-2 INVESTING IN THE FUTURE INVESTING IN THE FUTURE

Contents Executive summary

Accurate and timely diagnosis is the foundation of good cancer medicine – diagnosis not only Executive summary 03 of a particular cancer, but diagnosis at a molecular level to help inform appropriate treatment selection for improved patient outcomes and health system sustainability. Advances in personalized Introduction healthcare in oncology, through the discovery of targeted therapies, have transformed the 04 development of accompanying biomarker diagnostic tools that are changing the face of cancer treatment and patient survival. Biomarker diagnostic testing and healthcare sustainability 05 As medical research continues to We clearly already have excellent Improving access to biomarker identify the genomic (biomarker) cancer care facilities that many patients diagnostic testing is a crucial causes of tumors (the ‘oncogenic currently derive benefit from through component of health system Unravelling the genomic fingerprint of tumors 08 drivers’), it follows that robust improved diagnosis and long-term sustainability, driving efficiencies biomarker testing at the point of care. Biomarker testing is one part of now and in the future. The biomarker diagnosis is essential for identifying this care, which is taking place to some diagnostic test itself is as important Pan-tumor genomics grounded in data optimal, biomarker-directed treatment extent within dedicated specialized as the treatment selected – the 09 (or what is known as ‘precision centers of excellence and is conducted two cannot be separated. As such, medicines’) for patients across a by multidisciplinary teams of experts. improved diagnostic testing should Pan-tumor approach in the real world – broad spectrum of tumor types. be a priority for payers and policy approvals to date 10 However, many eligible patients are makers worldwide and considered Based on these advances, a new era of currently not benefiting from biomarker- as an investment in the future. In this cancer treatment is dawning that could directed care due to suboptimal testing paper we set out the background Diagnostic tests for biomarkers explained offer radical improvements in outcomes practices and heterogeneity of available and the case for improved access 12 for some patients and broader value tests. As a result, some cancer patients to biomarker testing with the aim to healthcare systems [1]. Treatment spend substantial periods of time of empowering patient advocacy An opportunity to improve quality and efficiency is moving away from traditional taking expensive medicines that just groups and patients to lead the ‘call within diverse healthcare systems 14 approaches based on a tumor’s don’t work, while other cancer patients for action’. After all, it is the right of location (e.g., lung or colon), and lack access to effective treatments every patient to be able to choose the towards a pan-tumor or tumor-agnostic – an inefficient use of health system treatment that best supports Conclusion approach that explores how a drug resources that negatively impacts their survivorship. 17 targets a particular genomic defect in patient outcomes, often resulting in the cancer. This allows the identification unnecessary distress. We need to get of effective therapies for cancers in the right treatment to the right patient at Call to action 18 different physical locations that share a the right time. common genomic alteration. Appendix and references 19

The development of this White Paper was initiated and fully funded by Bayer. Medical writing assistance was provided by communications agency FleishmanHillard, supported by Bayer. Bayer was also involved in the fact-checking of information. The named contributors provided input to the content and gave final editorial approval for the opinions and conclusions contained in this White Paper.

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Introduction Biomarker diagnostic testing and healthcare sustainability

How can we, patient advocates and policy makers, Good medical practice starts with early and accurate diagnostics as guardians of good health, help to improve patient and good treatment planning, of which biomarker testing, particularly selection for transformative precision medicines in cancer, is an essential component. With improved access to (targeted treatment with a genomic biomarker target) biomarker diagnostic testing for cancer and personalized cancer to enhance patient outcomes, while respecting the therapy, there is real potential to increase the health quality of variability in healthcare infrastructures and economies nations and improve patient outcomes, while lowering overall around the world? The answer could lie in greater healthcare costs [7]. access to biomarker diagnostic cancer testing, with sustainable healthcare and cost-efficiencies as a core Personalized treatment is an attractive There is a need to promote proposition, as in principle only technological evolution towards value proposition. those patients likely to benefit from innovative testing methods that treatment are identified. allow the identification of several markers for analysis in one upfront Molecular diagnostic tests not only diagnostic test to inform treatment The majority of healthcare systems 2030, and it is predicted there will patients and caregivers around the determine if a patient is eligible for now and in the future [9]. The financial globally are facing financial pressures be 27.5 million new cancer cases potential and availability of biomarker a targeted medicine but can also allocation for such a diagnostic test that are undermining sustainability worldwide each year by 2040 [3]. testing; and a harmonized and more be used to identify if a patient could will be offset through greater cost and the capability to innovate. The With this in mind, accurate diagnosis efficient regulatory framework across be suitable to participate in clinical benefits associated with precision cancer community needs to ensure through biomarker testing is an Europe that could increase access research. They can also be used therapeutics. The use of precision that access to important biomarker important consideration to ensure to, and potentially reduce the cost of, as prognostic tools to determine therapeutics is growing as many Patients enrolled in the National diagnostic testing is included in that the right patient has the right molecular testing [5]. Interestingly, up to how aggressive a cancer is and the countries acknowledge the impact Cancer Institute’s Molecular healthcare plans and budgeted for treatment at the right time to increase 60% of patients in Europe are currently potential outcomes for patients [8]. that biomarker testing has had on Analysis for Therapy Choice (NCI- accordingly, either through budget the chance of cancer survivorship. not offered biomarker testing according healthcare sustainability (Table 1). MATCH) phase 2 clinical trial all increases and/or reallocation of to a patient survey conducted by the had biomarker testing to look for resources. By doing so, healthcare There is growing recognition within ECPC, and 70% of respondents said 143 genes associated with cancer. systems, regardless of their the cancer community of the need that the importance of testing was not In the UK in 2014, around 3,500 more patients The study was done to determine sophistication, will realize economic for improved access to biomarker adequately explained to them [6]. whether targeted therapies for and societal benefits by giving testing. For example, the Innovative may have benefited from treatment with a targeted people whose tumors have certain patients the opportunity for greater Partnership for Action Against Cancer In this paper, we will discuss the medicine had they been tested [8]. gene mutations will be effective access to breakthrough therapies. (iPAAC) work stream on genomic benefits of investing in better access regardless of their cancer type. One testing acknowledges that genomics to biomarker diagnostic testing, of the goals of the trial was to find Healthcare professionals agree that is viewed as “the harbinger of a brave the case for sustainability, and how The Organisation for Economic Co-operation and Development (OECD) around 25% of patients with rare biomarker diagnostic testing is a new world in which healthcare is acting today could make this a reality The OECD recognizes the importance of adopting policies on biomarker testing cancers. fundamental driver to improving transformed”. The iPAAC states there tomorrow through a patient-centered for a more sustainable future of healthcare. In a report ‘Policy Issues for the treatment selection and better patient is a critical need for an appropriate ‘call for action’. Development and Use of Biomarkers in Health’, the OECD notes that long-term Of the first 6,000 patients who outcomes. Patients and their carers can policy response on the inclusion of investments in the development of sustainable initiatives and infrastructures had biomarker testing, 62.5% return to work sooner and contribute to genomics and testing in healthcare are necessary to facilitate biomarker discovery and development. Education were seen to have less common the economy, budgetary pressures on discussions. It calls for improved and communication among all stakeholders with a vested interest in improving or rare tumors, providing more healthcare systems are relieved, and education and training for all healthcare sustainability is also of importance if access to improved biomarker opportunities for these rare cancers cost-savings can be reinvested into stakeholders [4]. testing is to be realized [11]. to be studied than expected. This innovative research. was the first attempt to use Next- The European Cancer Patient Cancer Control Joint Action (CanCon) Generation Sequencing (NGS) Due to population growth and ageing, Coalition (ECPC) calls for increased Improving access to optimal treatment is outlined in the Cancer Control to study several therapies at the more people are diagnosed each access and decreased waiting times Joint Action (CanCon) Policy Paper ‘Enhancing the value of cancer care same time and to potentially bring year with cancer, and demand for for high-quality biomarker testing in through a more appropriate use of healthcare interventions’, which the ECPC targeted treatments to patients effective treatments is growing [2]. It order to make personalized healthcare co-authored. The paper includes recommendations on improving access with certain gene abnormalities, is anticipated that there will be a 62% more of a reality across Europe; more to medicines, surgery, and radiotherapy by reducing waste and improving regardless of their cancer type [10]. increase in cancer diagnosis by information to educate and empower efficiency, as well as making use of technology to improve cancer care [12].

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TABLE 1: EXAMPLES OF THE IMPACT OF BIOMARKER TESTING IN SELECTED COUNTRIES The uptake of new diagnostic technologies will depend not only on regulatory approval, but also reimbursement and evidence Country Impact of Biomarker Testing both from trials and real-world studies. Improved access can facilitate faster diagnosis and treatment, and for this to become a • The French National Cancer Institute (INCa) and the French Ministry of Health has established a “ national network of 28 molecular genetics centers that perform molecular tests for all patients in their reality, tests need to be integrated in the clinical setting and to be region, irrespective of the institution where they are being treated [13,14] affordable and available to all patients” [19]. France • The development and use of targeted therapies has steadily increased over recent years, European Cancer Patient Coalition, 2017 demonstrating the growing importance of precision medicine in the treatment of cancer, aside from other systemic treatments such as chemotherapy

• In order to address the need for improved access to personalized medicine, the Spanish Senate life-year saved. Furthermore, initiated sessions in 2018 on the ‘Study of Genomics’. The government also recently launched the biomarker testing before first- or second-line treatment correlated with Spain ‘Spanish Strategy for Personalized Medicine’, including an improved approach to biomarker testing better survival and limited additional • A study performed in Madrid showed that genomic testing increased quality-adjusted life years by costs [22]. 0.00787 per patient and saved costs from a national healthcare system perspective (by €13,867 per patient) and from a social perspective (by €32,678 per patient) [15] Many more biomarker tests are now available for multiple organ- • NHS England has a clear vision for genomic medicines with a dedicated national service, the NHS specific tumors, and these tests have Genomic Medicine Service (NHS GMS). The NHS GMS is currently being implemented to enable timely transformed patient outcomes over United and equitable access to the latest testing technologies and reimbursed treatments the years. Kingdom • The NHS Long Term Plan has committed to sequencing 500,000 whole genomes by 2023/24, including (England) people with specific types of cancer for which there is likely to be the greatest patient benefit from using whole genome sequencing, as well as to extending access to molecular diagnostics to enable Pan-tumour research focus genomic testing to be routinely offered to all people with cancer [16] Research has now moved on to another exciting field • New research from CVS Health presented at the American Society of Clinical Oncology (ASCO) 2020 of research that focuses on SUCCESS OF BIOMARKERS virtual congress, on access to diagnostic sequencing to detect more than one genomic driver mutation adjusted life year (QALY) gained, and using biomarkers for treatment IN CANCER AND IMPACT ON in lung cancer, concluded that broad panel sequencing (BPS) has been shown to optimize treatments the incremental cost-effectiveness selection across different U.S.A HEALTHCARE SUSTAINABILITY in patients with lung cancer was $145,000 per QALY gained [21]. tumors. This is called a pan- tumor approach to treatment, – Many payers are reluctant to pay for BPS as it is seen as more expensive than narrow panel Biomarker testing for cancer has Additionally, studies in the US and where tumors with a common sequencing (NPS). However, the authors concluded that BPS significantly reduces overall total costs been used for some years to identify Europe indicate that there could be a genomic mutation can be of lung cancer care. The average 6-month per member per month total cost was $11,535 +/- $9,168 molecular markers in patients to 34% reduction in chemotherapy use targeted with a single treatment, among those who underwent BPS compared to $20,039 +/-19,642 in those who underwent NPS. direct therapeutic approaches in if women with breast cancer received regardless of the organ or tissue This difference of $8,504 was statistically significant, p = 0.0022 [17] organ-specific cancers. One of the a genetic test of their tumor prior to first biomarkers to be discovered treatment [14]. in question. • Despite the evidence of potential for improved outcomes, 55% of advanced non-small cell lung cancer and reported in a peer review journal (NSCLC) patients carrying targetable biomarkers did not receive a targeted therapy [18] in 2001 was the HER2 protein in In NSCLC, ALK rearrangement metastatic breast cancer (MBC) [20]. and EGFR/KRAS mutations are the A biomarker test was developed main biomarkers that are tested to to seek out HER2 overexpression, determine if a patient is suitable for and only women with MBC who targeted therapies. When looking at expressed HER2 were treated with the the cost-effectiveness of biomarker monoclonal antibody, trastuzumab. testing for these mutations in NSCLC, it is more cost-effective to do this Biomarker testing can contribute before a treatment decision is made. to healthcare sustainability, and A review of costs associated with data show that use of an initial no biomarker testing compared with HercepTest that confirmed HER2- testing for at least one biomarker positive metastatic breast cancer had followed by appropriate treatment an incremental cost-effectiveness showed an incremental cost- ratio (ICER) of $125,000 per quality- effectiveness ratio of €13,230 per

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Unravelling the genomic fingerprint of tumors Pan-tumor genomics grounded in data

New knowledge about the discovery of biomarkers has created a paradigm shift in patient The field of pan-tumor genomics (tumor-agnostic or tumor-independent) is rapidly evolving and treatment and led to widespread enthusiasm around personalized medicine. The term demonstrates the exciting potential of genomic and protein targets for cancer treatment. ‘personalized medicine’ is frequently used interchangeably with other terms such as Researchers have already identified several tumor-agnostic biomarkers of potential clinical ‘precision medicine’, ‘genomic medicine’, and ‘precision oncology’ [23]. They all describe interest that continue to be examined further in order to determine their therapeutic benefit in the the use of an individual patient’s biomarker information to assist physicians in the diagnosis, real world. prognosis, treatment and prevention of cancer for that patient [24]. Genomic targets are identified by analyzing a tumor for different genomic markers (the drivers of cancer). In pan-tumor research, FROM ORGAN-SPECIFIC TO most established patient advocacy A greater understanding of cancer scientists look specifically for BIOMARKER PROFILING groups organize their efforts around a biology has led to the discovery of genomic targets that are common common feature such as the tissue or various genomic causes of cancer Traditionally, cancers have been across many different tumor types, organ in which a tumor is found. that can act as targets for therapy. classified and treated according to with the aim of finding effective Over the last two decades, significant More recently, there has been a shift the tumor’s type of tissue (histology) therapies for cancers that share a progress and technological advances towards a pan-tumor approach, - that is, the type of tissue in which common genomic alteration [23, 25]. have contributed to the development whereby therapies are targeted it originates or the location in the Some clinical trials use this pan- of anticancer therapies that target towards genetic mutations that are body in which the cancer first tumor approach, to look at multiple molecular alterations in tumors with common across many cancers. developed (primary tumor), such as different cell types, rather than an greater specificity than in the past. lung, breast, and colon. This means organ- or tissue-specific approach to Biomarker tests are already available that the diagnosis and treatment of identify several genomic markers in for many organ-specific cancers, and different tumors varies according tumors [23]. new therapies have emerged that to tissue or organ type. Due to this have changed the treatment outlook historical approach to treatment, for patients with these cancers. Definition of tumor-agnostic treatments

Tumor-agnostic (tumor- independent) treatment is a treatment strategy that seeks out genomic markers for a tumor The main genomic alterations – or • High tumor mutational burden regardless of biological tissue tumor-agnostic markers – that have (TMB-H). Measures the number of origin (histology). This treatment been identified as therapeutic targets gene mutations inside the cancer typically fulfills the following to date include: cells. High TMB is a biomarker criteria: of immunotherapy response and • Microsatellite instability high/ is expected be at the forefront deficient mismatch repair (MSI-H/ Tumors have one of precision medicine in the dMMR). Associated with cellular + oncogenic driver foreseeable future [30]. 1 repair mechanisms and the inability to repair mistakes in the DNA. • Fibroblast growth factor receptor Alterations are likely to Contribute to the development of a (FGFR). Mutations in FGFR predict response to a variety of cancers [28]. genes can drive urothelial, breast, therapy endometrial, squamous lung, and • Neurotrophin tyrosine receptor ovarian cancers [31]. kinase (NTRK). Can cause several Alterations are found different types of cancer, including across a variety of Extensive research into these and lung cancer, sarcoma, head and cancers other genomic alterations continues. neck cancer, thyroid cancer and Adapted from The European Society of cancers of the central nervous Medical Oncology (ESMO) [26, 27] system and others [29].

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Pan-tumor approach in the real world – approvals to date TABLE 2: APPROVED PAN-TUMOR AGENTS EMA Marketing FDA Approval as of November Agent Biomarker Authorization as of 2020 The treatment landscape for patients living with cancer is November 2020 GLOBAL MILESTONES IN evolving and the advent of precision oncology and a pan-tumor DEVELOPMENT OF PRECISION approach to treatment means that patients now have potential ONCOLOGY Pembrolizumab MSI-H or dMMR 23 May 2017 for greater access to treatments that can optimize outcomes Microsatellite instability high/ First-line treatment of patients DNA Sequencing to examine the building deficient mismatch repair with unresectable or metastatic based on their tumor biological make-up. 1970s blocks of DNA MSI-H or dMMR CRC • Philadelphia chromosome genetic PD-1 abnormality discovered in chronic Programmed cell death myeloid leukemia (CML) protein 1 • HER2 overexpression in breast cancer discovered • First gene therapy for cancer – chimeric antigen receptor-modified T cell (CAR-T) Larotrectinib NTRK gene fusions 26 Nov 2018 19 Sept 2019 Neurotrophin tyrosine For adult and pediatric patients Adult and pediatric patients 1980s A 21-gene-based test (Oncotype DX) receptor kinase with solid tumors that have an with solid tumors that predicts risk of recurrence and guides NTRK gene fusion display a NTRK gene fusion adjuvant therapy for women with certain types of breast cancer • First immunotherapy atezolizumab / chemotherapy combination approved for extensive small-cell lung cancer Measurements used to determine the value of pan-tumor • PARP inhibitors represent a major therapies may include: treatment advance in BRCA-positive ovarian cancer Entrectinib NTRK gene fusions 15 August 2019 28 May 2020 Neurotrophin tyrosine Adult patients with metastatic CHMP recommendation for • The efficacy and safety of • Cost and economic 1990s Human Genome Project commenced with receptor kinase NSCLC whose tumors are marketing authorization as the treatment. The impact evaluations can also aim of mapping all of the genes of the ROS1-positive monotherapy for treatment on survival and on tumor be considered. Health human genome ROS1 of adult and pediatric patients shrinkage, how long the economists may review • Trastuzumab and IHC diagnostic test Receptor tyrosine kinase 1 12 years of age and older, treatment effect is seen, treatments in line with approved for HER-2 positive metastatic with solid tumors expressing and if there are any adverse standard of care to compare breast cancer – 20 years after discovery of the HER2 gene a NTRK gene fusion events. cost to society, usually over a longer time frame. • Quality of life (QoL) 2000s Pan-tumor (tumor agnostic) research parameters, such as the • Ethical considerations. gains momentum – moving research from impact of the treatment Testing is as important as treating cancers based on the site of origin on a patient’s life. QoL treatment, and the earlier the to molecular drivers TABLE 3: SELECT PAN-TUMOR THERAPIES IN DEVELOPMENT [33] assessments can measure testing, the better, as it can • Imatinib approved for CML – 30 years after discovery of Philadelphia activities of daily living, change treatment outcomes. chromosome abnormality returning to work, and other Agent Target activities. 2010s • Several targeted therapies approved with genetic targets, including Selitrectinib TRK pembrolizumab, larotrectinib and Since 2017 three pan-tumor treatments, they must undergo entrectinib (Table 2) Repotrectinib ALK, ROS1 and TRK treatments have been approved biomarker diagnostic testing of • Pembrolizumab becomes first drug Debio 1347 FGFR (Table 2) by the US Food and their tumors, but there is currently to be approved with a tumor-agnostic indication in 2017 in the USA, and Erdafitinib FGFR Drug Administration (FDA) and the no universal genomic diagnostic larotrectinib is the first to be approved European Medicines Agency (EMA). test to determine if a patient is in Europe in 2019 Pralsetinib RET These treatments target certain suitable for pan-tumor treatment. genetic abnormalities in tumor cells Patients must currently be tested 2020s Research into other tumor agnostic Selpercatinib RET targets continues (Table 3) with genomic and are therefore not specific to any for each of the known genomic targets TRK, ALK, ROS1, FGGR, RET 1, TPX-0046 RET and SRC one particular cancer. In order for mutational targets individually. SRC, AXL kinase, FGFR and BRAF patients to have access to these Dubermatinib AXL kinase Adapted from ASCO Cancer Progress Timeline [32] PLX8394 BRAF

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Diagnostic tests for biomarkers explained TABLE 4: TESTING APPROACHES FOR PAN-TUMOR MOLECULAR TARGETS

Standard testing for cancer to determine the type of tumor and stage of the disease includes tissue biopsies, which establish the biologic profile of the tumor at a cellular level at diagnosis. For Test Benefits and challenges example, a lung cancer sample may be classified as of small-cell origin or non-small cell origin, or Next Generation Sequencing (NGS) [35, 36] may be squamous cell or adenocarcinoma. This is the ‘histology’ (the biological cellular make-up) of a tumor. These biopsies may also be tested in the laboratory using different methods for specific Target: DNA • Detects alterations in the DNA • Use of NGS has increased due to significant cost biomarkers that play a role in the development of that cancer, to help determine treatment choice. and/or RNA and/or RNA (genetic material) reductions and broader community acceptance • NGS can determine diagnostic • Potential for a significant positive impact on mutation biomarkers (if a person has detection, management and treatment of cancer Today, improvement in sequencing treatment of solid tumors continues treatment with TRK-inhibitor cancer), prognostic biomarkers (is • Effective at identifying mutations in cancer patients – technologies of the human genome to increase, it is likely that NGS will therapies, patients need to be tested the tumor aggressive for example, in a review, 37% of diagnosed patients proceeded to means that comprehensive genomic become the key diagnostic tool to for the NTRK gene fusion. and potential outcomes), and receive therapy matching their genetic profile profiling (CGP) of tissues has become inform treatment decisions. This Testing should account for all Can detect: predictive biomarkers (a patient’s genomic standard practice for sequencing approach could be used to seek potential genomic alterations. For potential response to treatment) • Can detect multiple genomic alterations and alterations the molecular profile across multiple out genomic markers, regardless of example, a diagnosis of NSCLC is mutations in a single test tumors [28]. The latest sequencing biological tissue origin for a pan- just the beginning; a genomic deep- methods, including NGS and whole tumor (tumor-agnostic) treatment dive is required to determine the Immunohistochemistry (IHC) [37] genome sequencing (WGS) provide strategy [34]. molecular make-up of the tumor opportunities to study tumors at time (e.g., EGFR mutation) to guide Target: Cell • Identifies proteins in cells of a • Produces consistent specific and reproducible results of diagnosis and at defined intervals Different tests are used to identify effective ecision-making on what is tissue • Can aid in distinguishing normal tissue from cancer during treatment to determine efficacy suitable patients for the different the most appropriate treatment for • In cancer diagnosis, there are tissue and/or detect resistance to treatment. types of tumor-agnostic treatments that patient. The cost of the different specific proteins that are unique and their molecular targets (Table 4). testing techniques will be dependent • Assesses whether a patient should receive or is or over-expressed that IHC can As the number of clinically relevant For example, in order to determine on any given country’s healthcare responding to therapy Can detect: detect predictive biomarkers for the which patients may benefit from infrastructure. protein expression

Reverse transcriptase polymerase chain reaction (RT-PCR) [38] CASE STUDY 1: MOLECULAR TESTING CAN BE LIFE-SAVING AND HELP OTHERS IN THE FUTURE – GERMANY Target: RNA • Detects RNA expression • The most sensitive technique for mRNA detection and analysis currently available • RT-PCR is used to assess Patient been missed previously. RNA- expression of genomic biomarkers • Used to quantify mRNA levels from much smaller 1. Female 30 years, never smoker based NGS was performed and in cancer samples presented with breathlessness detected a NTRK gene fusion. and fluid on the lung lining After starting on a TRK-targeted Can detect: 2. Metastatic adenocarcinoma of gene the right lung therapy, she experienced marked expression improvements in her symptoms, a The patient had extensive disease reduction in tumor size in both lung at diagnosis including bone and bone, and a partial response Fluorescence in situ hybridization (FISH) [39, 40] metastases. After molecular to treatment. As of March 2020, • Looks at the chromosomes • Can be used to form a diagnosis, to evaluate testing there appeared to be no the patient is free of symptoms Target: (genetic material in a cell) prognosis, or to evaluate remission of cancer to then genomic abnormalities that justified and has resumed her regular Chromosome allow for tailored treatment treatment with a targeted therapy. daily activities, including work. • This test can be used to visualize She was treated with standard Due to this case, in young never specific genes or portions of genes • Does not require living cells for testing platinum-based chemotherapy, but smokers, it is recommended that in cancer • Test results are ready in a few days after a year, unfortunately, she had testing for the NTRK gene fusion progressive disease. In searching should be routinely performed Can detect: for alternative treatments, the once a diagnosis of lung cancer is established. amplifications, patient had further investigations deletions, fusions for molecular targets that may have

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An opportunity to improve quality and efficiency within diverse healthcare systems

The heterogeneity of healthcare systems around the world, the available technologies, and infrastructure around testing at diagnosis all compound access to innovative medicines. This can result in a ‘not my problem’ attitude. The current treatment journey includes barriers or disincentives to upfront diagnostic testing, and treatment accessibility and reimbursement also presents a significant hurdle.

In 2010, the World Health Organization (WHO) commissioned a report on world health in response to a need ‘expressed by rich and poor countries alike, for practical guidance on ways to finance healthcare’. According to the WHO, a universal healthcare system provides healthcare and financial protection to all residents of a particular country or region [41]. The WHO highlights the need to focus first on opportunities to improve efficiency, rather than ways to cut spending on healthcare. Improved access to biomarker diagnostic testing is Even among countries with a payer- The currently available diagnostic Technology Assessment (HTA), and one such way to embrace this based healthcare system, patients tools may vary in sensitivity, reimbursement and funding [1]. To principle, while acknowledging the can experience variability in access specificity, precision, and accuracy. overcome these challenges, there is diversities of resources available to, and quality of, diagnostic testing. a need to improve awareness levels around the world within universal Under a payer-based system, a According to a European Cancer among government and regulatory CASE STUDY 2: HETEROGENEITY IN BIOMARKER healthcare systems. traditional approach to reimbursement Patient Coalition (ECPC) report policy makers, clinicians and patient TESTING AVAILABILITIES IN SPAIN of healthcare provision has focused entitled ‘Patients’ Access to Precision advocates of the concept of tumor- Heterogeneity of healthcare on volume-based incentives, but this Oncology’, personalized medicine is agnostic medicines and the value Patient They were able to do this because systems doesn’t just exist around is now shifting more towards value- the future of cancer treatment and these bring to patients. Also, for HTA it is a relatively inexpensive test that the world, but also within certain 1. Male 77 years, asymptomatic, based incentives that are founded should be standard practice. However, bodies and payers to consider tumor- is also paid for by pharmaceutical countries. In Spain, for example, non-smoker on quality and efficiency. Improved certain biomarker testing challenges agnostic therapies and genomic companies. The test results didn’t the availability of molecular testing 2. Squamous lung cancer access to genomic diagnostic testing persist due to variability from country profiling in appraisals, to ensure that show an EGFR mutation. can vary significantly, depending progressive disease is one such method for improving to country, administrative barriers funding mechanisms are available for on which healthcare system, efficiencies in diagnosis and delivery leading to delays in biomarker test these innovative treatments. In order to get a second opinion, public or private, a patient has The patient was diagnosed and of quality treatments to those patients results, and reimbursement and the patient went to a private access to (Case Study 2). treated in a public health hospital, who are most suitable. accessibility challenges related to There is also a need for more hospital and paid for an NGS- where NGS or other molecular country variations and resources sophisticated centers of excellence, based diagnostic test, which tests aren’t usually performed for Due to variability of healthcare available [42]. to invest in appropriate diagnostic revealed a NTRK2 gene fusion. squamous lung cancer, as it is infrastructures, it follows that the and data infrastructures and to ensure At this point, the patient was able often caused by smoking. However, best tests should be used based on Some of the barriers for patient testing protocols are in place and to receive a TRK-inhibitor, which, given that the patient wasn’t a resources available. There is also a access to molecular testing include: reimbursed across tumor types. following recent data, has a median smoker, the physician decided to need to ensure that diagnostics are low stakeholder awareness and expectation of progression-free run a PCR test to look for an EGFR consistently accurate from lab to lab prioritization, lack of diagnostic survival of more than three years. mutation. and across a given territory. infrastructure, issues with Health

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TABLE 5: CURRENT STATUS FROM SELECTED COUNTRIES ON TESTING, REIMBURSEMENT AND POLICIES IN PLACE CASE STUDY 3: CLINICIANS LEAD DEMAND FOR GREATER ACCESS TO DIAGNOSTIC TESTING IN FRANCE [50]

Country Testing/biomarker reimbursement / policy approaches Action 1. The availability of the 28 INCa Political call to action: In a • The industry is striving to offer genomic tests as a way of facilitating improved treatment access platforms resulted from strong letter to the Minister of Health, • Biomarker tests used: IHC, PCR, NGS, FISH demand by clinicians to improve parliamentarians raised awareness Brazil access to tests and ultimately to of the urgency to reform RIHN • Private healthcare: Reimbursement for biomarker testing is based on tumor type, following specific innovative treatments and the need to allocate specific guidelines for each of the biomarkers: HER-2, K-RAS,N-RAS, EGFR, BRAF and ALK 2. A wide range of stakeholders funding for precision oncology and • Public healthcare: FISH for HER2 is recommended by the public healthcare guidelines, but the mobilized to address risk of biomarker testing. As a measure cost reimbursed is not enough to pay for the full test access inequalities due to of their commitment, an article capped funding was published on access to Adapted from references [43, 44] genomic testing and their intention • Testing is performed using the 28 INCa platforms. RNA sequencing can only be performed in Medical call to action: Clinicians to commit to an inter-ministerial selected platforms, and its availability is increasing with the arrival of new therapies targeting estimate the current allocated mission on improved access to cancer with NTRK gene fusion France budget only covers 75% of the testing for the whole territory. • A specific assessment pathway for reimbursement of biomarker testing does exist, within HAS diagnostic tests requested, which remits. However, it requires extensive evidence. Only a few tests are reimbursed through this formal means that some patients may be Patient advocacy call to action: reimbursement pathway such as HER2 in breast cancer (FISH), EBER in child neuroblastoma deprived of clinically relevant tests. ‘Imagine for Margo’, a patient (FISH), and BCR-ABL This led to a demand by clinicians association, is involved in to accelerate access to approved sustaining research programs, such • Newer tests are funded through an alternative pathway, RIHN, allowing broader access to testing. reimbursement of tests. A specific as the MAPPYACT trial aimed at It requires data to be generated prospectively to then allow a formal HAS assessment committee was formed to ensure characterizing the genetic profile • Access is guaranteed through RIHN funding, but the budget is capped. As the number of best practices for the application of pediatric tumors refractory to biomarkers is increasing, optimal funding of tests remains a topic high on the healthcare agenda of testing, and the regular standard of care. evaluation of outputs, so that • Mutation tests used: EGFR and BRAF cost efficiencies and healthcare • Molecular Tumor Boards have been set up in some oncology centers in order to speed up sustainability were realized. Italy decisions on testing and personalized therapies • A Manifesto of Rights to Personalized Medicine has recently been published by Cittadinanzattiva Adapted from references [45] Conclusion • There is no standardized procedure or specific regulatory framework for the evaluation, implementation and financing of biomarkers in clinical practice There is no ‘one-size-fits all’ solution, but by working in • Biomarker testing is managed at the regional level, by each hospital, but there is currently no Spain concert, patients, healthcare professionals, advocates, national standardized testing process policy makers, payers, and industry can find a path to • Pharmaceutical companies fund some biomarker tests, while some are carried out within a better future in which genomic profiling is a routine academic research programs practice. The financial benefits are clear – if we find the Adapted from reference [46] right treatment for the right patient, and the right economic approach including addressing barriers to accessibility, we • Centrally reimbursed tests are listed in the national test directory: https://www.england.nhs.uk/ can improve healthcare sustainability, minimize impact on publication/national-genomic-test-directories/ budgets, and most importantly, improve patient outcomes in United • NHS England has recognized the significance of tumor-agnostic therapies as part of strategic a cost-effective manner. Kingdom personalized medicine and genomics ambitions (England) An important caveat remains, that while there is definite room • Larotrectinib became the first tumor-agnostic treatment to gain NICE reimbursement approval in for improvement in access to genomic diagnostic testing April 2020 via the Cancer Drugs Fund worldwide, heterogeneity of infrastructure in different regions • The focus is now translating access into uptake by embedded NTRK testing within cancer is an important factor that will influence what is possible. pathways across the NHS to ensure the timely identification of eligible patients for treatment Change cannot happen overnight, but incremental steps can Adapted from references [47-49] make a significant impact – through developing action plans that work for policy makers, through communication, and through listening to patients around the world.

16 17 INVESTING IN THE FUTURE INVESTING IN THE FUTURE

Call to action Appendix: Acronyms

Acronym Meaning Acronym Meaning We can increase awareness ALK Anaplastic Lymphoma Kinase MBC Metastatic Breast Cancer CGP Comprehensive Genomic Profiling MSI-H or dMMR Microsatellite Instability High/Deficient Mismatch Repair CHMP Committee for Medicinal Products for Human Use NGS Next Generation Sequencing about scientifically validated DNA Deoxyribonucleic Acid NSCLC Non-Small Cell Lung Cancer EGFR Epidermal Growth Factor Receptor NTRK Neurotrophin Tyrosine Receptor Kinase EMA European Medicines Agency PCR Polymerase Chain Reaction FDA Food and Drug Administration RNA Ribonucleic Acid biomarker testing, to give patients FISH Fluorescence In Situ Hybridisation RT-PCR Reverse-Transcriptase Polymerase Chain Reaction IHC Immunohistochemistry ROS1 Receptor Tyrosine Kinase 1 the potential for suitable targeted KRAS Kirsten RAS oncogene TMB-H High Tumor Mutational Burden cancer treatments, and drive References better healthcare sustainability 1. A.T. Kearney. Preparing Health Systems for Tumor-Agnostic Treatment. 2019 27. Offin M, Liu D, Drilon A. Am Soc Clin Oncol Educ Book. 2018; 38: 184–187. 2. International Agency for Research on Cancer. GLOBOCAN 2018. Available at: 28. Davis AA, et al. Am Soc Clin Oncol Educ Book 2018; 38: 998-1007. https://gco.iarc.fr 29. Penault-Llorca F, et al. J Clin Pathol 2019; 72:460–467. 3. Cancer Research UK. Available at: https://www.cancerresearchuk.org/health- 30. Buttner R et al. ESMO Open 2019;4:e000442. Available at: https://www.ncbi. professional/cancer-statistics/worldwide-cancer/incidence#heading-One nlm.nih.gov/pmc/articles/PMC6350758 through increased biomarker 4. Innovative Partnership for Action Against Cancer. Work Package 6 – Genomics 31. Helsten T, et al. Clin Cancer Res. 2016 Jan 1;22(1):259-67. in Cancer Control and Care. Available at: https://www.ipaac.eu/en/work- 32. American Society of Oncology. Available at: https://www.asco.org/research- packages/wp6 guidelines/cancer-progress-timeline 5. European Cancer Patient Coalition. Molecular Testing & Personalised Medicine. 33. Looney AM, Nawaz K, Webster RM. Nat Rev Drug Discov. 2020 Jun;19(6):383- diagnostic testing Available at: https://ecpc.org/policy/molecular-testing-personalised-medicine/ 384. 6. European Cancer Patient Coalition/European Alliance for Personalised Medicine. 34. Yoshino T, et al. Ann Oncol. 2020 Jul;31(7):861-872. Available at: https://ecpc.org/wp-content/uploads/2019/08/ECPC-patient- 35. Tan O, et al. Clin Genet. 2018 Mar;93(3):533-544. awareness-on-biomarkers-across-europe-2.pdf 36. Savelieff M. Available at: https://www.technologynetworks.com/diagnostics/ 7. Ciardello F, et al. Annals of Oncology 2014; 25: 1673-1678. Available at: https:// articles/next-generation-sequencing-ngs-stimulating-the-next-generation-of- core.ac.uk/display/33591330 cancer-diagnostics-and-treatment-319649 8. Cancer Research UK. Available at: https://www.cancerresearchuk.org/sites/ 37. Bueno R. Available at: https://cofactorgenomics.com/wk-6-2020- default/files/policy_august2015_mdx_final.pdf immunohistochemistry-in-cancer-diagnosis 9. European Cancer Patient Coalition. Available at: https://ecpc.org/wp-content/ 38. Infogalactic. Available at: https://infogalactic.com/info/Reverse_transcription_ 1 2 uploads/2019/08/ECPC-cancer-biomarkers-in-the-era-of-personalised- polymerase_chain_reaction Improve biomarker literacy – through educational Position diagnostic testing as integral to regulatory medicine.pdf 39. Genome.gov. Fluorescence in situ hybridization (FISH). Available at: https:// 10. National Cancer Institute. Available at: https://www.cancer.gov/news-events/ www.genome.gov/genetics-glossary/Fluorescence-In-Situ-Hybridization activities about the economic and clinical value of frameworks – champion the cause for improved access press-releases/2018/nci-match-first-results 40. Breastcancer.org. Available at: https://www.breastcancer.org/symptoms/ testing; by sharing best practices across borders; to diagnostic testing to be included in regulatory and 11. Organisation for Economic Co-operation and Development. Available at: https:// testing/types/fish#:~:text=Fluorescence%20in%20situ%20hybridization%20 www.oecd.org/health/biotech/49023036.pdf %28FISH%29%20is%20a%20test,present%2C%20the%20more%20 ensuring patient inclusivity in informed decision healthcare frameworks; keep evaluating outputs to 12. Grilli R, et al. Cancer Control Joint Action Policy Papers (Federici A, Nicoletti HER2%20receptors%20the%20cells%20have making on testing and treatment, mindful of patient measure value and cost-effectiveness of testing to G and Van den Bulcke M, eds), pp. 29–67. National Institute of Public Health, 41. World Health Organization. Available at: https://www.who.int/whr/2010/en strengthen the case for more testing. Slovenia and Scientific Institute of Public Health, Belgium 42. Florindi F, et al. Journal of Clinical Oncology35, no. 15_suppl. May 2017. expectations. 13. Planchard D, et al. Available at: https://ascopubs.org/doi/full/10.1200/ Available at: https://www.researchgate.net/publication/327478533_Value_ EDBK_100007 of_innovation_in_oncology_The_position_of_European_cancer_patients_on_ 14. Wilsdon T, et al. Available at: http://www.crai.com/publication/benefits- access_to_innovative_treatments personalised-medicines-patients-society-and-healthcare-systems 43. Ferreira CG, Achatz MI, Ashton-Prolla P et al. BrLancet Oncol 2016; 17: 15. Ramirez SP, et al. Available at: https://pubmed.ncbi.nlm.nih.gov/31300934 e363–70. 16. NHS England. Available at: https://www.england.nhs.uk/wp-content/ 44. Santos M, Coudry RA, Ferreira CG et al. Lancet Oncol 2019; 20: 20-23. 3 4 uploads/2020/10/BM2025Pu-item-5-diagnostics-recovery-and-renewal.pdf 45. Cittadinanzattiva. Available at: https://www.cittadinanzattiva.it/comunicati/ 17. Brito RA, et al. Available at: https://meetinglibrary.asco.org/record/190309/ salute/13496-manifesto-for-the-right-to-personalized-medicine-for- Listen to the science – utilize the new science, clinical Collaborate with professional and political experts abstract cancerpatients-today-the-presentation.html 18. Gierman H, et al. Available at: https://ascopubs.org/doi/abs/10.1200/ 46. Sociedad Espanola de Oncologia Medica. Estudio SEOM sobre el Acceso a research data and treatment advances as a bedrock of – put biomarker testing high on political and scientific JCO.2019.37.15_suppl.1585 Fármacos y Biomarcadores en Oncología. Available at: https://seom.org/images/ discussions; work with medical associations and medical organization agendas; work with cancer centers of 19. European Cancer Patient Coalition. https://ecpc.org/wp-content/ Estudio_SEOM_Acceso_2019_presentacion_resumen.pdf uploads/2019/08/ecpc-white-paper-the-value-of-innovation-in-oncology.pdf 47. NHS.uk. Available at: https://www.england.nhs.uk/2019/06/fast-track-game- regulators to include testing in clinical trial protocols; inform excellence and patient advocates to improve cross-talk 20. Slamon DJ, et al.N Engl J Med 2001; 344: 783–792. changing-cancer-drugs peers and partners about the dedicated specialized testing among decision makers; be realistic as to what can be 21. Elkin EB, et al. Available at: https://ascopubs.org/doi/full/10.1200/ 48. NHS.uk. Available at: https://www.england.nhs.uk/2020/04/nhs-strikes-deal-on- centers; call for standardized testing and best practices, achieved, as small steps make a difference; petition for jco.2004.04.158 first-in-a-new-generation-of-cancer-busting-drugs 22. Loubière S, et al. Available at: https://erj.ersjournals.com/content/51/3/1701467 49. NICE larotrectinib technology appraisal guidance. Available at: https://www.nice. and utilize resources with the best cost-benefit ratio. allocation of resources to fund more testing. 23. Yates LR, et al. Annals of Oncology 2018; 29: 30-35. org.uk/guidance/ta630 24. Ciardello F, et al. Annals of Oncology 2014; 25: 1673-1678. 50. Sénat. Available at: www.senat.fr/rap/r17-569/r17-5698.html 25. Martincorena I, et al. Cell 2017; 171: 1–13. 26. ESMO Oncology Pro. Available at: https://oncologypro.esmo.org/oncology-in- practice/anti-cancer-agents-and-biological-therapy/targeting-ntrk-gene-fusions/ overview-of-cancers-with-ntrk-gene-fusion/precision-medicine/tumour- agnostic-treatment 18 19 The development of this White Paper was initiated and fully funded by Bayer. Medical writing assistance was provided by communications agency FleishmanHillard, supported by Bayer. Bayer was also involved in the fact-checking of information. The named contributors provided input to the content and gave final editorial approval for the opinions and conclusions contained in this White Paper.