Date: 12 December 2022
News Source: www.meddeviceonline.com
The vast majority of cancer research and treatment resources and spend are directed toward therapeutics, especially those that treat late-stage cancers. While significant advancements have been made in the development of novel therapeutics that are extending lives of cancer patients, the most impactful driver of cancer survival in the future may not come from therapies at all, but rather from the diagnostic tools, especially liquid biopsies, that inform which, when, and how patients should be treated. In particular, blood-based early cancer detection is poised to fundamentally shift cancer care in the next decade. With the relatively recent launches of the first blood-based screening tests and their early uptake in real-world settings, and a deluge of additional R&D and commercial development expected in the near-term, we are witnessing the earliest days of what could be a transformative change in cancer care. Here, we summarize the current state of the early cancer detection liquid biopsy landscape and discuss some of the factors that will dictate success and present opportunities for diagnostic and other players seeking to participate in this market.
Early Cancer Detection
It is well known that cancer prognosis is better the earlier it is detected and treated. In the U.S., cancer screening is recommended for breast, colorectal, cervical, and lung cancers; however, these cancers account for <40% of new cancer cases each year. Traditional screening relies on imaging (e.g., mammograms, low-dose CT scans, colonoscopies) or tissue sampling (Pap smear). Recently, blood-based liquid biopsies have shown potential to supplement (or potentially replace) existing screening methods, as well as enable screening for dozens of cancers for which no screening options exist today.
As cancers grow, they shed cancer-specific markers into the blood and stimulate various response pathways, which in turn generate distinct signals. Researchers and diagnostic manufacturers are exploring and developing tests that detect these signals in blood. Blood-based testing provides various advantages over other screening methods. For example, blood testing is minimally invasive and generally widely accessible, which enables adherence. Additionally, blood tests can detect markers from any cancer that sheds into the bloodstream, so they can potentially pick up signals from many different types of cancers in a single test. However, blood testing is not a cancer detection silver bullet; not all cancers shed sufficient amounts of biomarkers into the bloodstream to be detectable at early stages. Additionally, if cancer-specific markers are identified in blood, it can be challenging to determine where in the body the cancer exists. Lastly, some of the markers and processes stimulated by cancer growth are not uniquely specific to tumorigenesis, which can lead to false positive results. Nonetheless, early evidence of the utility of liquid biopsies to detect cancer, as well as the scale of the market opportunity, are compelling enough to drive the development of blood-based cancer detection tests.
In the U.S., there are numerous early cancer blood tests in development and with varying levels of validation, but only three blood-based cancer detection tests backed by substantial clinical trial data are commercially available for clinical use: GRAIL’s Galleri (a multi-cancer test), Guardant’s Shield colorectal cancer test, and Epigenomics’ Epi proColon test. Early data and efforts by test manufacturers, as well as feedback from early clinical adopters, have illuminated key elements of technological and commercial success, as well as gaps and limitations that need to be addressed to realize the full promise of blood-based early cancer detection. These are areas where diagnostic and other market players can create value and establish a “right to play” in the EDx market:
Given the significance of the results and the scale at which these tests are intended to be implemented, early cancer detection requires tests that are both highly sensitive and specific, and ideally so for early-stage cancers (e.g., stages I and II). This is a high bar to meet and one of the biggest moderators of adoption to date. Current expectations for specificity range from at least 90% (for some single-cancer screening tests) to >99% (optimal for multi-cancer screening tests). At these specificity levels, the overall sensitivity of current tests ranges from ~50% to ~90%; however, the sensitivities for stage I/II cancers are generally lower, and clinical stakeholders are not yet won over by the first generation of tests. As one researcher studying the first commercial multi-cancer early detection (MCED) test noted, it is not ready for prime time, but if further studies confirm the blood test’s usefulness, it could become a “game changer.”
Assay manufacturers are continuing to explore novel ways to improve test performance. One of the primary ways companies seek to maximize test performance is through the analyte(s) being measured. Early market players have identified methylation as a key signal in early cancer development and have developed tests that assess methylation markers either alone (e.g., in the case of GRAIL and Epigenomics) or in combination with other classes of markers (e.g., in the case of Guardant). Other analytes and signals that are being explored in EDx tests include: DNA variants, DNA aneuploidy, proteins (both peripheral and from exosomes), DNA fragment lengths, hydroxymethylation, 5’ end motif, cell-free RNA (including coding and non-coding RNAs), synthetic biomarkers, circulating tumor cells (CTCs), glycans, metabolites, spectrometric signatures, and others. While companies have differing data and opinions regarding the utility of combining multiple markers vs. focusing on one, it is generally accepted that a “multi-omic” test will be more costly to run than a single-analyte test. At the end of the day, key stakeholders (clinicians, regulators, payors, and patients) care primarily about the output (i.e., assay performance) and not the input (i.e., analytes). Multiple companies have published impressive preliminary data using these analytes or combinations thereof in proof-of-principle or small case-control studies; however, large, prospective studies are the bar for clinical adoption, which leads to the next key factor for EDx test success.
Clinical Trial Design
Clinical, regulatory, guideline, and payor stakeholders expect to see significant amounts of clinical data prior to adopting, approving, recommending, and paying for early cancer detection testing. Only those players with prospective clinical data are expected to achieve any kind of market traction. Key considerations for these trials include:
Scale: Given that cancer is relatively uncommon in an average-risk population over a relatively narrow window of a few years, screening trials need to be large to develop statistically significant and clinically compelling results. To date, key studies have targeted 10,000 to 35,000 patients, though studies aiming to drive large-scale implementation of multi-cancer detection tests reach 80,000 to 100,000+ patients (e.g., GRAIL’s NHS Galleri study and Exact Science’s announced SOAR trial) to ensure adequate numbers of detected cancers across multiple cancer types. Conducting studies at this scale in a timely fashion requires significant resources and diagnostics and clinical operational experience, which companies must be able to demonstrate to address this market.
Diversity: The study population needs to be diverse and mimic a “real-world” population. Early detection models that are not trained in a diverse population will not yield the real-world results to succeed (e.g., long-term mortality benefits at a population level). Additionally, given that large-scale screening is likely to require some level of government support and approval, some regulatory stakeholders like to see that a test was studied and validated on patients within their country. Additionally, pharmaceutical companies are seeking to leverage early detection tests to improve identification and enrollment of patients for their early-stage drug trials and will demand that such tests identify the maximum number of patients, requiring that they successfully identify patients of all races.
Outcomes: As the blood-based screening landscape is nascent, most trials are focusing initially on measures of detection (e.g., sensitivity, specificity, positive and negative predictive values) and the ability to accurately localize a cancer. However, to become part of the long-term standard of care and secure maximum adoption and reimbursement, EDx tests will ultimately need to demonstrate improvements in mortality. While it seems intuitive that earlier detection should lead to improved mortality, it is not a foregone conclusion, and proving this requires not only accurate detection and localization of cancer but also clear and actionable interventional steps following a positive test result. This is especially challenging for multi-cancer early detection tests, for which numerous potential clinical protocols and pathways exist. Ultimately, companies or tests that can prove superior mortality benefit will likely be entrenched in the EDx market long-term.
As with any new treatment or diagnostic, one of the biggest drivers or moderators of adoption is coverage and reimbursement. In the U.S., Congress must approve Medicare coverage of preventive services and has done so for colorectal, lung, breast, prostate, and cervical cancers, but it has not yet done so for multi-cancer early detection tests. Legislation to cover MCED testing (e.g., the Medicare Multi-Cancer Early Detection Screening Coverage Act of 2021) has been introduced and is a key lever in opening up the market opportunity for blood-based screening in the U.S.
That being said, reimbursement by a government body, or even private insurers, is not necessary to drive initial adoption. None of the commercially available offerings has broad payor coverage yet; however, companies are finding creative ways to market and sell their tests. GRAIL, for example, which offers its test for $949 out of pocket, has established dozens of partnerships with self-insured employers, concierge medicine companies, life insurance companies, and health systems to offer their Galleri test. In its first full year on market, GRAIL is forecasting $50 million to $70 million in revenue. Similarly, Guardant, which offers its Shield CRC detection test for $895 out of pocket, has noted rapid initial adoption of its test. However, there is a limit to the number of patients who are willing and able to pay for such a test out of pocket.
Ultimately, in the U.S., both CMS coverage (which generally requires FDA approval) and private payor coverage (which generally requires recommendations from key guideline agencies, such as the U.S. Preventive Services Task Force and/or American Cancer Society) is needed to realize maximum market potential. The USPSTF, which is the primary guideline agency for screening, is not expected to make updated recommendations for colorectal or lung cancer screening (the cancers where the most clinical evidence for EDx is being generated) until 2026. As mentioned above, maximal payor coverage is likely not to be achieved until assay developers can demonstrate improved survival outcomes.
Outside of the U.S., coverage of EDx testing is likely to take longer to evolve. Ex-U.S., many patients are not accustomed to paying out of pocket for healthcare, overall spend on healthcare is lower, and some countries have not implemented screening programs at scale. Population-level reimbursement and adoption will rely largely on acceptance by nationalized health systems, which have a high bar for coverage and which are typically price sensitive. In the meantime, preliminary adoption is likely to occur among a small number of wealthy individuals who can afford the out-of-pocket costs. In Europe, GRAIL is conducting a landmark study with the UK’s National Health Service NHS to evaluate Galleri for use in an average-risk population. This study is in the first stage of a large-scale clinical study (~140,000 patients, which could expand to 1 million+ patients in subsequent stages), with the objective of informing a national-level coverage decision by the NHS. Many European countries are likely watching and waiting for the results of this trial to inform population-level blood-based screening policies in their own countries.
There are two general business models for delivering clinical diagnostics: “decentralized” (e.g., testing conducted at the point of care or near the patient, using kits and reagents purchased by the lab) and “centralized” (e.g., testing conducted at a single lab to which samples are mailed, and testing is conducted as a service on behalf of clinicians or other labs). Today, most players in the EDx space are pursuing a centralized business model, at least initially. The primary drivers of centralization are:
However, there are also potential drivers for decentralization in the future, primarily:
In the early detection market, strong assay performance, broad reimbursement, and an effective business model are table stakes – to win in this market requires establishing ancillary services and infrastructure around an assay to drive adoption and clinical impact. For example, a critical barrier to adoption of existing EDx assays is that clinicians are not confident in how to handle a positive result: Is it a true positive? What steps are needed to confirm the result? Who should the patient be referred to next? How should the result be communicated to the patient? What sort of clinical decisions can or should be taken right away?
Another moderator of adoption is compliance with ordered tests. For instance, the sampling for screening tests is often not performed in the ordering clinician’s office. Patients may be provided a kit for self-sampling that they then have to ship to the testing lab, or a patient may be referred to a phlebotomy lab for a blood draw. In many cases, patients fail to follow up and provide or ship the sample, requiring diagnostic providers to invest in patient outreach personnel and resources. Successful companies in the EDx space will have to establish a streamlined experience for all stakeholders involved, from the point of ordering through the clinical follow-up. This will become especially important as the market matures and more competing offerings are available.
Early market leaders are currently developing this ancillary support infrastructure and incorporating it into their clinical trial designs. GRAIL, for example, has established a partnership with Quest Diagnostics, a diagnostics company with national reach, to leverage its phlebotomy network for sample collection. GRAIL is also including measures such as “healthcare resource utilization,” “patient self-report of acceptance,” “patient self-report of satisfaction,” “number and types of diagnostic tests required to achieve diagnostic resolution,” and “changes in anxiety after a positive result” as outcome measures in its clinical trials to help determine what types of process and educational/information support patients and clinicians need to implement testing as effectively as possible. Given the strains on clinicians’ time and resources, the extent to which the implementation of blood-based screening can be a frictionless experience will have a significant impact on uptake.
While we are in the top of the first inning with respect to blood-based cancer screening, the pace of development and adoption is expected to accelerate significantly over the next approximately five years. By 2027, the LBx cancer screening market is expected to be among the largest of all diagnostic markets in the world, with plenty of upside remaining (many expect that it represents the single largest diagnostic market opportunity). Blood-based early cancer detection testing presents various opportunities for stakeholders throughout the diagnostic and clinical value chains to create significant clinical and commercial value.