Cancer accounts for just over a quarter of all deaths in England in a typical year. The NHS Long Term Plan (LTP) was published in January 2019 and set out stretching ambitions and commitments to improve cancer outcomes and services in England in the following ten years. Earlier and faster cancer diagnosis are among its central ambitions.
It is with considerable humility, but also great pride, that I have the honour of working for a company, GRAIL, which has embarked on an extraordinarily challenging mission to find many types of cancer earlier, before symptoms appear, when there are more treatment options, and a greater potential for cure.
Galleri® , GRAIL’s multi-cancer early detection (MCED) test, has been assessed in published case-control and interventional studies in the intended use population. The results demonstrate consistent findings throughout, and Galleri is now the subject of real world evidence generation and the largest prospective randomised controlled trial of an MCED test ⎯ the NHS-Galleri trial conducted in England.
Traditionally, cancer screening programmes have taken a decade or more from publication of effectiveness to be implemented on a population-scale. This means that, including the duration of clinical trials, it has historically taken some 20-30 years from having a validated technology to achieving broad benefits for patients and society. With the rapidly growing burden of cancer ⎯ it is soon to become the world’s biggest killer ⎯ and the pace of technology change, many experts believe this paradigm must change.
As set out in a recent letter from NHS England to the Lancet, the NHS is keen for its patient population to benefit as quickly as possible from new, safe and effective technologies where there is an urgent unmet need, such as with late cancer diagnosis. Therefore, in addition to the long-term aim, NHS England plans to look at a snapshot of selected first year results (the prevalent screening round with one year of follow-up) from the NHS-Galleri trial to assess whether there is enough compelling early evidence to initiate a ‘pilot’ of up to one million tests within the NHS setting. This type of ‘in-service evaluation’ would offer a Galleri test to a similar ‘asymptomatic’ population as the trial. As well as generating real-world data to supplement the trial evidence, this pilot opportunity would allow the NHS to learn about how best to implement a multi-cancer screening programme rapidly.
NHS England will base its decision on robust, demanding, pre-specified criteria, including the positive predictive value (PPV) of the Galleri test, the number of late stage cancers detected, and the total number of cancers detected in the intervention arm compared with the control arm. Notably, this is not an interim analysis of the trial primary endpoints, as any such analysis requires data from all three rounds of screening. The pilot will only proceed if the early results are exceptionally compelling enough to begin implementing a pilot program before the trial completes and the final results are known. Similarly, these results will only be made public should the pilot proceed, in order to place necessary focus on the integrity of the ongoing trial.
Importantly, the early look at certain selected metrics will provide only a limited view, which may or may not be seen in the final results in 2026. Early results from cancer screening trials do not always reflect the final results, and often do not tell the whole story. The National Lung Screening Trial, for example, provides a salutary example: participants similarly underwent three annual screenings. Ultimately, the trial demonstrated a significant relative reduction in mortality for those with low-dose CT screening. However, no reduction in stage IV cancers was observed after the first year of screening because it was a prevalent screening round. This is because a prevalent screening round includes many asymptomatic cancers in later stages that have not been ‘swept out’ by that first year of screening. As expected, in NLST the stage IV incidence reduced after that first year of screening – and was maintained throughout the follow-up period. Crucially, the trial also demonstrated a 20% relative reduction in mortality that was maintained throughout the longer-term follow-up period. The NHS-Galleri study design and primary endpoints accept this ‘prevalent screening round effect’ and acknowledge that assessing a lasting reduction in late-stage disease requires multiple years of screening to ‘sweep out’ those later stage cancers.
Working in partnership with NHS England, world-class statisticians, epidemiologists and clinicians, we designed the 140,000 person NHS-Galleri trial to include three successive rounds of Galleri screening in addition to standard screening for those in the intervention arm, compared to a control group only receiving standard screens. This trial was conducted with a view to informing eventual implementation of Galleri within a national screening programme if recommended by the UK National Screening Committee.To ensure a representative, diverse population was recruited, we employed a fleet of mobile clinics staffed with phlebotomists, to enable access for participants in places with access challenges to health clinics ⎯ from ethnically and socioeconomically diverse cities to remote rural outposts. This approach had the additional benefit of not burdening overstretched GP surgeries, not least as the bulk of the recruitment took place during the COVID-19 pandemic in 2021.
The active period of the NHS-Galleri trial comes to an end with the final blood draw anticipated to take place in July 2024. The primary objective of the trial is to demonstrate that the use of Galleri, alongside standard of care, can lead to a significant reduction in the incidence of late stage cancers ⎯ in-line with the UK’s overall goal of increasing the proportion of early-stage cancers detected. This will require an assessment of the data accumulated following all three annual rounds of screening, and it is expected that this analysis will be completed in 2026. Exploratory mortality analyses and modeled mortality based on observed stage-shift will also be undertaken, as well as longer term follow-up via national centralised data collection. Planned, comprehensive health economic evaluation and analysis will provide necessary cost-effectiveness data.
We hope that NHS-Galleri will demonstrate highly compelling early evidence from which the NHS is able to make a decision to move forward with the proposed Multi-Cancer Blood Test Programme so that more patients can benefit more quickly. Such a pilot, if so agreed, would provide a suitable balance between being able to learn valuable implementation lessons to fulfill an unmet need rapidly, with the subsequent further decision dependent on longer-term measures of effectiveness. Whether or not a pilot is undertaken, for any number of reasons, GRAIL would continue to request that the UK National Screening Committee makes a decision about a population screening programme in due course, based on the final study results and full economic evaluation. We look forward to the NHS’s assessment of the early results in the coming months.