Nov ’25 – The rollout of ctDNA testing: what this means for patients and healthcare professionals
In this blog, consultant medical oncologist Dr Matthew Krebs, clinical lead for cancer genomics in the North West of England, explains the impact of recent changes to lung cancer testing in England.
Following a successful pilot, NHS England has made circulating tumour DNA (ctDNA) testing available for all eligible patients who have a suspected diagnosis of advanced non-small cell lung cancer (NSCLC).
This change promises to significantly reduce the wait time for genetic testing results, allowing tailored treatments to be introduced more quickly for patients.
In this blog, Matthew explains what this change means and the effect it will have on patients and healthcare professionals.
What is ctDNA testing and how does it work?
Circulating tumour DNA (ctDNA) testing, sometimes known as a ‘liquid biopsy,’ is a method of detecting fragments of cancer DNA which are released from tumours into a person’s bloodstream. In ctDNA testing, a simple blood sample can be analysed for these pieces of DNA.
Advanced sequencing technology is then used to look for genetic alterations in the DNA, including ALK rearrangements, which drive growth in specific cancers.
If these features are identified, a patient can be prescribed targeted therapies which are far more effective in treating specific cancers than more standard treatments.
What are the advantages of ctDNA testing?
The most significant advantage of ctDNA is its speed. Following a simple, non-invasive blood test, results can be delivered within two weeks – much more quickly than genomic testing from tissue which takes three to four weeks.
This gives the multi-disciplinary team (MDT) all the information they need to make decisions about treatment ina a quicker time frame.
What do the changes mean in practice?
Until now, a treatment plan for a patient with lung cancer has relied solely on a tissue biopsy. When lung cancer is suspected, doctors take a small sample of the tumour. Part of this sample goes to the histopathology lab, where pathologists confirm whether cancer is present and identify the type. Another part is sent to the regional genomics hub, where molecular testing is carried out to look for specific genetic alterations, such as ALK rearrangements, that can guide treatment decisions.
From May 2025, following a successful pilot, ctDNA testing has been added into the lung cancer diagnostic process in England. The test has been added to the NHS’s National Genomic Test Directory, which means clinicians can order it for eligible patients.
If a scan suggests that a patient has advanced non-small cell lung cancer they will now be offered a ctDNA test early on, alongside the tissue biopsy. The test can usually deliver results in around two weeks.
In the past, the first MDT meeting often happened before genetic test results were available, which could delay treatment decisions. With ctDNA testing, the team is more likely to have the results in time, helping them plan the best treatment pathway without unnecessary delays.
Does ctDNA testing remove the need for a biopsy?
It is important to note that ctDNA testing does not replace the need for a tissue biopsy. A biopsy is still needed to confirm the presence, type and grade of the cancer, and to be used for genetic testing should the ctDNA fail (for example, if there is not enough cancer DNA in the blood sample).
While the processes are still being smoothed out in practice, the ultimate intent is that if the ctDNA detects a mutation, targeted treatment can be started and genetic tissue testing will no longer be needed. If the ctDNA result is inconclusive, the genetic testing can still be carried out from the tissue sample.
CtDNA testing also offers an extra layer of reassurance. In instances where a biopsy doesn’t provide enough tissue for genetic testing, or if a patient is too unwell and/or the tumour site is too difficult to access, ctDNA testing means patients can still access appropriate treatment without delay.
What are the challenges and limitations of ctDNA testing?
While some hospital trusts have been using ctDNA testing during the NHS England pilot, to others it remains new. As with any new technology, introducing or scaling up this testing will require new infrastructure, processes and training, which means there may be implementation challenges while these new systems are embedded.
Another factor to consider is the sensitivity of ctDNA testing. Not all tumours release enough DNA into the bloodstream to be detected by the test, which can lead to a false negative result. In practice, there are three scenarios on the basis of ctDNA results:
A positive ctDNA result (showing an actionable genomic alteration) provides the information needed to guide targeted treatment. Tissues genomic testing is not required
An informative negative ctDNA result means there is enough ctDNA present and no actionable genomic alternation has been found. Standard treatment can be prescribed and tissue testing is not required.
An uninformative negative ctDNA result means there is insufficient ctDNA present and does not rule out the presence of mutations, so tissue testing is still needed to be certain.
Will ctDNA testing only be carried out during diagnosis?
For now, ctDNA is only being rolled out by NHS England to support diagnosis and treatment selection. However, there is potential for it to be used in other ways in future, including monitoring the progress and status of cancer, and checking a patient’s response to treatment.
Key takeaways for patients
CtDNA testing is carried out via a blood sample, making it quicker and less invasive than a tissue biopsy.
A positive result can often guide treatment immediately.
An uninformative negative result doesn’t rule out mutations; tissue testing would still be needed.
Results are usually available within 2-3 weeks, faster than traditional tissue testing.
Key takeaways for healthcare professionals
ctDNA testing is recommended alongside tissue biopsy for advanced NSCLC.
Check your local guidelines to find out the correct sample collection and handling guidelines.
Be aware of false negatives due to low tumour DNA shedding.
Consider ctDNA results together with imaging and tissue data for treatment decisions.
The national genomic test directory outlines which tests are commissioned by the NHS in England, and which patients will be eligible for a test. Access the directory here: National genomic test directory
Scotland, Wales and Northern Ireland each have their own arrangements for requesting genomic tests. Find out more about how to request genomic testing in the devolved nations here: Genomic testing in the devolved nations
Understanding the ALEX study: what it means for patients and healthcare professionals
In this blog, Senior Clinical Research Fellow Dr Federico Monaca, explains the the results of a clinical trial based in ALK therapy regimes.
The ALEX study is one of the most influential clinical trials in the field of ALK‑positive lung cancer. It compared two targeted therapies – alectinib and crizotinib – as first‑line treatment for people with advanced ALK‑positive non‑small cell lung cancer (NSCLC).
This large, global phase III trial focused primarily on progression‑free survival, while also assessing outcomes in the brain, overall survival and safety. A total of 303 adults with stage III/IV ALK‑positive NSCLC (ECOG 0-2) took part, including individuals with asymptomatic brain metastases.
Key findings from the ALEX trial
With more than nine years of follow‑up, the results show a clear and sustained benefit for patients treated with alectinib.
Median overall survival reached 81.1 months with alectinib compared with 54.2 months for crizotinib — a 22% relative reduction in the risk of death, although the study was not powered for a formal comparison of overall survival.
Alectinib more than tripled median progression‑free survival (34.8 vs 10.9 months). The survival advantage was seen in patients with and without baseline brain metastases, reinforcing the importance of early and effective systemic and intracranial disease control.
The risk of cancer spreading or progressing in the brain was significantly lower with alectinib.
Rates of severe (grade 3–5) side effects were similar between treatment groups, but the pattern of side effects differed. Long‑term use of alectinib did not reveal unexpected safety concerns.
What do the results mean in practice?
The ALEX study firmly positions alectinib as a leading first‑line treatment option for advanced ALK‑positive NSCLC, alongside other next‑generation ALK inhibitors such as lorlatinib.
Alectinib’s predictable and generally well‑tolerated safety profile makes it particularly appealing for patients who may need treatment over many years. At the same time, its strong systemic and intracranial activity provides confidence that the disease can be controlled effectively from the outset.
Importantly, ALEX has become a benchmark for future drug development. Newer, fourth‑generation ALK inhibitors are now being tested directly against alectinib in first‑line trials, and its outcomes are frequently used as the standard against which emerging therapies are measured.
What patients need to know
For someone newly diagnosed with ALK‑positive advanced NSCLC, the ALEX results offer reassurance about what modern targeted therapy can achieve.
Alectinib can keep cancer controlled for a median of nearly three years.
Around half of patients were still alive at seven years.
It provides far stronger protection against brain metastases than older treatments like crizotinib.
Side effects are generally manageable, even with long‑term use.
In practical terms, many people can expect their cancer to be managed as a long‑term condition. Treatment discussions with an oncologist may include whether alectinib, lorlatinib or another ALK inhibitor is the best first‑line option based on individual needs and preferences.
What healthcare professionals need to know
For clinicians, ALEX reinforces alectinib’s role as a cornerstone of first‑line therapy for ALK‑positive NSCLC — particularly for patients with existing CNS involvement or those at high risk of developing brain metastases.
When choosing between available ALK inhibitors, the combination of:
prolonged progression‑free survival
strong intracranial efficacy
a well‑established safety profile
makes alectinib a compelling alternative to lorlatinib, rather than a therapy that has been superseded by it.
ALEX has also set the performance threshold for next‑generation ALK TKIs. Ongoing trials with fourth‑generation agents now use alectinib as the active comparator, and future treatment strategies will likely evolve based on how these newer drugs measure up against the ALEX standard.
Understanding the CROWN study: what it means for patients and healthcare professionals
In this blog, Clinical Research Fellow Dr Emine Cil, explains the results of the CROWN study, one of the most important clinical trials in ALK-positive lung cancer.
The CROWN study compared two targeted therapies, lorlatinib and crizotinib, as first-line treatment for people with advanced ALK-
positive non-small cell lung cancer (NSCLC). This international phase III trial included 296 patients with previously untreated advanced ALK-positive NSCLC. Participants were randomly assigned to receive either lorlatinib or crizotinib. The study looked at how long treatment could control the cancer, including disease in the brain, while also assessing safety and other important clinical outcomes. The latest analysis, presented after approximately seven years of follow-up, provides some of the longest-term data available for a first-line targeted therapy in advanced ALK-positive NSCLC.
Key findings from the CROWN study
After seven years of follow-up, lorlatinib continues to demonstrate remarkable and sustained disease control.
Median progression-free survival (the length of time before the cancer worsened) has still not been reached with lorlatinib, compared with 9.1 months with crizotinib.
At seven years, 55% of patients treated with lorlatinib remained progression-free, compared with 3% of those treated with crizotinib.
Patients who remained progression-free after the first two years of lorlatinib treatment had a 79% probability of remaining progression-free at seven years.
The benefit of lorlatinib was seen in patients both with and without brain metastases at the start of treatment.
Lorlatinib provided particularly durable protection within the brain, with no new intracranial progression events observed after the first 30 months of treatment.
Median time to intracranial progression was not reached with lorlatinib, compared with 16.4 months with crizotinib.
These findings demonstrate a significant prolonged period of disease control for a single targeted treatment in advanced NSCLC. Although follow-up for overall survival is continuing, there had not yet been enough survival events at the seven-year analysis for the study’s planned second interim overall survival assessment.
What do the results mean in practice?
The CROWN study strengthens the evidence for lorlatinib as a first-line treatment option for advanced ALK-positive NSCLC.
Perhaps the most striking finding is the durability of disease control. More than half of patients treated with lorlatinib had not experienced disease progression after seven years, and median progression-free survival has still not been reached. This suggests that, for many patients, long-term control of advanced ALK-positive NSCLC is achievable with a single targeted therapy.
The study also highlights lorlatinib’s effectiveness in the brain. ALK-positive lung cancer has a tendency to spread to the brain and the the long-lasting intracranial control seen in CROWN suggests that lorlatinib can both control existing brain metastases and reduce the risk of new ones developing.
These findings support the growing view that, for some patients, advanced ALK-positive NSCLC may increasingly be managed as a long-term condition rather than a rapidly progressing disease. As patients remain on treatment for longer, managing side effects and maintaining quality of life become increasingly important aspects of care.
What patients need to know
For someone newly diagnosed with advanced ALK-positive NSCLC, the CROWN results provide encouraging evidence about what modern targeted therapies can achieve.
At seven years, 55% of patients receiving lorlatinib had not experienced disease progression.
Median progression-free survival has still not been reached after approximately seven years of follow-up.
Lorlatinib provides strong and long-lasting protection against cancer progressing within the brain.
Patients who remain progression-free during the first two years of treatment have a high likelihood of experiencing several years of disease control.
Like all cancer treatments, lorlatinib can cause side effects and requires ongoing monitoring. Common side effects include increases in cholesterol and triglyceride levels, weight gain, and effects on thinking, mood or memory.
Most neurological side effects reported in the CROWN study were mild or moderate and could often be managed through dose adjustment. Previous analyses have also suggested that reducing the dose to manage side effects does not necessarily reduce the effectiveness of treatment.
When choosing a treatment, patients and their healthcare team will need to balance the potential for long-term cancer control against possible side effects and their impact on day-to-day life. Discussions about treatment should always take into account an individual’s medical history, priorities and preferences.
What healthcare professionals need to know
For clinicians, the seven-year CROWN update provides compelling evidence for the long-term efficacy of first-line lorlatinib.
The exceptional progression-free survival, sustained systemic disease control and durable intracranial efficacy support its role as an important first-line treatment option for advanced ALK-positive NSCLC. The study also reinforces lorlatinib’s ability to delay or prevent the development of new brain metastases.
Long-term toxicity management remains an important consideration as patients may now remain on treatment for many years. Hypercholesterolaemia, hypertriglyceridaemia and weight gain remain common adverse events, although no increasing cardiovascular event rate has been observed despite these metabolic effects.
Neurocognitive adverse events also warrant careful assessment, particularly in patients with pre-existing risk factors such as psychiatric illness, previous brain radiotherapy, brain surgery or use of psychiatric medications.
An additional area of interest comes from exploratory circulating tumour DNA (ctDNA) analyses. These findings suggest that lorlatinib may suppress the emergence of new ALK resistance mutations. As a result, resistance following first-line lorlatinib may increasingly involve alternative signalling pathways rather than conventional on-target ALK resistance mechanisms.
Patients who progressed earlier in their treatment course appeared to have greater genomic complexity, including higher rates of TP53 mutations, additional genetic alterations and higher blood-based tumour mutational burden. While these findings remain exploratory, they may eventually help identify patients who are more or less likely to achieve long-term disease control.
Future directions
The exceptional duration of response reported in CROWN are changing the questions being asked in ALK-positive NSCLC research.
Future studies are likely to focus not only on extending progression-free survival but also on:
Identifying patients at risk of early resistance through biomarkers such as ctDNA
Understanding resistance mechanisms to first-line lorlatinib
Optimising treatment strategies for patients who develop oligoprogressive disease
Combining targeted therapy with local treatments such as radiotherapy
Reducing long-term treatment toxicity while maintaining disease control
Longer follow-up will be needed, particularly for overall survival. However, the seven-year CROWN results clearly demonstrate that prolonged disease control is achievable for many patients with advanced ALK-positive NSCLC.
As outcomes continue to improve, the focus of treatment is evolving beyond controlling cancer alone. Preventing resistance, protecting the brain, managing long-term side effects and preserving quality of life are becoming increasingly important goals for both patients and healthcare professionals.
References
Shaw AT, Solomon BJ, Felip E, Bauer TM, Liu G, Goto Y, Wu YL, Soo RA, Mazieres J, Kim DW, Wang IM, Paolini J, Polli A, Rifi N, Toffalorio F, Mok TSK. Lorlatinib versus crizotinib as first-line treatment for advanced ALK-positive non-small-cell lung cancer: 7-year update from the phase III CROWN study. Ann Oncol. 2026 Sep;37(9):1242-1252. doi: 10.1016/j.annonc.2026.05.692. Epub 2026 May 29. PMID: 42217582.
Tony S.K. Mok et al. Lorlatinib vs crizotinib as first-line treatment for advanced ALK+ non-small cell lung cancer: 7-year update from the phase 3 CROWN study. J Clin Oncol 44, 8502-8502(2026). DOI:10.1200/JCO.2026.44.16_suppl.8502
