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Take a look at a selection of our recent media coverage:

Three NSCLC indications included in positive CHMP opinion for tislelizumab

1st March 2024

The monoclonal antibody tislelizumab (brand name Tevimbra) has received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) for the treatment of non-small cell lung cancer (NSCLC) across three indications, its manufacturer BeiGene has announced.

Tislelizumab has been recommended by the CHMP for use in combination with carboplatin and either paclitaxel or nab-paclitaxel for the first-line treatment of adult patients with squamous NSCLC who have locally advanced NSCLC and are not candidates for surgical resection or platinum-based chemoradiation, or metastatic NSCLC.

The second indication is for use in combination with pemetrexed and platinum-containing chemotherapy for the first-line treatment of adult patients with non-squamous NSCLC whose tumours have PD-L1 expression on ≥50% of tumour cells with no EGFR or ALK positive mutations and who have locally advanced NSCLC and are not candidates for surgical resection or platinum-based chemoradiation, or metastatic NSCLC.

Tislelizumab is also recommended as a monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC after prior platinum-based therapy. Patients with EGFR mutant or ALK positive NSCLC should also have received targeted therapies before receiving tislelizumab, the CHMP said.

The positive opinion for these indications is based on the results of three Phase 3 trials which demonstrated the benefit of tislelizumab as a first- and second-line treatment for patients with NSCLC.

Dr Mark Lanasa, chief medical officer, solid tumors at BeiGene, said: ‘Through three Phase 3 clinical trials enrolling nearly 1,500 patients across the world including in the European Union, tislelizumab has been shown to be an effective therapy for patients with treatment-naïve and treatment-resistant NSCLC.’

He added that the positive CHMP opinion ‘brings us one step closer to providing an important treatment option to patients in Europe with lung cancer, which is among the most common cancers and a leading cause of cancer death in the region.’

Statistically significant tislelizumab trials

The RATIONALE 307 trial looked at first-line tislelizumab in combination with chemotherapy for patients with advanced squamous NSCLC.

It met its primary endpoints with the median progression free survival at 7.7 months for tislelizumab in combination with paclitaxel and carboplatin (hazard ratio, HR: 0.45 [95% CI: 0.326-0.619]; P< 0.001) and 9.6 months for tislelizumab in combination with nab-paclitaxel and carboplatin (HR: 0.43 [95% CI: 0.308-0.60]; P< 0.001).

This was compared to 5.5 months for paclitaxel and carboplatin alone, at a median study follow-up of 8.6 months.

The most common grade ≥3 treatment emergent adverse events were decreased neutrophil levels, neutropenia and leukopenia.

RATIONALE 304 also considered tislelizumab in combination with chemotherapy as first-line treatment and focused on patients with locally advanced or metastatic non-squamous NSCLC.

The study met its primary endpoint, with first-line tislelizumab in combination with chemotherapy resulting in statistically significant improvement in progression free survival compared to chemotherapy (HR: 0.65 [95% CI: 0.47-0.91]; P=0.0054) along with higher response rates and longer response duration.

The most common grade ≥3 treatment emergent adverse events were associated with chemotherapy and included neutropenia and leukopenia.

Looking at second- and third-line treatment, the RATIONALE 303 trial looked at tislelizumab versus docetaxel in patients with advanced NSCLC who progressed on prior platinum-based chemotherapy.

This trial met its primary endpoint, with second- or third-line tislelizumab resulting in statistically significant and clinically meaningful improvement in overall survival compared with docetaxel in the intent-to-treat population (HR: 0.66 [95% CI: 0.56-0.79]; P<0.0001), regardless of PD-L1 expression.

At the final analysis, overall survival in the PD-L1 positive population was also significantly improved in favour of tislelizumab (median 19.3 vs 11.5 months, respectively; HR: 0.53 [95% CI: 0.41-0.70]; P<0.0001).

The most commonly reported grade ≥3 treatment emergent adverse events were pneumonia, anaemia and dyspnoea.

Adagrasib approved in the UK for NSCLC after earlier EU rejection

6th November 2023

Conditional marketing authorisation has been granted for adagrasib (brand name Krazati) by the UK‘s Medicines and Healthcare products Regulatory Agency (MHRA), its manufacturer Mirati Therapeutics has announced.

Adagrasib is a monotherapy indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with KRASG12C mutation who have progressive disease after prior therapy with, or intolerance to, platinum-based chemotherapy and/or anti-PD-1/PD-L1 immunotherapy.

The KRASG12C protein causes the cancer cells to grow out of control and it regenerates every 24-48 hours. Adagrasib is a highly selective and potent oral small-molecule inhibitor which is optimised to sustain target inhibition. attaches to the protein and stops it from working, which may slow down or stop the growth of the cancer. 

The drug is available in 200mg tablet form, with the recommended dose of three tablets taken at the same times twice a day.

The MHRA approval was based on the results of the KRYSTAL-1 open-label Phase 1/2 multiple-expansion cohort trial evaluating adagrasib as monotherapy and in combination with other anti-cancer therapies in patients with advanced solid tumours harbouring the KRASG12C mutation.

In the trial, adagrasib was found to be a central nervous system (CNS) penetrant, which may be important given that CNS metastases frequently occur in NSCLC and lead to poor prognosis, Mirati Therapeutics said.

In a presentation at the recent European Society of Medical Oncology Congress, the company also shared data from the KRYSTAL-7 trial which demonstrated compelling efficacy and safety of adagrasib in combination with pembrolizumab in NSCLC.

Commenting on the approval, Dr Shobhit Baijal, consultant medical oncologist at The University Hospital Birmingham NHS Trust, said: ‘Some 14% of people living with NSCLC harbour the KRASG12C mutation yet there are limited targeted treatment options for patients with this devastating disease.

‘The expansion of treatment options for NSCLC benefits patients and clinicians alike. As someone intensively involved in the management of lung cancer patients, I look forward to Krazati being available for use in clinical practice.‘

NSCLC accounts for approximately 80-85% of the 43,000 lung cancer cases in the UK each year and an estimated 13-14% of these produce the KRASG12C protein. 

In July 2023, the European Medicines Agency issued a refusal of the conditional marketing authorisation for adagrasib after its ‘human medicines committee (CHMP) noted that comprehensive data for this medicine were not yet available and that there were uncertainties about how well the medicine worked‘.

The EMA concluded that Mirati Therapeutics did not provide evidence that the drug fulfils an unmet need for the type of approval it sought. The EMA therefore ‘could not justify making the medicine immediately available to patients while further data were still awaited‘.

Mirati Therapeutics disagreed with the opinion and intended to request a formal re-examination.

In the US, adagrasib was previously given accelerated approval by the FDA in December 2022.

Circulating tumour DNA biopsy helps identify NSCLC patients suitable for radiotherapy

6th October 2023

Taking a pre-radiation biopsy of circulating tumour DNA (ctDNA) in patients with oligometastatic non-small cell lung cancer (NSCLC) may help identify those most likely to benefit from locally consolidative radiotherapy (RT), according the findings of recent study.

Published in the journal NPJ Precision Oncology, the researchers sought to risk-stratify and identify the patients with oligometastatic NSCLC most likely to benefit from locally consolidative RT, which could help to achieve prolonged remission.

They performed 1,880 liquid biopsies and approximately 20% of patients (n = 309) had their ctDNA measured prior to RT and after their diagnosis of oligometastatic disease. 

Patients with undetectable ctDNA before RT had significantly improved progression-free survival (PFS) (p = 0.004) and overall survival (OS) (p = 0.030).

In contrast, patients with detectable ctDNA pre-RT had a median PFS of 5.4 months versus 8.8 months for those with undetectable levels (Hazard ratio, HR  = 1.57, 95% CI 1.15 – 2.13, p = 0.004). There were similar findings for OS, with a median OS of 16.8 months versus 25 months (HR = 1.65, 95% CI  1.05 – 2.61, p = 0.030). Multivariate analysis, including additional parameters, revealed a similar trend.

ctDNA biopsy a ‘more precise measure of disease burden‘

Based on these findings, the authors wrote: ’Our analysis reveals that ctDNA testing performed pre-RT can risk-stratify those patients with truly oligometastatic NSCLC from those who likely harbour widespread micrometastatic disease (below current imaging limits of detection).’

Senior study author Aadel Chaudhuri, an assistant professor of radiation oncology at the Siteman Cancer Center, based at Barnes-Jewish Hospital and Washington University School of Medicine in St Louis, said: ‘Our findings suggest the level of ctDNA, rather than the number of tumours themselves, is a more precise measure of disease burden.’

The authors added: ‘This approach should be prospectively evaluated in a clinical trial that redefines oligometastatic NSCLC to include a discrete liquid biopsy metric encompassing a low or undetectable ctDNA level.‘

Alectinib shows promise in early-stage ALK-positive non-small cell lung cancer

8th September 2023

The use of adjunctive alectinib reduced disease recurrence in the early setting for people with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) compared to platinum-based chemotherapy, its manufacturer Roche has announced.

Alectinib (brand name Alecensa) is the first and only ALK inhibitor to show a reduction in the risk of disease recurrence or death for people with early-stage ALK-positive NSCLC in a Phase 3 trial.

A statistically significant and clinically meaningful improvement in disease-free survival (DFS) – the study’s primary endpoint – was found when alectinib was used as adjuvant therapy in patients with completely resected stage IB to IIIA, ALK-positive NSCLC.

Around 80-85% of lung cancers are due to NSCLC, and 4-5% of patients with NSCLC are ALK-positive. Despite adjuvant chemotherapy, roughly half of all patients with early lung cancer (45-76%, depending on disease stage) still experience a cancer recurrence following surgery.

Alectinib and the ALINA trial

The ALINA study is a Phase 3, randomised, active-controlled, multi-centre, open-label study evaluating the efficacy and safety of adjuvant alectinib compared to platinum-based chemotherapy in 257 patients.

The primary endpoint is DFS and secondary outcome measures include overall survival (OS) and the percentage of patients with adverse events. The OS data were immature at the time of the interim analysis. However, there have been no unexpected safety findings observed.

The findings from ALINA will be presented at an upcoming medical meeting and submitted to health authorities globally, including the US Food and Drug Administration and the European Medicines Agency.

Commenting on the interim analysis of alectinib, Levi Garraway, Roche’s chief medical officer and head of global product development, said: ‘Alecensa has transformed outcomes for people with advanced ALK-positive NSCLC, and now these strong results provide evidence for the first time that this medicine could also play a pivotal role in early-stage disease where there is significant unmet need.

‘If approved, Alecensa has the potential to treat cancer before it has spread in a setting where treatment can increase the chances of cure, which is our ultimate goal at Roche. We look forward to sharing these data with regulatory authorities in hopes of bringing this to patients as quickly as possible.‘

Specific enzyme tissue expression close to tumour may predict survival in NSCLC

4th September 2023

High levels of two enzymes, CD39 and CD73, involved in the adenosine pathway are associated with reduced patient survival in early-stage non-small cell lung cancer (NSCLC) if found in tissue near the tumours, according to the findings of a new study.

Understanding the pathways of immune suppression is crucial to the development of new therapeutic targets for immunotherapy. In the study by the Centre for Inflammation Research at the University of Edinburgh and funded by the charity Cancer Research UK, researchers investigated why cancer immunotherapy fails so often by examining molecules that can interfere with the activity of T cells.

Published in the Journal for Immunotherapy of Cancer, the study revealed that higher levels of the CD39 and CD73 enzymes may help predict patient survival and indicate whether or not treatments will work. The researchers say the findings could help to pave the way for improved immunotherapies, allowing them to work more effectively in more patients.

NSCLC is the most common form of cancer, accounting for more than 80% of cases. While it is already known that T-cell subsets play a key role in shaping anticancer responses, there is still much to be learned to enable the development of diagnostic and therapeutic approaches.

The roles of the two enzymes, CD39 and CD73 have already been established. For instance, CD39 converts extracellular adenosine triphosphate to adenosine monophosphate and which is ultimately hydrolysed into adenosine by CD73. This liberated adenosine has highly immunosuppressive effects, enhancing the activity of suppressive immune cells.

CD39 levels in untreated NSCLC

For the study, the researchers turned to a cohort of 162 treatment naive early-stage NSCLC patients. They quantified the expression and localisation of CD39, CD73 and the tissue resident memory marker CD103.

They showed that in early, untreated NSCLC, patients had up-regulated expression of CD39 in the tumour tissue of natural killer cells, fibroblasts and T cells. In contrast, CD73 expression was mainly found among fibroblasts and Epcam+cells in the tumour tissue.

Further analysis revealed how CD39 expression was mainly localised in the tumour stroma, whereas CD73 expression was equally distributed between the tumour nest and stroma. Moreover, this high expression of both CD39 and CD73 in the tumour stroma was associated with poor recurrence-free survival at five years.

The team also observed that CD8+T cells within the tumour nest expressed CD103 and that the density of CD39+CD103+CD8+ T cells in the tumour nest, conferred a survival advantage, as witnessed by improved recurrence-free survival at five years.

Dr Ahsan Akram, Cancer Research UK clinician scientist fellow at the University of Edinburgh’s Centre for Inflammation Research, said: ‘This study helps us to understand that we need to know the types of T cells in the cancer and their location within the tumours to begin to appreciate the complexity we are dealing with.

‘We hope these results will lead to more research in this area, and in the future could help to identify patients who will do well with immunotherapies, as well as identifying earlier those that may not, so alternative treatments can be tried.‘

Further research and tests are needed alongside the integration of new technologies before any application in clinical practice is possible.

Is two years enough for immune checkpoint inhibitor therapy in non-small cell lung cancer?

20th July 2023

Immune checkpoint inhibitors have transformed the management of non-small cell lung cancer, but how long should treatment be continued for optimal survival? Clinical writer Rod Tucker takes a closer look at the evidence.

It has long been recognised that a hallmark of cancer is immune evasion and that the immune system is held back by inhibitory immune checkpoint receptors and ligands. The discovery that immune checkpoint inhibitors (ICIs) could interrupt these immune checkpoints and thereby provide an anti-tumour effect, leading to cancer regression, was a major therapeutic advance in oncology.

The first ICI to receive FDA approval was ipilimumab in 2011 and, since then, there have been several other agents approved by regulatory authorities across the world.

Lung cancer is the leading cause of global cancer incidence and mortality and it accounts for an estimated two million diagnoses and 1.8 million deaths worldwide, with non-small cell lung cancer (NSCLC) responsible for more than 80% of cases.

ICIs have been deployed in the management of NSCLC and drugs such as nivolumab have proved to be very effective treatments. Nevertheless, an important and practical consideration is how long to continue with the therapy. Guidance on the use of ICIs, such as the advice in the UK from NICE for pembrolizumab in NSCLC, recommends that treatment is halted after two years. However, in its guidance, the clinical experts at NICE accept that the optimal treatment duration is unknown and they acknowledge that extended duration treatment courses are likely to be burdensome for patients, hence the restriction.

But is this somewhat arbitrary limit of two years sufficient to derive an optimal survival response, or should it be longer? In the absence of objective evidence, clinicians are left to ponder whether adhering to this duration best serves the interests of their patients. Although some evidence indicates a prolonged survival with ICIs after treatment has ceased, there is clearly a need for more definitive data.

Immune checkpoint inhibitors and survival

CheckMate 153 was the first randomised trial to examine the optimal duration of ICI therapy in patients with NSCLC. The trial compared a fixed one-year treatment regimen with nivolumab to a continuous one with exploratory analyses examining the incidence of adverse events, progression-free survival and overall survival. The results suggested a significant progression-free survival advantage favouring continuous treatment (hazard ratio, HR = 0.56, 95% CI 0.37 to 0.84).

The longest safety and efficacy data for patients with advanced NSCLC comes from the phase Ib KEYNOTE-001 study using pembrolizumab and included both previously treated and treatment naive patients. The findings, published in 2019, offered an insight of the five-year survival in those with advanced disease and the results were impressive. After 60.6 months, among previously treated patients, the median overall survival was 10.5 months in previously treated patients compared to 22.3 months in treatment-naive cohort.

Nivolumab also appears to provide impressive five-year survival data. In a study of previously treated patients with advanced NSCLC given nivolumab, the estimated five-year overall survival rate (after 96 weeks of therapy) was 16%.

Although these findings make clear that ICIs do improve survival in the longer term following cessation of treatment, there still remains the unanswered question as to how long is enough to derive these survival benefits.

The findings of a recent retrospective analysis could furnish clinicians with the answer they have been looking for.

Is two years enough?

Cognisant that most ICI trials continued for up to two years, researchers from the University of Pennsylvania evaluated the association between duration of therapy with overall survival. Publishing their findings in the journal JAMA Oncology, the team compared overall survival in those who had received ICI treatment for two years and those whose therapy continued for longer.

Survival outcomes were dichotomised as either between 700 and 760 days (i.e. two years, fixed duration) or greater than 760 days (i.e. an indefinite duration). After various adjustments for potential confounders, survival was found to be 79% in the two-year fixed-duration group and 81% for the indefinite-duration group. The hazard ratio for death associated with fixed-duration ICI therapy compared with the indefinite-duration group was non-significant (HR = 1.33, 95% CI 0.78 – 2.25, p = 0.29).

While there are recognised limitations from retrospective analyses, these findings do suggest that up to two years of ICI therapy is sufficient and that a longer duration – which is more costly and burdensome for patients – offers no survival benefit.

While guidance restricting the use of ICI therapy in NSCLC to no longer than two years might appear somewhat random, the latest evidence, although prefaced by important caveats, does appear to support that premise. Furthermore, the latest data should also offer reassurance to clinicians that these current restrictions are unlikely to affect their ability to deliver optimal care for patients with NSCLC.

Perioperative pembrolizumab improves event-free survival in early-stage lung cancer

22nd June 2023

Perioperative pembrolizumab in patients with early-stage non-small cell lung cancer (NSCLC) leads to a significant improvement in event-free survival, but not overall survival, according to the findings of a recent randomised, placebo-controlled clinical trial.

Existing evidence points to an event-free survival benefit from using neoadjuvant durvalumab, an anti-programmed cell death-1 agent in resectable stage NSCLC. However, whether similar advantages would arise from the perioperative and adjuvant usage of pembrolizumab, a programmed cell death protein 1 inhibitor, in early stage NSCLC is uncertain.

Recently, an international research group published a randomised, placebo-controlled trial in the New England Journal of Medicine, to evaluate perioperative pembrolizumab in patients with early-stage NSCLC

Eligible participants had resectable stage NSCLC and were randomised 1:1 to either perioperative pembrolizumab (200 mg) or placebo once every three weeks, with cisplatin-based chemotherapy. This was followed by surgery and then adjuvant pembrolizumab (200 mg) or placebo once every three weeks.

A dual primary endpoint of event-free survival and overall survival was used, with secondary endpoints of a major pathological response, pathological complete response and safety.

Event-free survival findings

A total of 797 participants, of whom 397 were assigned to the pembrolizumab group, were included in the analysis.

The median time from randomisation to the data-cut-off date was 25.2 months. Event-free survival at 24 months was significantly higher in the pembrolizumab group compared to placebo (hazard ratio, HR, for progression, recurrence or death = 0.58, 95% CI 0.46 – 0.72, p < 0.001). In contrast, the estimated 24-month overall survival was not significantly different to placebo.

A major pathological response occurred in a significantly higher proportion of participants assigned to perioperative pembrolizumab (p < 0.0001). Similarly, there was a significantly higher pathological complete response (p = 0.0001).

Any treatment-related adverse events cross the treatment phases were reported in a similar proportion of patients (96.7% vs 95%, pembrolizumab vs placebo).

Neoadjuvant nivolumab provides significant 5-year overall survival in lung cancer

20th February 2023

A significant five-year overall survival rate has been observed with the use of neoadjuvant nivolumab in resectable non-small cell lung cancer.

In a 2018 global study, lung cancer was found to be the most commonly diagnosed cancer (11.6% of all cases) as well as the leading cause of cancer deaths. The most common form of lung cancer is non-small cell lung cancer (NSCLC) which accounts for around 80-85% of all cancers. The use of programmed death 1 (PD-1) protein inhibitors as a treatment for patients with advanced NSCLC have been shown to produce a durable response and encouraging survival rates. Until recently, the value of PD-1 blockage in patients with resectable NSCLC has been unclear. However, in a 2018 trial it was found that two preoperative doses of nivolumab in adults who had early, i.e. stage I, II of IIIA, surgically resectable NSCLC, did not cause a delay to surgery and was able to induce a major pathological response in nearly half (45%) of resected tumours. While these were impressive, there was uncertainty over the longer term outcome of such patients.

In the current study, a team from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, US, provided the longest known follow-up study of patients given neoadjuvant nivolumab therapy with any type of cancer. The patient cohort was derived from the team’s earlier 2018 trial described above. Eligible participants received two doses of nivolumab (3mg/kg bodyweight) every two weeks with surgical resection planned for roughly four weeks after the first dose. In this follow-up, the researchers examined exploratory endpoints such as recurrence-free survival (RFS) and overall survival (OS) from the date of the patient’s surgery. They also considered the proportion achieving a major pathological response (MPR).

Five-year overall survival and neoadjuvant nivolumab

A total of 20 patients were included and followed for a median of 63 months. The five-year RFS rate was 60% and the OS 80%. In addition, the researchers reported that the use of nivolumab was associated with few side effects and did not delay surgery.

At the time the analysis was undertaken, the hazard ratio (HR) for the presence of a MPR, though not significant, was in the direction of improved RFS (HR = 0.61, 95% CI 0.15 – 2.44). In fact, at the five-year follow-up, eight of nine patients with a MRP were alive and free of disease. In contrast six of the 11 patients without MRP at a tumour relapse, three of whom died.

The authors concluded that five years, the clinical outcomes associated with neoadjuvant therapy were comparatively favourable to the earlier observed response. They added that while there was a trend towards improved RFS, it was difficult to draw any firm conclusions due to the small sample size.

Citation
Rosner S et al. Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer. Clin Cancer Res 2023

Results of CANOPY-A trial of canakinumab in non-small cell lung cancer released

18th August 2022

Results show that adjuvant treatment with canakinumab in adults with non-small cell lung cancer failed to meet the primary endpoint of disease-free survival compared with placebo

According to a Novartis, results from their CANOPY-A trial show that canakinumab failed to meet the primary endpoint of disease-free survival in adult patients with stages II-IIIA and IIIB (T>5cm N2) completely resected (R0) non-small cell lung cancer (NSCLC).

Lung cancer was responsible for approximately 2.21 million cases globally in 2020 and 1.80 million deaths. Moreover, between 80 and 85% of all lung cancers are due to NSCLC and while surgery remains the only potentially curative modality for early-stage NSCLC, 30% to 55% of patients develop recurrence and die of their disease despite curative resection.

CANOPY-A was a randomised, double blind, placebo-controlled study designed to evaluate the efficacy and safety of canakinumab compared with placebo as an adjuvant therapy in NSCLC. The rationale for CANOPY-A arose after a finding from data obtained in the CANTOS trial, designed to examine the role of canakinumab in preventing further myocardial infarction, stroke, or cardiovascular death in patients with elevated C‐reactive protein.

While CANTOS observed how anti-inflammatory therapy targeting the interleukin-1β innate immunity pathway, led to a significantly lower rate of recurrent cardiovascular events than placebo, the authors also noted a dramatic reduction in the number of incident cases of lung cancer.

Canakinumab is a human immunoglobulin monoclonal antibody with a high affinity and specificity for IL-1β, blocking its interaction with the IL-1 receptor. Furthermore, it has been suggested that IL-1β inhibition might represent an effective anti-tumour therapy. Therefore, Novartis considered that there was a potentially sound rational to examine the role of their monoclonal antibody as a cancer therapy.

In the CANOPY-A trial, 1382 patients were randomised 1:1 to either canakinumab, 200 mg subcutaneously every three weeks, or matching placebo for up to one year and all patients received cisplatin-based chemotherapy before randomisation.

The primary outcome for the study was disease free survival (DFS). Canakinumab was not superior to placebo and the results will be presented at a future medical meeting.

Commenting on these findings, Jeff Legos, Executive Vice President, Global Head of Oncology and Haematology Development, Novartis, said: ‘While we are disappointed CANOPY-A did not show the benefit we hoped for, every trial generates scientific evidence that supports future research and development, and we look forward to continuing to pursue new therapeutic options for people living with lung cancer, whose needs remain urgent and significant.’

Residual ctDNA predicts relapse in lung cancer

13th April 2022

Detection of ctDNA after treatment of patients with lung cancer is associated with greater disease recurrence and a reduced overall survival

The presence of residual ctDNA after treatment of patients with non-small cell lung cancer (NSCLC) is associated with a shorter recurrence-free survival and overall survival. This was the key finding of a study carried out in Cambridge, UK.

In 2020, there were over 2.2 million cases of lung cancer which resulted in nearly 1.8 million deaths. Lung cancer has two main forms; small cell and non-small cell, and in the UK, the latter accounts for around 85% of all cases.

Treatment options for NSCLC depend upon disease stage and range from surgical resection or radiotherapy (stage 1) through to surgery and adjuvant chemotherapy or chemo-radiotherapy for those with stage 3. However, an important consideration for any of the different forms of treatment, is the ability to detect the presence of post-therapy residual disease.

One emerging potential biomarker is circulating tumour DNA (ctDNA), which is a component of cell-free DNA shed by malignant tumours into the bloodstream and other bodily fluids. It has the potential for prognostication, molecular profiling and monitoring of patients with cancer and has, for example, been shown to be an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer.

In fact, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumour malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance.

For the present study, the researchers set out to assess ctDNA levels in patients with stage 1 to 3 NSCLC to determine whether detection of this DNA tumour fragment post-therapy could predict patient outcomes.

Using samples from the Lung cancer circulating tumour DNA study (Lucid), the team first determined the levels of ctDNA prior to lung cancer treatment and then sought to detect the DNA two weeks to four months after therapy.

Predictive value of ctDNA

A total of 363 plasma samples from 88 patients with early-stage NSCLC (stages 1, 2 and 3) treated with curative intent surgery (61), surgery and adjuvant chemotherapy/radiotherapy (8) and chemo-radiotherapy (19) were included in the study.

Prior to therapy, ctDNA was detected in 24%, 77% and 87% of patients with stage I, II and III disease respectively. Post-treatment, ctDNA was found in 64.3% of patients (28) who had a clinical recurrence of their cancer.

Detection of ctDNA within the time period of two weeks to 4 months post-treatment occurred in 17% of patients and was associated with shorter recurrence-free survival (hazard ratio, HR = 14.8, 95% CI 5.82 – 37.48, p < 0.00001) and a reduced overall survival (HR = 5.48, 95% CI 2.18 – 13.76, p < 0.0003).

Interestingly, ctDNA was also detected 1 – 3 days after surgery in 25% of patients but not associated with disease recurrence.

Among those where ctDNA was found before treatment, there was also a reduced overall survival (HR = 2.97, p = 0.01) and recurrence free survival (HR = 3.14, p = 0.003) compared to samples where ctDNA was not detected prior to treatment.

The authors concluded that their data supported the clinical utility of ctDNA testing to identify residual disease and recurrence and that this was a potentially sensitive tool to determine which patients were at high risk of relapse and who could benefit from additional adjuvant therapy.

Citation
Gale D et al. Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer Ann Oncol 2022

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