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25th November 2024
A second interim analysis of the KEYNOTE-671 trial has shown that adding perioperative pembrolizumab to neoadjuvant chemotherapy for early-stage non-small-cell lung cancer (NSCLC) is effective and safe. This combination of medication showed significant overall survival benefit for patients who lived longer without cancer progression, recurrence or death and increased health-related quality of life.
This follows the results of the first interim analysis which found that adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage NSCLC but did not improve overall survival.
The global phase 3 trial was undertaken at 189 medical centres between May 2018 and Dec 2021 and involved 797 participants. All participants were 18 or older and had resectable stage II, IIIA, or IIIB (N2) NSCLC.
Patients were randomly assigned to one of two medication groups, with 397 undertaking treatment with pembrolizumab: four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every three weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every three weeks).
The control group had four cycles of neoadjuvant placebo (administered intravenously every three weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every three weeks).
Groups were stratified based on disease stage, levels of the PD-L1 protein in cancer cells, lung cancer types and geographical regions. Researchers compared rates of overall survival and event-free survival between the two groups.
At 36 months, overall survival rates were 71% (95% CI 66–76) in the pembrolizumab group and 64% (95% CI 58–69) in the placebo group. Median event-free survival was 47.2 months in the pembrolizumab group and 18.3 months in the placebo group.
Serious side effects (grade 3–5) were more common in the pembrolizumab group (45%) compared to the placebo group (38%). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group.
The authors concluded that the use of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was beneficial in patients with resectable, early-stage NSCLC due to significant overall survival benefits and the manageable safety profile, supporting its use in this patient group.
Reference
Spicer, J et al. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet 2024; Sept. 28: DOI: 10.1016/S0140-6736(24)01756-2.
21st October 2024
Consultant clinical oncologist Dr John Conibear speaks to Kathy Oxtoby about the changing treatment landscape of non-small cell lung cancer, durvalumab’s latest approval by the MHRA for the resectable form, and his hopes for the future management of the condition.
The UK has one of the worst five-year survival rates for lung cancer in Europe, and new treatment options are urgently needed to offer patients a better chance of long-term survival.
This July, the Medicines and Healthcare products Regulatory Agency (MHRA) granted marketing authorisation in Great Britain for durvalumab (brand name Imfinzi) for the treatment of adults with resectable non-small cell lung cancer (rNSCLC).
This anti-programmed death ligand 1 monoclonal antibody is now indicated in combination with platinum-based chemotherapy as a neoadjuvant treatment before surgery, followed by durvalumab as adjuvant monotherapy after surgery, in those who have no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements or aberrations.
This joins durvalumab’s existing indication for the treatment of adult patients with locally advanced, unresectable NSCLC, meaning the drug is now approved in Great Britain for both resectable and unresectable forms.
The latest approval from the MHRA is based on positive data from the AEGEAN Phase III trial in rNSCLC, which showed that durvalumab-based treatment before and after surgery reduced the risk of recurrence, progression events or death by 32% versus neoadjuvant chemotherapy alone.
Dr John Conibear is a consultant clinical oncologist and clinical director for thoracic oncology at Barts Cancer Centre, London, and oncology lead for the National Lung Cancer Audit (NLCA). He says the AEGEAN Phase III trial represents ‘a promising step forward in the management of patients with resectable lung cancer’.
‘The trial demonstrates that the combination of immunotherapy with traditional chemotherapy, in both the neoadjuvant and the adjuvant setting improves pathological response rates and disease-free survival,’ he says. ‘That could potentially lead to better long-term outcomes and increased survival rates for these resectable patients.’
The use of durvalumab in combination with chemotherapy for treating rNSCLC is still pending approval from the National Institute of Health and Care Excellence (NICE) and is currently not recommended by the organisation in its initial draft guidance, which has been out for consultation and is now being considered by the committee.
Dr Conibear says the results of the trial show that ‘the addition of this drug does seem to reduce the relapse of patients with lung cancer in this resectable setting, and it increases the rates of complete responses’. For him, there is ‘clearly synergism between chemotherapy and immunotherapy in this setting’, and Dr Conibear is in favour of durvalumab being available on the NHS for routine use in this patient group.
‘From a clinician’s point of view, I want to do what’s best for my patients, and it’s a shame if durvalumab is considered unsuitable on the basis of financial availability rather than clinical benefit,’ he says.
Whether NICE changes its current stance, only time will tell.
Dr Conibear’s insight into the importance and value of durvalumab for lung cancer patients comes from more than 20 years of working in oncology, including thoracic oncology.
It was during the early part of his training as a junior doctor in 2003 that he chose this specialism. ‘As a medical specialty, oncology is dynamic, and always seems to evolve, because of the nature of the treatment we can offer patients,’ says Dr Conibear.
Patients with cancer require ‘a compassionate and thoughtful approach to their care’, he says. ‘Oncology fuses both the science and compassion of medical care into one specialty, which I find attractive.’
His particular interest in thoracic oncology was sparked towards the end of his oncology training. ‘I was involved in clinical trials looking at improving outcomes in patients with locally advanced lung cancer, and through that I began to appreciate the complexities in diagnosing and treating lung cancers.’
During the last decade since Dr Conibear became a consultant, the treatment landscape of NSCLC, in both the UK and Europe, has evolved significantly. ‘That’s been driven by advancements in targeted therapies, immunotherapy and the more personalised approach to patient care,’ he says.
Understanding the molecular biology of NSCLC has made a huge difference, with clinicians ‘now able to identify specific gene mutations, which allows us to use specific targeted therapies, and these offer better efficacy and often fewer side effects compared to traditional chemotherapy’.
Then there is the advent and evolution of immunotherapy. ‘This has revolutionised NSCLC treatment, both in the early, locally advanced and metastatic settings. This has become the standard of care for many patients with NSCLC, and led to significant improvements in survival rates,’ he says.
‘Through these advances in treatment, and the combination of these treatments, whereby you create a personalised multimodality approach, we’ve seen improvements in patient survival. We see patients not only cured of their disease, but also living with their disease for much longer than we ever saw in the past,’ he adds.
However, in the UK, what is clear from ongoing data analysis – such as the National Lung Cancer Audit’s ‘State of the Nation 2024’ report – is that much more needs to be, and potentially can be, done. ‘There is still an unmet need when it comes to treating patients with both early and advanced lung cancer in regard to the number of patients who don’t seem to be receiving optimal cancer-driven care’, Dr Conibear says.
‘We’re trying to explore the reasons behind that – the potential biases and inequalities that are causing these differences to occur, both within regions of the UK, and also the UK compared to our European brothers and sisters.’
The AEGEAN Phase III trial is evolving the treatment landscape further, says Dr Conibear.
Durvalumab has become ‘a cornerstone in the management of unresectable locally advanced NSCLC’, and ‘the AEGEAN trial potentially, as the data matures, could reveal durvalumab to have a similar role in resectable patients,’ he suggests.
Until now, treatment has been focused on just the neoadjuvant use of chemoimmunotherapy in resectable patients before they have surgery.
‘What this trial demonstrates is expanding that treatment beyond surgery, so that patients then come back after surgery to receive further immunotherapy,’ Dr Conibear says. ‘Essentially, we’re intensifying the patient’s treatment to see an improved long-term outcome – we hope.’
Dr Conibear would like durvalumab to ‘translate into a meaningful improvement in long-term survival and push the bar higher in what we consider to be standard outcomes for these patients’, and he believes there is certainly potential for this to happen.
While clinicians and multidisciplinary teams (MDTs) working in lung cancer care understand the role of durvalumab in treating patients with unresectable lung cancer, Dr Conibear says ‘there is a knowledge gap now for people in those teams to understand the role of durvalumab in that resectable patient group, following the results of the AEGEAN trial’.
If NICE’s final ruling is in favour of durvalumab for treating rNSCLC ‘then there will be a need to target education towards these clinicians to expand that knowledge base’, he says. This could include educational initiatives such as workshops, seminars and webinars focused on the role of durvalumab in non-small cell lung cancers. And guidelines and protocols will need to be updated to reflect these evolutions of approaches to patient care.
Ongoing professional development should be encouraged, ensuring that the MDT attends training sessions to stay up to date with the latest practices and treatment recommendations, he says.
As patients are becoming increasingly complex in terms of the personalised approach required for their care, Dr Conibear sees a greater need for case discussions and the sharing of ‘knowledge and experience between multidisciplinary team meetings’. There is also a role for direct peer-to-peer learning and encouraging experienced oncologists to share insights through mentorship programmes or peer-led discussions, he adds.
‘And what mustn’t be forgotten is the dissemination of information to patients, arming them with the knowledge of what’s available, and what’s potentially suitable for them so they can also be an advocate for their own care,’ he says. ‘Patient education and advocacy are also important to dispel the limitations on what we offer our patients.’
As to further developments in the management of NSCLC beyond durvalumab, attention is turning to new mutations, which Dr Conibear says are ‘potentially druggable’ and ‘could form further aspects of that personalised approach to patient care in the resectable and unresectable lung cancer setting’.
Then there are advances in diagnostics, in particular liquid biopsies – the ability to collect and analyse circulating tumour DNA and circulating tumour cells. ‘We can use these measures to understand resistance patterns to treatment so that we potentially have a more dynamic and adaptive treatment plan that we can offer our patients,’ he says.
‘We can see at a microscopic level whether the treatment is working or not, so that we can make clinical management decisions more quickly than we have done historically.’
Dr Conibear also highlights the integration of artificial intelligence and machine learning into clinical practice. ‘These tools are capable of analysing large data sets, including imaging, genomic data and clinical data,’ he says. ‘It seems with the right algorithms you’re capable of predicting patient outcomes and responses to therapy, and possibly even unwanted adverse events or effects more accurately. This technology could help us to enhance this personalised treatment approach to patients.’
And with the AEGEAN trial showing the benefit of immunotherapy and chemotherapy before, and now also after surgery, ‘it’s demonstrating, again, the importance of a multimodality approach to these patients’, Dr Conibear says. ‘As we move on, we’ll see the potential of other treatments added into this approach.’
It’s no secret that Dr Conibear would like durvalumab to be available to real-world rNSCLC patients who are eligible for the treatment. ‘And it would be great to not see it as the final step, but a stepping stone in terms of improving things further for these patients,’ he says.
‘Ultimately, I hope durvalumab plays a pivotal role in advancing lung cancer treatment, thereby contributing to higher survival rates, improved quality of life and pushing the bar higher on the idea of a personalised approach to these patients’ care. I’m optimistic we’ll see that.’
Update:
On 6 December 2024, AstraZeneca announced that NICE has published final draft guidance recommending durvalumab in combination with platinum-based chemotherapy as a neoadjuvant treatment before surgery, followed by durvalumab as adjuvant monotherapy after surgery for the treatment of adults with rNSCLC (tumours ≥4 cm and/or node-positive) and no known EGFR mutations or ALK rearrangements, for NHS use in England and Wales.
25th April 2024
The monoclonal antibody tislelizumab has been approved by the European Commission (EC) for use in patients with treatment-naive and relapsed non-small cell lung cancer (NSCLC), its manufacturer BeiGene has announced.
This follows its positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use in March 2024.
The approval of tislelizumab (under the brand name Tizveni, but also known as Tevimbra) is across three indications, including first- and second-line use, which are:
Tislelizumab, which is a PD-1 inhibitor, is also approved in the European Union for the treatment of locally advanced or metastatic oesophageal squamous cell carcinoma (OSCC) after prior chemotherapy.
The NSCLC indications were approved under the brand name Tizveni. However, BeiGene plans to combine the NSCLC indications with the second-line OSCC indication under the brand name Tevimbra, which will launch in the first EU countries later in 2024.
Commenting on the approval, Dr Luis Paz-Ares, head of the medical oncology service at University Hospital October 12 in Madrid, Spain, said: ‘Non-small cell lung cancer remains one of the most common and deadly cancers in Europe, with 50% of patients diagnosed already progressed to advanced stages, making it difficult to treat.
‘Across three phase 3 studies, tislelizumab has been shown to improve outcomes for patients with certain types of NSCLC, providing a new option for those facing the disease.’
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: RATIONALE 307 and RATIONALE 304, which both looked at first-line treatment in combination with chemotherapy for various types of NSCLC, and RATIONALE 303, which looked at tislelizumab as second- and third-line treatment compared with docetaxel.
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.’
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.
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.
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.
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.‘
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.
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.‘
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.
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.
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.
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.
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.
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.
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).
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