Molecular testing before the start of treatment is good clinical practice (GCP) and confers considerable benefits in survival, according to Professor Joanna Chorostowska-Wynimko (National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland). “The combination of science, genetics and clinical pharmacology really improves survival in lung cancer”, she said

She traced the discovery of treatable mutations in lung cancer and showed how progressive improvements in the treatment of non-small cell lung cancer (NSCLC) had led to impressive improvements in overall survival.

Antimicrobial stewardship

In most European countries more than 25% of E. coli isolates are now fluorquinolone-resistant and in some countries the rate is over 50%, explained Dr Marina Odalović (University of Belgrade, Serbia)  Antibiotic usage patterns vary considerable across Europe. She noted that national recommended targets by 2030 include:

• A reduction in the total consumption of antibiotics by 3-27%
• 65% of antibiotics used should be in the Access group as defined by the WHO AWaRe classification
• A reduction in the incidence of MRSA bloodstream infections by 3-18%

Dr Odalović emphasised the role of pharmacists in the optimisation of antimicrobial use and reduction of antimicrobial resistance. Finally, she reminded the audience that antibacterial agents in the clinical pipeline combined with those approved in the past six years are still insufficient to tackle the ever-growing threat of the emergence and spread of drug-resistant infections.

Delirium and dementia 

Professor Anita Weidmann (University of Innsbruck, Austria) described the challenging problem of delirium superimposed on dementia (DSD). Older adults with dementia are five times more likely to develop delirium when hospitalised and for many this can persist after discharge.

There are many diagnostic tools for delirium but only three are suitable for DSD. A number of risk factors, including diabetes mellitus, pain and treatment with benzodiazepines, have been identified. Anti-psychotic drugs are recommended for treatment but there is no evidence to support this, said Professor Weidmann. In closing she described how a consensus guideline (Consensus Guideline on Medication Factors in Delirium – COMeD) had been developed to combat the shortage of information about medication and prescribing in DSD.

Point-of-care screening interventions

In recent years Portuguese community pharmacists have been involved in a multinational project for early detection of atrial fibrillation. Dr Carolina Ferreira (Health Solutions Manager, Ezfy, Portugal) described how pharmacists had been trained to check pulses, record results and make referrals when irregular pulses were detected. In total 56 participating pharmacies had made 1699 pulse checks and identified 77 cases with irregular pulses. Of these, 24 received confirmed diagnoses and treatment.

Another project had involved screening of people aged 50-79 years for colorectal cancer. In total 143 people had positive faecal occult blood tests and were instructed to make appointments to see their doctors. At the time of follow up information was available for 65 participants; 53 had doctors’ appointments of whom 28 had further tests, six were diagnosed with benign polyps and two with adenomatous polyps.

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It is often important to get cancer patients to quit smoking, but it is not always that easy.

“Data suggest that between 15 and 60 per cent of people who smoked before they were diagnosed with cancer continue to smoke after their diagnosis. It is crucial to help people with cancer quit smoking, because it will lead to better cancer treatment prognoses, prevent secondary cancer, and increase quality of life,” says Rubén Rodríguez-Cano, an associate professor at the Norwegian University of Science and Technology (NTNU’s) Department of Psychology.

Degree of addiction

Because smoking and cancer often go hand-in-hand, it is especially useful to determine how addicted people are to smoking. That makes it possible to estimate how likely it is that people will manage to quit, and consequently predict cancer patients’ chances of surviving.

The researchers may also be able to use a similar approach to estimate the risk that smokers who are still healthy have of developing cancer at a later date.

“We are currently conducting another study on the risk of developing lung cancer, which is being led by Professor Oluf Dimitri Røe. Among the variables are nicotine addiction, smoking history and BMI,” says Rodríguez-Cano.

However, investigating smoking addiction requires considerable resources. Therefore, Rodríguez-Cano wanted to find out whether there is a more efficient way of measuring the degree of a smoker’s addiction.

He collaborated with people from one of the foremost cancer hospitals in the world, the University of Texas MD Anderson Cancer Center in Houston, Texas.

Long and short tests

Several tests can be used to ascertain smoking addiction. The gold standard is the Fagerström Test for Cigarette Dependence (FTCD).

“But this test is too extensive when we want to check a large number of patients to assess smoking risk at group level,” says Rodríguez-Cano.

So, is a longer test really necessary? A simplified version called the Heaviness of Smoking Index (HSI) comprises only two questions:

• How many cigarettes do you smoke per day?
• How soon after you wake up do you smoke your first cigarette?

And these two questions are sufficient. Try it yourself.

A simplified test is often sufficient

“We investigated nearly 6000 cancer patients to see if it made any difference whether they took the full test or the simplified one,” says Rodríguez-Cano.

It generally did not make a difference.

“The results in predicting cigarette addiction were equally good for both the full and the simplified tests.

In addition, the simplified test is just as good at predicting the smoking abstinence at 3, 6, and 9 months after quitting smoking following specialised treatment,” says Rodríguez-Cano. However, it is not that straight forward.

…but not for all smokers

For some reason, the simplified test does not work as well for everyone.

“The effectiveness of the simplified test for men and women depends on the patient’s race,” Rodríguez-Cano explains.

Basically, the shortest test did not work as well for Non-Hispanic Black people with a cancer diagnosis. The researchers do not know whether this is due to social or genetic factors – or a combination of both.

“Both the full test and the simplified test are useful tools, but our research shows that it may be necessary to tailor the tests for different groups,” says Rodríguez-Cano.

Nevertheless, the research may make it easier to investigate smoking addiction than before. This can reduce the burden on the healthcare system as well as on cancer patient treatment.

Reference: Rubén Rodríguez-Cano, George Kypriotakis, Jason D Robinson, Maher Karam-Hage, Janice A Blalock, Jennifer A Minnix, Diane Beneventi, Paul M Cinciripini, Comparing the Fagerström Test and Heaviness of Smoking Index in Predicting Smoking Abstinence in Cancer Patients, Nicotine & Tobacco Research, 2024; ntae120, https://doi.org/10.1093/ntr/ntae120

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In 2016 the UKLCC report, 25 by 25, described the steps required to reach a five-year survival for lung cancer patients of 25% by the year 2025. The NHS Long Term Plan later set an ambition to diagnose 75% of cancer at stages I and II (instead of stages II and IV). This was “a big ask in lung cancer”, said Professor Rintoul. There was also a levelling up agenda to ensure that people with lung cancer had outcomes in line with other cancers.

When the pandemic hit in 2020 there was a big drop in two-week wait referrals and many thousands of people with lung cancer probably died without ever having been recognised as lung cancer patients. At that stage the estimated five-year survival was 17.6% (for patients diagnosed 2014 to 2018) and was “on an upward trajectory”. However, during the pandemic five-year survival fell to about 13%.

The key findings of the NLCA report were:

• In 2020 in England, curative treatment rates for stage I/II with good performance status fell from 81% (in 2019) to 73%.
• The surgical resection rate fell from 20% to 15%
• Overall, there were more emergency presentations, patients had worse performance status and were less likely to have pathological diagnosis.

Moreover, NHS England targeted lung health checks in England were just getting under way when the pandemic struck and had to stop or slow down as a result.  Activity has since picked up and there are now just over 40 lung health check programmes running across England.

The first recommendation in the UKLCC report is that there should be a roll out of a full lung cancer screening programme across all four nations at the earliest opportunity. This “would do more to improve lung cancer survival than any other intervention – that’s probably the biggest winner we could have”, said Professor Rintoul.

Other key recommendations include the funding of twice-yearly public awareness campaigns and a dedicated lung cancer telephone helpline to ensure that people who are worried about signs and symptoms of lung cancer have access to support and can “get advice about what to do next”, he said.  Many clinicians have heard from patients and families who have struggled to find appropriate information and services, he explained.

The full report sets out no fewer than 10 recommendations, all of which are focused on measures to rebuild and recover from the consequences of the pandemic on lung cancer and get back on track to deliver a step change in lung cancer outcomes.

About the UKLCC

The UK Lung Cancer Coalition (UKLCC) is the UK’s largest multi-interest group in lung cancer. It was set up in 2005 with the founding ambition to tackle poor lung cancer survival outcomes and, specifically, to double five-year survival by 2015, which was effectively achieved. It is now looking to redouble five-year survival to 25 percent by 2025. The UKLCC’s membership includes leading lung cancer experts, senior NHS professionals, charities, and healthcare companies with an interest in fighting lung cancer. For more information about our work and members, visit:  www.uklcc.org.uk

Based on a presentation given by Professor Robert Rintoul at the BTOG Annual Conference, 27-28^th January 2022

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An international team of scientists, led by Nanyang Technological University, Singapore (NTU Singapore), has linked increased air pollution to an uptick in cases of lung adenocarcinoma (LADC) worldwide. The same study also concluded an overall lower consumption of tobacco worldwide is statistically linked to less people contracting lung squamous cell carcinoma (LSCC).

Lung adenocarcinoma is a type of cancer for which research strongly suggests that genetic, environmental, and lifestyle factors play a part, while lung squamous cell carcinoma is often linked to a history of smoking.

This study, done in collaboration between NTU and the Chinese University of Hong Kong, showed that a 0.1 micrograms per cubic metre (μg/m³) increment of black carbon[1], also known as soot, in the Earth’s atmosphere, is associated with a 12 per cent increase in LADC incidence globally.

Black carbon is a pollutant that is classified as under PM2.5[2], and the research team found that it has increased globally by 3.6 μg/m³ yearly from 1990 to 2012.

Meanwhile, a one per cent decline of smoking prevalence was associated with a nine per cent drop in LSCC incidence globally. The number of smokers worldwide decreased by 0.26 per cent a year, cumulatively falling by nearly six per cent from 1990 to 2012.

Lung cancer remains the leading cause of cancer with an estimated 1.8 million deaths in 2020, according to CA: A Cancer Journal for Clinicians[3]. Global statistics have highlighted the trends of lung cancers, but understanding what may be causing them has been unclear, until the NTU-led study, which has associated the incidence of the cancers to tobacco consumption and air pollution.

Professor Joseph Sung, NTU’s Senior Vice President (Health and Life Sciences) and Dean, Lee Kong Chian School of Medicine (LKCMedicine), who led the study, said: “In our study, we were able to determine that the global increase of lung adenocarcinoma is likely associated with air pollution. It had always been unclear, in the past decades, why we are seeing more females and more non-smokers developing lung cancer worldwide. Our study points to the importance of environmental factors in the causation of specific types of lung cancer.”

Associate Professor Steve Yim, from NTU’s Asian School of the Environment, who holds an appointment at LKCMedicine, the first author of the study, said: “Our study provided us with an indication as to the reason behind the rising trend of lung adenocarcinoma, despite the decreasing trend of smoking prevalence. Our findings pinpoint the necessity and urgency to reduce air pollutant emissions especially black carbon.”

The study analysed data from the World Health Organisation from 1990 to 2012 for data on lung cancers, while the dataset for age-standardised smoking prevalence rates from 1980 to 2012 was derived from the Institute for Health Metrics and Evaluation, an independent global health research centre at the University of Washington. The statistics on pollution were obtained from National Aeronautics and Space Administration (NASA). Pollutants that were analysed were black carbon, sulfate[4], and PM_2.5.

Gender and geography have a role to play

The links between lung cancers and black carbon also vary between different genders across different continents. For instance, the link between the pollutant and the incidence of both LADC and LSCC was stronger in females than in males.

Globally, a 0.1μg/m³ annual increment of black carbon was linked to a 14 per cent rise in LADC in women, compared to nine per cent in men. As for LSCC, the same increase in the pollutant was linked to a 14 per cent increase in females, compared to eight per cent in the opposite sex.

The study found that the link between air pollutants and LADC varied across continents. In North America, a 0.1 μg/m³ increment of black carbon was linked to a ten per cent increase in LADC cases, compared to seven per cent in Europe.

In the study, global data demonstrates that the drop in LSCC is more significant among males, said the researchers, and that the declining trend coincides with the declining trend of tobacco consumption.

However, despite the overall decreasing trend of tobacco usage, a positive association between smoking and LSCC was demonstrated for females in Asia, North America and Oceania, where a one per cent increment in the number of female smokers was associated with a 12 per cent increase of the cancer in those geographies.

Impact of population growth and rising air pollution

The scientists explained that despite lower overall percentage of smokers worldwide, there were more smokers worldwide due to massive population growth from 1980 to 2012, resulting in the number of female smokers increasing seven per cent.

The rising incidence of LADC is particularly prominent in Asia, where emissions of black carbon and sulfate have been on the rise, according to the scientists.

LADC among males in Asia saw the largest increasing trend, increasing by 24 per cent yearly, mainly contributed by the prominent rises in Japan (38 per cent yearly) and South Korea (37 per cent yearly). For females in Asia, LADC increased by 25 per cent year, similarly, with both Japan (43 per cent yearly) and South Korea (36 per cent yearly) showing a clear increasing trend.

The researchers highlight the prominent trend of air pollution in Asia, in which black carbon (11.9 μg/m³/year) and sulfate (35.4 μg/m³/year) showed the highest increase worldwide, with South Korea presenting the largest increase for both pollutants.

The combustion of fossil fuel for power generation or transportation has long been known as the source of particulate air pollution in most urban settings. It also worsens climate change by increasing the carbon dioxide emissions, which cause global warming.

Prof Sung added: “Results of this study should give us fair warning that air pollution should be better controlled to protect health and avoid premature deaths from lung cancer or related illnesses, particularly in populations that live near urban areas, which are known to experience high levels of pollutant emissions. Air pollution, together with climate change, is one of the greatest environmental threats to human health. Our findings underscore the urgent need for further research into how pollutants such as black carbon and sulfate lead to the development of lung adenocarcinoma, and for international leaders and experts to look into mitigation strategies for air pollution.”

Assoc Prof Yim added: “While national environmental regulatory bodies commonly measure and report on the levels of fine particulate matter, our results pinpoint the importance to measure individual types of particulates, especially, black carbon. The information would be useful for formulating effective emission control policies, supporting policies for sustainable development.”

The team plans to carry out further research to investigate the functions of black carbon and sulfate in the development of LADC, which could lead to new studies to combat the surge of the cancer. The team also hopes to explore other pollutants that might be linked to lung cancers.

[1] Black carbon is the sooty black material emitted from gas and diesel engines, coal-fired power plants, and other sources that burn fossil fuel.

[2] Atmospheric particulate matter (PM) that has a diameter of less than 2.5 micrometers — about three-hundredths the diameter of a human hair.

[3] CA: A Cancer Journal for Clinicians. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries (2020).

[4] Sulfates come from the combustion of petroleum-derived that contain sulfur. Inhaling them can cause reduced lung function, aggravated asthmatic symptoms, and increased risk of emergency department visits, hospitalisations, and death in people who have chronic heart or lung diseases.

Journal Reference:

1. Steve H.L. Yim, T. Huang, Jason M.W. Ho, Amy S.M. Lam, Sarah T.Y. Yau, Thomas W.H. Yuen, G.H. Dong, Kelvin K.F. Tsoi, Joseph J.Y. Sung. Rise and fall of lung cancers in relation to tobacco smoking and air pollution: A global trend analysis from 1990 to 2012. Atmospheric Environment, 2022; 269: 118835 DOI: 10.1016/j.atmosenv.2021.118835

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“Most genomic studies of lung cancer have focused on patients with a history of tobacco smoking,” said senior author Ramaswamy Govindan, MD, a professor of oncology at Washington University School of Medicine in St. Louis, Missouri. “And even studies investigating the disease in patients who have never smoked have not looked for specific, actionable mutations in these tumors in a systematic way. We found that the vast majority of these patients have genetic alterations that physicians can treat today with drugs already approved for use. The patient must have a high-quality biopsy to make sure there is enough genetic material to identify key mutations. But testing these patients is critical. There is a high chance such patients will have an actionable mutation that we can go after with specific therapies.”

As background, the investigators noted that, in the U.S, 10% to 15% of lung cancers are diagnosed in people who have never smoked. In parts of Asia, the proportion runs as high as 40%.

The researchers performed whole-exome analysis on 88 never-smoker lung tumors and RNA-sequencing on 69 never-smoker lung tumors.

They compared their findings with data from 76 never-smoker and 299 smoker lung tumor samples previously sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium, both projects of the (U.S.) National Institutes of Health (NIH)

The investigators verified never-smoker status by analyzing mutation patterns in the subjects who claimed such status, and then comparing the results to mutation patterns in tumors of subjects who had smoked.

Prior research has indicated that tumors from smokers have about 10 times the number of mutations as the tumors of never-smokers.

They found a significantly higher high prevalence of “clinically actionable driver alterations” in never-smoker lung cancer tumors compared with smoker tumors (78%-92% vs 49.5%, respectively; P < .0001).

Notably, such clinically actionable targets are potentially responsive to targeted therapies available as Food and Drug Administration (FDA)-approved drugs or as experimental drugs in clinical trials.

They researchers reported that, mysteriously, only about 7% of the never-smokers showed evidence of being born with mutations raising the risk of cancer.

“There appears to be something unique about lung cancer in people who have never smoked,” Govindan said. “We didn’t find a major role for inherited mutations, and we don’t see evidence of large numbers of mutations, which would suggest exposure to secondhand smoke. About 60% of these tumors are found in females and 40% in males. Cancer in general is more common among men, but lung cancer in never-smokers, for some unexplained reasons, is more common among women. It is possible additional genes are involved with predispositions to cancers of this kind, and we just don’t know what those are yet.”

Govindan added, “The most important finding is that we identified actionable mutations in the vast majority of these patients — between 80% and 90%,” Govindan said. “Our study highlights the need to obtain high-quality tumor biopsies for clinical genomic testing in these patients, so we can identify the best targeted therapies for their individual tumors.”

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The coronavirus pandemic prompted a number of changes in patient care in medical oncology. “One of the things that we have learned and I hope we will continue to take forward even when the pandemic is under control is that doing virtual visits is an effective way of helping to care for our cancer patients”, says Dr Schenk.  This works particularly well for those that are doing well on long-term tyrosine kinase inhibitor (TKI) therapy ….. and for surveillance visits “where we are updating scans and making sure things are OK”, she comments.

For patients, virtual visits they eliminate the stresses of having to drive to the hospital, find parking space, and find their way through the academic institution. Virtual visits allow doctors to see patients in other areas of the country without patients having to travel long distances.  “I think that’s one of the major points of change that we will carry forward even after the pandemic”, emphasises Dr Schenk.

Early in the pandemic  there was much concern about having enough personal protective equipment (PPE) and also about how to do things safely in the face of many unknown risks.  “I think our understanding really crystallised as we got more information about the virus as well as tried to continue practising and that is – cancer does not wait – when people are eligible for curative intent therapy we should do everything we can to provide curative intent therapy as per the normal standard outside of the pandemic”, says Dr Schenk.  An article in a medical journal had examined the costs and outcomes as a result of delays in cancer therapy.

“They were able to look at a number of different cancers and what they saw was that even a four-week delay could reduce the chances of patients being cured. I think that has played out in our clinical practice. Patients, unfortunately, are coming to us with more advanced disease; we are seeing early stage cancer patients less [often]”, she says. In part this was probably because services were initially reduced to “the bare essentials” and also because patients were afraid to come into a large medical centre where there were sick people.

Other ways that the hospital worked around the pandemic involved organisational changes such as reducing the number of visitors permitted able to accompany patients to appointments or for infusion therapy.

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Dr Schenk now has a number of patients under her care who receive pembrolizumab alone and whose lung cancer is probably not going to recur.  “They have no evidence of disease and they’ve been on it for several years. It’s really incredible – that is not how it was [in the past]”, she says.

Dr Schenk identified two sets of trial results to be presented at the World Conference on Lung Cancer (January 2021). Again, they reinforce the importance of biomarkers in this field.

The CODEBREAK 100 trial involves the KRAS inhibitor, sotorasib. KRAS has been recognised as an oncogenic driver in lung cancer for more than 40 years and there have been ongoing attempts to find a drug to inhibit KRAS.  KRAS is found in 12-13% of patients with adenocarcinoma of the lungs. A number of KRAS inhibitors are being used in clinical trials at present. “This is exciting because it appears that we are starting to get signals of efficacy from this drug even in the phase 1 trials”, says Dr Schenk. At WCLC, presentation of the phase 2 data for sotorasib is expected. “This will give us a better idea of response rate and duration of response as well as some of the side effects and adverse events”, she adds.

The Lung Cancer Mutation Consortium (LCMC)3 trial of neoadjuvant atezolizumab represents a new approach. In this trial atezolizumab – a PD-L1 inhibitor – was given to patients before they underwent resection of their lung cancers. The hypothesis was that giving immunotherapy before surgically resecting lung tumours would help to drive better outcomes.

“The hope is that the immune system can be activated to start eliminating some of the cancer cells. I am really excited about this because I think that neo-adjuvant (before the surgery) immunotherapy either alone or in combination with chemotherapy is going the be the next breakthrough for our patients with lung cancer and I am hopeful that this will result in more cures of patients up front so that we have fewer patients with metastatic disease”, explained Dr Schenk. LCMC3 is expected to report its primary analysis of outcomes and safety.

The use of neo-adjuvant therapy is likely to increase in future. Dr Schenk says,

“It is exciting to see all these therapies that were new to all of us not that long ago really making these leaps further into curative intent therapy.  Right now in the US we use durvalumab. If patients have unresectable stage 3 lung cancer they get concurrent chemotherapy and radiotherapy and then we give them a PD-L1 inhibitor, durvalumab, for a year and that has significantly increased cure rates for that population of patients. So, hopefully, moving it to an even earlier stage, where patients are able to have their cancer resected, this will result in even better outcomes.”

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The other trial that has really come to the forefront in discussions in academic oncology practice in the United States is the ADAURA trial. This trial randomised patients with completely-resected, EGFR-positive, non-small-cell lung cancer (NSCLC) to receive either standard of care (SoC) treatment or SoC plus osimertinib. This trial again illustrates the importance of biomarkers.

“This is one of the trials where these biomarkers that we often use in metastatic disease may also become important in patients with early stage disease where we treat them with curative intent”, says Dr Schenk.

The ADAURA trial recruited patients with NSCLC with the EGFR mutation – a feature that in the metastatic setting is often sensitive to tyrosine kinase inhibitors (TKIs) that prevent certain mutations from being active and causing cancer cells to grow. Patients in the osimertinib group received the drug for a period of three years.

The reason that this trial has generated so much discussion and so many different opinions on what to do, is that it was an early report on the data and so we don’t have clear survival data [to show whether] adding osimertinib would help patients live longer. What we have is a measure called ‘disease-free survival’”, explains Dr Schenk.  This shows that patients, who received osimertinib for three years, had reduced chances of recurrence of their lung cancer compared to the control group. However, previous trials of a similar design have been carried out with early-generation EGFR inhibitors and the results showed that eventually the survival curves met, meaning that adding early-generation EGFR-TKIs did not help to cure more patients. Some clinicians argue that the degree of disease-free survival is so significant that patients need to be presented with the data and have an opportunity, with their physician, to make an educated choice about whether or not to take osimertinib.

“The way this trial has changed my clinical practice is that I have this type of discussion with patients with completely resected lung cancer who are EGFR-positive and we really talk about the pros and the cons because right now we simply don’t know whether this helps cure more patients with resectable lung cancer”, says Dr Schenk.

Surgical resection may not remove every trace of lung cancer.  “What we know about lung cancer is that it has a propensity to recur even with excellent surgeries – not only taking out the tumour but also taking out the lymph nodes in the middle of the chest. Unfortunately lung cancer has a high likelihood of recurring and so one of the main things that we talk about with patients is the use of adjuvant chemotherapy”, explains Dr Schenk.  Adjuvant chemotherapy is part of the SoC for larger lung cancers and those that involve lymph nodes in the chest. It has been shown to provide a survival benefit after surgery, presumably by helping to kill the very small number of residual tumour cells that remain after surgery. “The ADAURA trial is trying to add on to that because even with surgery and chemotherapy, even with no evidence of disease, unfortunately a large number of patients still have recurrence of their lung cancer”, says Dr Schenk. The ADAURA trial is trying to improve those numbers further by adding targeted therapy for a specific mutation.

It is possible for a tumour to ‘escape’ from the effects of a targeted agent. “Right now in the United States osimertinib is the first-line choice for patients newly-diagnosed with metastatic EGFR-positive adenocarcinoma. While the vast majority of patients have a response to therapy, meaning that the disease shrinks and is under control for some time, often years, eventually it does recur”, says Dr Schenk.  The cancer cells are able to develop mechanisms to evade the inhibitory effects of osimertinib. Some of these are known but others have yet to be described.  It is therefore possible that in the ‘curative intent’ setting patients could undergo the surgery, undergo chemotherapy if appropriate, and then take  osimertinib for three years and still experience a recurrence of the cancer.  In this situation “one of the concerns is that the lung cancer might no longer be responsive to osimertinib because the cancer was able to determine a way around that therapy”, she says.

Many oncogene-driven lung cancers, such as those with the EGFR mutation, have a propensity to develop brain metastases or they are present at the time of diagnosis. In the ADAURA trial “there were fewer CNS recurrences with the osimertinib and that would also be a result that is expected because osimertinib is able to get into the tissue of the brain, it’s able to penetrate the blood brain barrier (BBB) so that it is able to exert its anti-cancer effects in that area as well”, says Dr Schenk.

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“Biomarkers are king! When patients are diagnosed with metastatic lung cancer, biomarkers are really important for helping people like me decide what therapies are best to treat my patient with”, explained Dr Schenk.

The first trial that she discussed was one that illustrated the importance of the programmed death ligand 1 (PD-L1) as a biomarker. PD-L1 is a marker on cancer cells that is used to decide whether or not patients should receive immunotherapy alone or whether they might receive immunotherapy plus chemotherapy.

Recently, a five-year update to KEYNOTE 024 was published. This was a large trial that randomised patients with metastatic non-small cell lung cancer (NSCLC) to receive either pembrolizumab alone or standard of care chemotherapy. The updated, five-year overall survival results were “remarkable”, said Dr Schenk.  Of the patients who received pembrolizumab alone, almost a third were still alive at five years. “Additionally, if patients happen to have a recurrence of their lung cancer, retreating with pembrolizumab at that time is also an effective way to get the cancer under control again”, she adds.

“This trial is one that firmly establishes the role of the PD-L1 biomarker for patients with lung cancer as well as the choice of using pembrolizumab as a first line option in patients with a high PD-L1 status”, says Dr Schenk.

The cut-off level for PD-L1 is set at 50%, so if more than 50% of cancer cells express PD-L1, it is considered to be ‘PD-L1 high’. “This cut point is one where you can have a discussion with patients about whether we use immunotherapy alone or whether we use immunotherapy plus chemotherapy”, explains Dr Schenk.

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Their findings appear in the Sept. 8 issue of the NEJM/New England Journal of Medicine.

Capmatinib is a powerful and selective inhibitor of the MET protein. MET is involved with multiple processes within cells. Activation of the MET gene, which codes for the MET protein, happens in a variety of cancers. Among patients with non–small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4%, and MET amplifications occur in 1 to 6%.

“Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation,” the authors noted.

The investigators conducted a phase 2 study evaluating capmatinib therapy in patients with MET-dysregulated advanced NSCLC. They assigned subjects to cohorts according to previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue).

Subjects received capmatinib (400-mg tablet) twice daily.

The primary end point was overall response (complete or partial response). The key secondary end point was response duration.

The researchers enrolled 364 subjects.

They reported that, among subjects with NSCLC with a METexon 14 skipping mutation, overall response was 41% of 69 subjects who had received one or two lines of therapy previously and in 68% who had not received treatment previously. Median duration of response was 9.7 months and 12.6 months, respectively.

They reported limited efficacy among previously treated subjects with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients).

Among subjects with MET amplification and a gene copy number of 10 or higher, the researchers found an overall response rate of 29% of previously treated subjects and 40% of those who had not received prior treatment.

Most frequently reported adverse events were peripheral edema (51% of subjects) and nausea (45% of subjects), and the symptoms were manageable.

“There are many advances in NSCLC treatment that are helping people live longer and better with their disease, and it is really important that all newly diagnosed patients with NSCLC get broad molecular profiling to determine what their optimal first-line therapy should be,” said senior author Rebecca Suk Heist, MD, investigator in the Massachusetts General Hospital/MGH Cancer Center in Boston and associate professor of medicine at Harvard Medical School. “If we don’t test, we don’t know.” Heist noted that MET exon 14 skipping and amplification join a number of other drivers of NSCLC for which researchers have developed targeted therapies. “It is critically important that all patients have their lung cancers tested for these to know whether there is a targeted treatment option or not,” she said.

Results from this study became the basis for the (US) Food and Drug Administration’s May 2020 approval of capmatinib for the treatment of NSCLC patients with MET exon 14 skipping.

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Primary care services need to make it relatively easy for patients who are concerned about their symptoms to obtain some telephone advice – and at present that is not happening in many practices, explains Professor Baldwin. At the moment we are in a situation where a large number of people are sitting at home with their cancer getting worse because it is getting to a later and later stage.  The other major concern is that many patients will never be diagnosed with lung cancer and their deaths will be recorded as ‘pneumonia’ or ‘possible covid-19’. The numbers of cancer patients coming through the system have fallen but cancers will not have stopped developing. The problem with lung cancer is that the median survival [at diagnosis] is only six months so already 35% of people will have died. This is the reason why this issue is urgent and important, he says.

Messages for Primary care

Differentiation of the Cs is a document that the lung cancer CEG hopes will help to mitigate the mixed messages about presentation with lung cancer. Professor Baldwin would like GPs to read the document and consider how it could work in their practice, and, in particular, consider how to “re-open the gates” for people who think they might have lung cancer.

“I’ve seen one or two you tube videos made by GPs explaining to patients how important it is to get in touch if they think they might have lung cancer. That’s incredibly helpful but it’s only getting to a small minority. We need to do this nationally”, says Professor Baldwin. “We need to get back to where we were before – making fantastic progress with lung cancer prior to the covid pandemic and primary care is an absolutely essential cog in the machine”, he adds.

Community pharmacists

“I regard community pharmacists as part of the primary care team and the interface between the patients and healthcare team”, says Professor Baldwin. He suggests that community pharmacists read the document and understand that they have got an incredibly important role in guiding patients to the appropriate further action. “In fact, any health care professional who interfaces with patients should read this document and use the opportunity to get the message over”, he says.

Di­fferentiation of the Cs in Lung Cancer: Cancer vs COVID-19 can be found at:

https://www.healthylondon.org/wp-content/uploads/2020/03/Differentiation-of-the-Cs-in-lung-cancer_-Cancer-vs.-COVID.pdf

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“The issue with lung cancer is that the median survival at diagnosis is just under six months, so, over the lockdown period we will have lost an awful lot of people”, he says.

The current policy drive is to achieve early diagnosis of lung cancer through rapid presentation of patients with symptoms to primary care and rapid referral for investigations and diagnosis. During the early months of the covid pandemic the message was ‘if you have a cough, stay at home’ whereas the message for early lung cancer awareness and diagnosis is just the opposite – ‘if you have a cough for more than three weeks, call your doctor because it could be more something serious’. “More than for any other cancer, these two messages were diametrically opposed and therefore we felt, given the massive reduction in referrals that we had seen, we needed to give some guidance about how we might deal with situation”, says Professor Baldwin. The result was the document, Differentiation of the Cs, that provides guidance on how to differentiate between the coughs of covid-19 and lung cancer.

Should there be a second wave of covid-19, there should be a clearer message for people about how they should think about the possibility of cancer and get in touch with primary care services.

Screening

There is “a lot of work to do to mitigate the damaging effect of the covid pandemic”, says Professor Baldwin. All cancer screening programmes were paused during the covid pandemic but they have now started again. The targeted lung health check programme had just started. Initially this involved 14 pilot sites but now 23 sites are planned. All are functioning again now but there is a backlog to be tackled because of the number of tests not performed during the pandemic. Work is still needed on the awareness and early diagnosis campaign and this could be linked with screening, to emphasise the importance of presenting early if symptoms occur, he explains.

The CEG provides multidisciplinary expert advice on the diagnosis and management of lung cancer and helps to drive improvements in care. One example of this is the National Optimal Lung Cancer Pathway.

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