No magic bullet, but a growing arsenal against lung cancer

pharmafile | February 23, 2011 | Feature | Research and Development |  ASA404, Cancer, Iressa, NSCLC, Tarceva, afatinib, crizotinib, figitumumab, lung cancer, non small cell lung cancer, non-small cell lung cancer 

A man in his 70s is waiting for his appointment with the oncologist after being referred there by his family doctor.

He has been coughing up blood for the last three months and has realised that it isn’t getting any better. He’s been a smoker since he was a teenager, and goes through a pack of 20 cigarettes a day. He’s had the scans, the biopsy and the blood tests, and now the oncologist is about to tell him he has lung cancer. The prognosis is bad, and the man probably won’t see out the year.

For thoracic oncologists, this is a typical day. Lung cancer is the biggest cancer killer globally and general prognosis is poor, with patients living on average just ten months after diagnosis. Every 30 seconds, someone in the world dies of the disease.

Despite major advances in fighting other cancers, mortality rates in lung cancer remain stubbornly high. Moreover, its threat is growing worldwide – smoking accounts for the vast majority of lung cancers and while rates in the west are in slow decline, rates of smoking in countries like China and India are very high, with accompanying lung cancer rates.

Academic researchers and the pharmaceutical industry, are however, learning more and more about lung cancer, in particular the many harmful genetic mutations which are the cause of the cancer.

Not one cancer, but many

One of the most striking advances of the last 10 years is the discovery of many different sub-types of lung cancer.

It is now clear that these different sub-types are caused by a huge range of possible mutations, unique to lung cancer. This is likely to originate in the highly carcinogenic nature of cigarette smoke, which wreaks havoc with the normal functioning of many different lung cells, causing severe mutations.

A groundbreaking mapping of the genome of small cell lung cancer found more than 23,000 mutations, largely triggered by exposure to cigarette smoke.

The researchers at the Sanger Institute calculated that this meant a typical smoker acquires one new mutation for every 15 cigarettes they smoke.

The majority of lung cancer patients, around 80%, come under the umbrella heading of non-small cell lung cancer (NSCLC), which covers a number of cancers which arise in different kinds of tissue within the lung.

The most common of these are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. But in recent years, it has become clear that beyond this histological level, each patient will also have a combination of genetic mutations that are driving their disease. This means that our man’s appointment in the doctor’s office may be a typical occurrence, but there is increasingly no such thing as a typical lung cancer patient.

Alan Barge, head of oncology at the Anglo-Swedish pharma firm AstraZeneca, told me:  “The disease we used to call lung cancer is now at least 30 or 40 different biologically driven diseases based on underlying molecular abnormalities. The notion that lung cancer is a single disease that requires a single treatment is now outdated.”

Dr Sanjay Popat, a medical oncologist at the Marsden Foundation Trust and senior lecturer in medical oncology at Imperial College London, says that when lung cancer was seen as a single disease, one all-encompassing blunt instrument could be used to knock it down.

“This blunt instrument was chemotherapy and until around ten years ago, this was the only real pharmacological option open to medical oncologists.”

Chemotherapy is a good tool for killing rapidly dividing cancer cells, but unfortunately most chemotherapy also attacks healthy cells. It is also highly toxic, with most regimens delivered just below the level that could kill a patient. This is why there is an increased need for more advanced pharmacological treatments. Not only that, but many types of lung cancer show very limited response to this harsh medicine.

Gene mutations

Iressa, developed by AstraZeneca for NSCLC, targets a particular mutation in patients who have an overactive epidermal growth factor receptor (EGFR). It is one of the leading treatments for NSCLC today, but its value was very nearly overlooked.

Shortly after it was launched in 2002, AstraZeneca was obliged to withdraw the drug after post-marketing studies suggested it was no better than placebo in prolonging the lives of lung cancer patients. But cases then started to emerge that showed patients with NSCLC who had never smoked, responded dramatically to Iressa.

It slowly became clear that the drug was most effective in patients who were i) of Asian ethnicity ii) women and iii) were ‘never  smokers’ – the more of these conditions the patient fulfilled, the more likely they were to respond.

Alan Barge cites an example from 2002 when one American woman with advanced lung cancer experienced a very positive response to prescribed Iressa: “Her cerebral metastases disappeared and she stopped having seizures – it was only experiences like this that led scientists and science in general to look at the molecular pathology of tumours and they found, to their surprise, that there was a specific, activating series of mutations.”

These mutations came from a particular binding site of the enzyme and those mutations activated the EGFR pathway that makes the tumour ‘addicted’ to it. This particular mutation sends out molecular signals to increase cell division, form new blood vessels, and inhibit a built in ‘cell death’ mechanism.

By inhibiting EGFR, Iressa could block the signals which helped the tumour to grow.

Another very similar drug, Roche’s Tarceva, which also targets EGFR is now the leading new agent in the field. It has been shown to extend progression-free survival by an average of 3.3 months in combination with chemotherapy, compared to chemotherapy alone. Another significant advantage of these drugs is that they have far fewer undesirable side-effects compared to chemotherapy.

Beyond Iressa and Tarceva

But EGFR only represents around 10% of lung cancers in the West and around 30% in Asia, meaning Iressa is only effective in a subgroup of patients. The overall picture of NSCLC is incomplete, Barge warns, “as for every mutation we do know of, there is another we do not”. [See table over the page The genes behind NSCLC]

Not only that, but the tumours of patients receiving Iressa and Tarceva eventually develop resistance to the drugs, with new molecular abnormalities arising.

To combat this, new drugs are being developed to pick up where the others have failed. German pharma firm Boehringer Ingelheim is currently developing it drug afatinib to step in as a second-generation treatment that works by being ‘irreversibly binding’, meaning it is active against receptors that are resistant to Iressa and Tarceva.

But the biggest problem remains the fact that most NSCLC patients do not have the EFGR marker, but other mutations. Many pharma and biotech companies are now looking to target other important gene sequences involved in the cancer, callled ‘oncogenes’.

Pfizer, the world’s largest pharmaceutical company, is developing crizotinib, which targets the ALK gene.

In its latest trial, 90% of the 82 patients in the study saw tumour shrinkage after an average of two months on the drug. This has excited Pfizer as most observers expected only 10% of these patients to have this result. Just 1 – 6% of patients are likely to benefit from crizotinib and it will need a diagnostic kit for it to be effective, but this figure could grow as more of the population is tested.

Crizotinib represents one of a small arsenal of drugs, slowly being built up against what is now a plurality of diseases. These represent small pieces of the jigsaw of the genes which cause NSCLC.

This is the downside to the targeted drugs of today, but many medical oncologists, Dr Popat included, are confident that the next ten years will yield more discoveries and more options for patients. “We are a product of the Human Genome Project – unlocking more and more genes is leading to better targets,” he said.

Diagnostics

Targetting drugs to specific gene mutations means that they must be used in tandem with diagnostics – a patient without the targeted gene is unlikely to benefit.

The UK drugs watchdog NICE approved Iressa and an accompanying diagnostics kit back in July 2010 – this is only the second time the body has approved funding of a personalised medicine programme after Roche’s breast cancer drug Herceptin.

Barge said that if you don’t have a molecular target to measure, then diagnosis is much more difficult. “One of the more pragmatic approaches by regulators and cost-effectiveness bodies is the notion of risk-sharing, whereby they will only approve a drug if it proves its efficacy. If it doesn’t, then they’ll simply ask for the money back.

“The reality is that in the future, we’re probably going to see more of that, because people just aren’t going to be willing to pay for drugs in the patient population when they don’t always work.”

Given the painstaking and slow nature of discovering all of the oncogenes involved, isn’t there a shortcut to better lung cancer treatments, a new approach which would be a ‘silver bullet’ which would unlock all lung cancers? Dr Popat told me that: “Personally, I don’t believe there can be a silver bullet that can destroy all types of cancer. At the moment, the science simply doesn’t suggest this.

“The targeted sub-types that drill further down into the disease is the best way forward and I think the pharmaceutical industry is going in the right direction.”

Failures

There have also been myriad numbers of late-stage NSCLC drug failures, including Bayer’s Nexavar and Merck’s cancer vaccine that was halted last year due to safety concerns.

Pfizer’s NSCLC candidate figitumumab also failed in a late-stage tiral and in November, Novartis and Antisoma’s promising and novel ASA404 was pulled from trials after it twice failed to meet its primary endpoints.

Tyrosine kinase inhibitors

All of these drugs are tyrosine kinase inhibitors (TKIs). Tyrosine kinases are a family of protein messengers which pass on instructions to the cell. In cancer cells, these  are frequently the mechanisms which have gone haywire, and so pharma companies are targetting them to stop the cancer in its tracks.

Tumour cells require the same nutrients to grow and without it, they cannot grow more than around two millimetres, equivalent to 200-300 cells. To grow larger, a solid tumour develops its own blood supply via angiogenesis by sending out tyrosine kinase to call surrounding blood vessels to break off and help fuel its growth.

This ability is not found in normal, non-cancerous cells and represents a certain mutation in the genes of the cell. In NSCLC, these mutations that cause angiogenesis – EGFR, ALK, etc., are what the current drugs are targeting and with each new drug, the pharma industry is hoping to tick off the missing elements of the pie chart in order to have targeted drugs dedicated to each patient, regardless of mutation. 

As we have seen, even the most successful of NSCLC cancer drugs using this mechanism can only extend progression-free survival by an average of 3.3 months, meaning our man in the doctor’s office may see a full year of life, rather than just ten months.

Because of these obvious limitations, some researchers are looking at alternative approaches to attacking lung cancer cells.

Cancer vaccines

Therapeutic vaccines represent a completely new and different way of attacking a tumour.

French biotech firm Transgene is just one of a number of companies exploring this cutting-edge area of medical science. It is preparing to launch late-stage trials of its new lung cancer vaccine candidate, TG4010. The drug is being tested in combination with chemotherapy in patients with advanced MUC1-expressing NSCLC and with normal levels of activated Natural Killer (aNK) cells.

The drug uses the Modified Vaccinia Ankara (MVA) vector for vaccination, a weakened strain of the poxvirus that has been tested as a smallpox vaccine and has shown in studies to stimulate an immune response to antigens.

MUC1 is a tumour-associated antigen that provides a viable target for the TG4010 as it has the potential to generate an immune response to ‘attack’ the cancer.

It is believed that around 60% of this group over-express MUC1, making it more effective for larger populations for those new treatments such as crizotinib that can only help around 6% of NSCLC patients.

This is still a new area, and the only cancer vaccine to date to make it to the market has been Dendreon’s prostate cancer drug Provenge that received FDA approval in May, but it represents a different method of tackling NSCLC and a further option for patients. 

These therapeutic vaccines work by teaching the patient’s immune system to recognise and destroy the tumour.

The first ever cancer vaccine, Provenge for prostate cancer, is already available in the US. Transgene is hoping to follow suit with its own NSCLC vaccine TG410 that works by provoking a full body immune response killing cancer cells expressing the target tumour antigen, MUC-1.

Shaun Brown, director of communications at Transgene told me that around two-thirds of stage IV NSCLC patients are eligible to be treated with the vaccine.

Brown says TG410 was different to Iressa and Tarceva as first, it is a biological product, whereas the others are small chemical entities but second, TG4010 can be “complementary and synergistic to the two other drugs”, opening up the potential to combine treatments and extend survival.

It uses the patient’s own immune system to fight the tumour. “This therapeutic approach also offers a unique opportunity to be combined with classical surgery, radiotherapy, chemotherapy and current targeted cancer drugs,” Brown added.

Stem cell treatment

Another cutting edge area of research is the targeting of stem cells. OncoMed and GlaxoSmithKline are developing a novel approach with their stem cell drug OMP-59R5 that has recently begun clinical trials and could eventually play a major role.

A phase I study of OMP-59R5 began in January for patients with advanced solid tumour cancers after pre-clinical studies showed it decreased the frequency of tumour-initiating cells across a variety of cancer types.

Cancer stem cells are a small, resilient subset of cells found in tumours that have the capacity to self-renew and differentiate, leading to tumour initiation that drives its growth, recurrence and metastasis.

Also referred to as ‘tumour-initiating cells’, these cells were first discovered in breast cancer by OncoMed’s scientific founders and have subsequently been identified in many other types of solid tumour cancers, including cancers of the head and neck, lung, prostate and pancreas. Cancer stem cells appear to be preferentially resistant to both standard chemotherapy and radiotherapy, meaning a new therapy for this particular type of cancer will need to be developed.

In lung cancer, this could prove a whole new way of detecting and attacking the tumour that attempts to stop growth internally by focusing inside the cell, rather than on the proteins outside of it.

Early diagnosis

Pharmaceutical agents are not the most effective way of treating this disease – NSCLC, unlike any other type of cancer, is in theory the easiest cancer to eradicate: if globally every person stopped smoking, the rates of NSCLC for the next generation could drop by as much as 90 per cent.

But of course this is not the reality and people have every legal right to smoke; this shifts the onus onto the smoker to be aware of NSCLC symptoms in order to gain an early diagnosis and benefit from available treatments.

The general rule in treating cancer is: the earlier the diagnosis, the better the prognosis.

However, early stage diagnoses remain difficult for the simple fact that patients will only see their doctor only when they are ill, and noticeable NSCLC symptoms will only occur when the disease has progressed to a later stage.

I asked Dr Popat whether all smokers over the age of 40 should automatically be scanned for symptoms of the disease.

“This question has long been asked and there have been trials in scanning older smokers for the disease, but false positives occur that require further investigation.

“This means the patient must undergo an invasive procedure such as a biopsy or a bronchoscopy. If patients have these tests and there is no cancer, then they have undergone an invasive procedure for nothing.”

NSCLC has four stages of escalation ranging from I (early stage) to IV (late stage).

Dr Popat said that survival rates across the stages are all relatively poor as patients diagnosed at phase I have equal survival rates as those diagnosed at phase IV. This further erodes the utility of early screening and the necessity of public health messages as the key to prevention over early detection.

But new evidence is challenging this view as recent research has suggested that heavy smokers may in fact benefit from screening for lung cancer.

A new study published in December has found that regular smokers who received three-dimensional X-rays to look for the presence of early tumours had a significantly lower risk of dying over a ten-year period.

The results are in keeping with those of a much larger study published in November that showed that CT scans reduced the death rate among 53,000 current and former heavy smokers by 20%, compared with screening using regular chest X-rays.

There is a concern among healthcare professionals and charities that this will encourage people to continue to smoke as they can now detect if they have the disease and will simply keep smoking if they don’t.

This fear has been further compounded by recent positive screening tests that were funded by the American tobacco industry; controversy will continue to hang over screening smokers and governmental actions to reduce smoking may be the only alternative.

Stubbing out the smoking habit

Governments around the world have in the last few years begun to address the most obvious solution to the terrible cost of smoking, and limiting and banning smoking in public places. In England, a ban was introduced in 2007 and recent data has shown that this has already had a measurable effect on the number of heart attacks suffered.

This suggests fewer people are smoking (or people are smoking less) which could translate into reduced lung cancer rates, but this affect won’t be seen for decades.

But even more creative approaches are needed to encourage more smokers to quit.

In July 2010, NICE’s Citizens’ Council – a group that brings the views of the public to NICE’s decision-making processes – voted in favour of giving smokers incentives to quit smoking and stay off cigarettes permanently.

A number of small-scale pilots are running in the UK, including a scheme that offers pregnant women supermarket vouchers if they stop smoking. Many people find such ‘bribes’ morally questionable, but the rationale is that if it works, it should be used.

Conclusion

But what does all of this mean for our man in the consultation room? There’s no doubting that medical science has come a long way in treating NSCLC and that research during the next ten years will narrow its focus to help more and more patients.

All forms of lung cancer are aggressive and respond only minimally to treatment; even with the new targeted drugs, getting just a few weeks more of progression free survival is not guaranteed, and many will still miss out on such treatments because they do not express the ‘right’ genetic mutation.

The arsenal will continue to be built up, but smokers certainly cannot rely on a ‘cure’ being discovered any time soon. The message remains that stopping is your best chance of protecting yourself against lung cancer, as even the most fortunate of NSCLC patients will only survive five years after being diagnosed.