The long journey towards targeted cancer therapy

Henry Scowcroft

Cancer Research UK

Henry Scowcroft discusses the situation in the UK today regarding targeted cancer treatments, both those approved by NICE, and those currently being evaluated in clinical trials. Henry also shares his thoughts on the barriers pharma needs to overcome in order to keep up with this new era of personalised medicines.

The saying ‘You wait for ages, then two come along at once’ is more often associated with elusive buses rather than medical milestones. But in 2012 – after years of having very little to offer patients with metastatic melanoma – the UK’s NICE approved not one but two new therapies for this most devastating form of skin cancer:- vemurafenib and ipilimumab.

Both of these drugs are next-generation ‘targeted’ treatments, and both can have profound effects in some patients. Inevitably, the arrival of these drugs led some to pronounce that the age of ‘personalised medicine’ had finally arrived.

But has it? What needs to be done to usher in this new era? Are we “nearly there yet?”, or is there still heavy traffic ahead?

‘Breakthrough’ drugs

Vemurafenib (also known as Zelboraf) targets a specific mutation in the BRAF gene – known as BRAF V600E – that produces a permanently active kinase protein. Consequently, BRAF V600E-postitive patients are highly likely to respond to the drug. And the response can be temporarily stunning – the disease disappears entirely for weeks, and sometimes months. Doctors involved in the initial trials have spoken of it being a ‘miracle drug’, unlike anything they’ve seen before.

But here’s the kicker: sooner or later resistance develops, followed by relapse. This is emphatically not a cure.

Iipilimumab (Yervoy), works in a completely different way, targeting an ‘off-switch’ called CTLA-4, on the surface of a patient’s T-cells. Cancer cells can cloak themselves in molecules that flip this off-switch, allowing them to hide from the body’s own defence mechanisms. Ipilimumab blocks this from happening, allowing the immune system to destroy the tumour.

But in practice, only one in 10 patients respond, and just one in 100 benefits in a lasting way. And unlike vemurafenib – where there’s a gene test available – there’s no way to predict who will respond to ipilimumab, nor how well.

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“Targeted drugs, it could be argued, are great validation for basic researchers and drug developers – but arguably less so for the majority of cancer patients.”

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So we have two extremely expensive new drugs, both of which can have profound yet often short-lived effects, neither of which is a ‘cure’, and for one we have very little idea about who will benefit. Furthermore, both can cause significant side effects – rashes, skin problems, diarrhoea and, in the case of vemurafenib, non-melanoma skin cancers (which are unpleasant but easy to treat in most cases) and even leukaemia.

This is not a unique story. Other ‘targeted’ drugs – for example EGFR inibitors like gefitinib and erlotinib, or VEGF inhibitor bevacisumab – have similar downsides.

The backlash

Targeted drugs, it could be argued, are great validation for basic researchers and drug developers – but arguably less so for the majority of cancer patients. And cancer research has a long history of hyperbole, not least President Nixon’s ‘War on Cancer’ in the 1970s.

Given the cognitive dissonance between promises of great steps forward, and the clinical reality of these newest agents (and others), there’s recently been a glut of critical comment pieces in the media and academic journals.

The cost of the new generation of drugs is getting out of all proportion to the added benefit,” said The Lancet¹. New drugs are “failing to live up to expectations and priced so high that treatment is becoming unaffordable,” said the Guardian². “Are we losing the war on cancer?” asked the Independent³.

Publicly funded cancer research organisations have to toe a tricky line between hope and caution. We’re extremely hopeful that the future holds genuine progress. But there are some substantial hurdles to be overcome first.

Biological barriers

The most serious obstacle in the way is cancer’s fearsome complexity and extreme plasticity.

In early 2012, researchers showed how genetically diverse a single patient’s disease can be. No two samples from a kidney cancer patient’s primary tumour, or the secondaries, were the same. And researchers are now finding evidence that even the individual cells that make up a tumour can be profoundly different from each other. This diversity – outlined beautifully in a recent article in the New England Journal of Medicine  – goes a long way to explaining the limited success of targeted drugs developed thus far4.

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“The most serious obstacle in the way is cancer’s fearsome complexity and extreme plasticity.”

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How this heterogeneity arises needs to be fully understood. Genetic diversity could be pre-existing in a tumour (i.e the tumour is a symbiosis of a number of sub-clones), or it could arise over time as a tumour becomes more and more disordered and unstable. In reality both of these processes are likely to be at play.

Regardless, researchers are again making progress on these fronts. For example, some of the key mechanisms of vemurafenib resistance have already been identified and, fortunately, experimental drugs already exist to target them (for instance GSK’s MEK inhibitor, trametinib). Combination trials are underway, and are showing promise. Recent data also suggests combining the drug with EGFR inhibitors could be useful in overcoming this resistance.

In a third example, vemurafenib was tested on BRAF V600E bowel tumours. This didn’t work so well. But researchers have discovered why, and how to get round this – combining vemurafenib with EGFR inhibitors.

So the true metaphor for curing cancer may not be a ‘magic bullet’, but rather a ‘magic toolkit’, of options to be used in series or parallel, adapting to the evolving biology of a patient’s tumour.

Monitoring this evolution will be a huge challenge. Sequential biopsies are invasive, monitoring circulating tumour DNA in its infancy. And the timeframes needed to integrate gigabytes of biological data are, as one researcher wryly puts it, “currently in excess of median survival times”.

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“So the true metaphor for curing cancer may not be a ‘magic bullet’, but rather a ‘magic toolkit’…”

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On top of this, a toolkit is next to useless unless you know how to use the tools in it. There’s a lot of effort ahead to work out how to combine targeted drugs safely, and it may be that side effect profiles of targeted therapies in combination are significantly less rosy than as single agents.

Social, ethical and financial barriers

So much has been written about the need for a better economic model of drug development that it’s tedious to recap here – so we won’t. Suffice to say that this is going to become ever more urgent as targeted therapies emerge from trials against a background of economic austerity.

But there are other barriers that also need to be dealt with, as outlined last year in another excellent New England Journal of Medicine article, ‘Preparing for Precision Medicine’5:

First, combination trials require collaborations between companies which have been historically reluctant to work together, to be set up swiftly, with the minimum of bureaucratic fuss. Designing robust, ethical trials to rapidly answer questions of ever-smaller patient populations will be no mean feat.

Second, our 100-year-old system of tumour classification – based on anatomy and pathology, not genetics – needs an overhaul if we’re to recruit patients to these new trials, and make sense of their results.

Third, health services need to be able to link molecular test results to a patient’s record, and to make them available across the NHS records system, not buried in a paper archive.

Fourth, these new systems and ways of working will need highly skilled doctors, nurses and pathology staff, who can operate and make best use of them.

Fifth, we need to get more patients into trials, in a proper, informed manner, their data needs to be held and accessed in an ethical way, but with appropriate access to maximise benefit while reducing duplication.

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“…clearing the path to targeted treatment requires urgent and sustained action…”

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Finally, this is going to be an expensive journey (at least initially) – we need to demonstrate some significant progress, and quickly, to convince wider society it’s worth it.

None of the above is impossible. But clearing the path to targeted treatment requires urgent and sustained action, from industry, government, researchers, the medical profession and regulators.

And finally…

We need to remember that almost all patients have surgery to remove their tumour, while just under half of those who are cured receive radiotherapy. These treatments are all too often forgotten in the rush to welcome new drugs, despite the latter not being ‘cures’ – at least not yet. And we know that the UK’s radiotherapy services need serious investment if they’re to become world-class, while uptake of surgery around the UK is patchy.

So, while we rush to welcome the dawn of the new age of high-tech cancer drugs, we also need to make sure that there’s sufficient attention – and investment – given to all forms of cancer care.

The last decades have seen great strides forward in our quest to tackle cancer. The next decades offer the promise of many, many more – but it’ll be a while before we can say we’ve reached our destination.

References:

1. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60059-8/fulltext

2. http://www.guardian.co.uk/society/2012/oct/28/targeted-cancer-drugs-expectations-experts

3. http://www.independent.co.uk/life-style/health-and-families/health-news/are-we-losing-the-war-on-cancer-8231614.html

4. http://www.nejm.org/doi/full/10.1056/NEJMra1204892

5.http://www.nejm.org/doi/full/10.1056/NEJMp1114866

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About the author:

Henry spent four years at university studying biochemistry before realising that the laboratory life wasn’t for him, and going to work for a science journal instead.

From there, he went on to do a Masters in Science Communication and, after a brief flirtation with science journalism, in 2003 he started working in Cancer Research UK’s Science Communications team.

From 2005 to 2010 he worked in the charity’s Digital department, helping to launch – and then relaunch – their News &amp, Resources website. In 2011 he moved to back to the Science Comms team, where he now spends his days managing the charity’s news feed and this blog. He’s also a Visiting Lecturer on City University’s Science Journalism MA course.

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