A significant minority of patients with advanced and aggressive cancer have survived more than 10 years after treatment with one of the first successful targeted cancer drugs.
Long-term results from a major international clinical trial reveal that a fifth of patients with advanced gastrointestinal stromal tumours (GIST) continue to survive a decade after first taking the targeted drug imatinib, also known as Glivec.
Some 10% of patients are still on the trial after 10 years, living free of any progression of their cancer – providing evidence that targeted cancer therapy can deliver dramatic, long-term responses even in patients with advanced cancer that has spread round the body.
Imatinib was the first example of a small-molecule targeted cancer treatment – a drug designed to hit specific cancer proteins – to be approved for use in patients, and the second successful targeted therapy overall, after the breast cancer drug Herceptin.
Since then many more targeted drugs have been developed but there has been debate over their true potential because of the tendency of cancers to evolve resistance against them.
Researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, along with colleagues at 56 centres across Europe and Australia, conducted a phase III clinical trial of imatinib in 946 patients.
Their trial investigated the drug as a treatment for GIST, a rare tumour of the stomach or intestines, in patients where it had metastasised, or spread to other parts of the body.
Targeted cancer treatment a major step forward for patients
The study is published in the Journal of Clinical Oncology, and was carried out by the European Organisation for Research and Treatment of Cancer (EORTC) and other international trials groups, with support from Novartis.
The study recruited patients in 2001-2 when treatment with imatinib was very new. It was set up to judge whether there was a survival benefit from taking 800mg of the drug daily, rather than the standard 400mg given to patients.
Researchers found that overall the increased dose had no extra overall survival benefit, although the disease was controlled for longer.
Patients in a small subgroup with a specific mutation in the gene KIT – one of the targets of the drug – were found to benefit from the increased dose. Their disease was under control for much longer, and the new follow-up data showed these patients lived longer as well.
Strikingly, a substantial minority of patients could continue to take either dose of the drug long term, without developing resistance to treatment.
Patients continued to take imatinib throughout because doctors did not want to take the risk that the disease might recur.
A pioneer of targeted cancer therapy
Imatinib targets a type of molecule called tyrosine kinases that some cancers rely on to grow.
It was seen as a pioneer of targeted cancer therapy when it reached the market some 15 years ago, with particularly dramatic results in a specific form of leukaemia.
Study co-author Professor Winette van der Graaf, Professor of Personalised Oncology at the ICR, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:
“Since our study began, a wide range of targeted therapies have become available for many different types of cancer. Targeted cancer treatment has been a major step forward for patients, but unfortunately most drugs have only extended lives by months or a few years, because of the tendency of cancers to evolve resistance against them.
“It was remarkable to see 10% of the patients responding to imatinib for a decade without showing signs that the cancer was becoming resistant to treatment. Imatinib in GIST is still one of the best examples of active targeted agents and we should use these examples to better understand why this happens.”
Professor Winette van der Graaf's Clinical and Translational Sarcoma Team aims to identify, characterise and clinically implement genetic predispositions to a variety of cancers, particularly breast, ovarian, testicular and childhood cancers.
Interrogating the genetics of GIST tumours
Professor Ian Judson, who led the UK arm of the study at the ICR, and The Royal Marsden NHS Foundation Trust, said:
“We’ve never previously seen patients with this cancer surviving for so long on imatinib. We now need to interrogate the genetics of GIST tumours to work out what it is about these people that makes them such long term-survivors.”
Howard Harrison, aged 73, is a patient at The Royal Marsden. He was diagnosed with a gastrointestinal stromal tumour (GIST) in 2000. He had surgery to remove his stomach and gall bladder. When the cancer spread in 2001, his oncologist transferred him to The Royal Marsden to take part in the imatinib clinical trial. Mr Harrison said:
“I was previously told that I would be dead in two years but thankfully the oncologist at my local hospital transferred me to The Royal Marsden for this trial and it improved my prospect enormously.
“I have been taking this drug every day for the last 16 years and although there are side effects it is nothing compared to the alternative.
“If I hadn’t received this drug the logical conclusion is I wouldn’t be here now and I wouldn’t have been able to meet my three grandchildren. My cancer was seen as untreatable but thanks to this drug I have almost no lesions on my liver.
“My quality of life is 99% and similar to any other 73-year-old.”