Author:

Rachel Brazil

Introduction

Tyrosine kinase inhibitors (TKIs) are cancer therapies that were part of a revolutionary new ‘targeted’ approach to cancer treatment that was introduced into clinical practice around the start of the 2000s. They are small molecules rationally designed to interfere with signals that play a role in helping cancer cells survive and grow. They inhibit the pro-cancer signalling by binding to the implicated tyrosine kinase receptor within a cell membrane. In contrast to cytotoxics, which affect replication and growth of all cells, this new approach was specifically targeted at cancer cells.

The first TKI cancer therapy, imatinib, was developed by a European pharmaceutical company, led by European chemists and physician scientists, in the face of widespread scepticism. The drug, which prevents a BCR-ABL protein from exerting its role in the oncogenic pathway in chronic myeloid leukaemia (CML), turned out to be effective and safe beyond all expectations, achieving full approval in the US and Europe within record time. The clinical development of imatinib for CML was led by the US oncologist and cancer researcher Brian Druker. It was European oncologists, however, who drove its parallel clinical development – still under its experimental name ST1571 – in patients with a rare sarcoma called gastrointestinal stromal tumour (GIST).

Even though CML is a relatively rare and relatively simple cancer, the success achieved by this new type of treatment generated huge excitement. It even made the front cover of TIME magazine, which posed the question: “Is this the breakthrough we’ve been waiting for?”

Though TKIs, and targeted treatments in general, have not been the ‘breakthrough’ the optimists had hoped for, the success of imatinib opened the way to the development of more than 45 further TKIs that now play an important role in treating a wide variety of cancers.

This front cover of the May 28, 2001, issue of TIME magazine reflected the wave of optimism that the outstanding results that imatinib (Gleevec) was achieving in controlling chronic myeloid leukaemia could be replicated for other cancers.

How TKIs hit the cancer research agenda

The relevance of tyrosine kinase signalling to cancer – and the potential therapeutic implications – first became clear with the discovery of the Philadelphia gene, and particularly its link to almost all cases of chronic myeloid leukaemia (CML). In 1960, the US pathologist Peter Nowell, from the University of Pennsylvania, Philadelphia, showed that chromosomal abnormalities lead to the formation of a fusion gene, called BCR-ABL1, which codes for a hybrid tyrosine kinase signalling protein that binds to the cell receptor. Its production could not be switched off and caused uncontrollable cell division.

Work in the area started in the early 1980s, when Japanese researcher, Hiroyoshi Hidaka, discovered that some naphthalene sulphonamide compounds inhibit several protein kinases (Hidaka et al., 1984). These compounds were being developed as antagonists of the calcium-binding protein calmodulin, which also plays a role in cancer. This was followed with a discovery by another Japanese researcher, Tatsuya Tamaoki, that the anti-fungal agent staurosporine, a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus, markedly inhibits protein kinase C – a signalling molecule know to be involved in tumorigenesis and metastatic dissemination (Tamaoki & Nakano, 1990).

With potential molecules discovered, the challenge was, whether it was possible to engineer something that could specifically target cancer cells. Would it be possible to design selective inhibitors that would bind to a receptor tyrosine kinase that was abundant in cancer cells, without inhibiting fundamental processes in the body that are vital for life, such as the proliferative functions in the bone marrow?

The majority of researchers thought not, recalls Alex Matter, the Swiss physician scientist and drug developer who spearheaded the discovery of imatinib, while he was heading up the Oncology Therapeutic Area at Novartis, in Basel, Switzerland. “Many people thought this was a bad idea, because all tyrosine kinases and ATP binding pockets are ubiquitous, and many people were convinced that it would never be possible to make a relatively specific selective inhibitor. This proved to be wrong,” he says.

Ciba-Geigy bets on a TKI

With such low expectations, most pharmaceutical companies were reluctant to get involved. However, in the mid-1990s, the Swiss pharmaceutical company Ciba-Geigy – which became part of Novartis after a merger with another Swiss company in 1996 – decided to take on the task of developing a drug that could inhibit the mutant activity of BCR-ABL1 to treat CML.

Using computer modelling, British biochemist Nicholas Lydon and colleagues at Ciba-Geigy designed staurosporine analogues that would fit the binding sites of the mutant fusion protein via high throughput screening. “In the old days, it was about 20,000 compounds, and this delivered some initial leads,” says Matter. Based on these leads they were able to optimise a compound to select the most effective TKIs.

The company collaborated with the US oncologist and cancer researcher Brian Druker, then working in the lab of Tom Roberts at the Dana Farber Institute in Boston. Here Druker developed enzymes for screening TKIs. He then moved to Oregon Health & Science University (OHSU), where he tested various compounds, supplied by Lydon, on human bone marrow cancer cells. One compound caused a 92–98% decrease in BCR-ABL cells formed, without causing normal cell death (Druker et al, 1996). This compound, referred to as ST1571, would later be renamed ‘imatinib’, and given the brand name Glivec (or Gleevec). At this stage, though, the future impact of imatinib was completely unforeseen, says Matter, “We had no idea.”

Earlier data on STI571, which turned out to be erroneous, had suggested it was not bioavailable, and would therefore not reach the bone marrow cells in vivo, to exert its anticancer effect, Matter recalls. This made most of his colleagues hesitate about progressing the drug. “The critics were in the majority,” he remembers, “but we just felt we should give it a try and see what happens. In cellular systems, [and] in a mouse system, Nick Lydon clearly showed very convincing activity, and this gave us confidence to go forward.”

The first clinical trial for imatinib was carried out in the US by Brian Druker in June 1998, involving just 31 patients. They all experienced complete remission, and in some cases, the genetic mutation driving the cancer was no longer found in blood cells,” (Druker et al., 2001). Everybody showed a response, with the exception of one patient who didn't take his pills,” remembers Matter, “so this changed the picture completely, because before, nobody believed that this was possible.”

After the first results of this first trial, the development was rapid, and the biggest problem was producing enough of the active substance to do further trials, Matter recalls. “Since nobody believed in the compounds, it was not manufactured – we were sitting on [only] one kilogramme.” Novartis then agreed to build a factory in Ireland purely to manufacture imatinib. “This factory was built basically overnight, and allowed them to proceed with the clinical trials,” he says. Phase II trials confirmed the results, and the drug received approval from the US regulators, the FDA, in May 2001 – less than three years after the clinical programme began – with approval by Europe’s regulators, the EMA, following in November that year.

Sarcoma specialists spot an opportunity

During this time, research from a Japanese team led by Seiichi Hirota showed that gastrointestinal stromal tumours (GIST) were linked to increased activity of another tyrosine kinase receptor called KIT, which is expressed on the surface of haematopoietic stem cells (Hirota et al, 1998). These tumours occur most commonly in the stomach or small intestine, and are very rare, with an annual incidence of approximately 10 per million population in Europe. “[Hirota] found that GIST frequently carried a mutation in the KIT gene, which turned on KIT receptors, so that they were permanently switched on,” explains Ian Judson, a former head of the Sarcoma Unit, at the Royal Marsden Hospital, in London, who specialised in the management of GIST, and was involved at that time in research into the role of TKIs for these rare tumours.

It turned out that imatinib was also an inhibitor of KIT, making it a potential treatment for GIST.

Sarcoma specialists on both sides of the Atlantic were quick to spot the opportunity. Among them was Jaap Verweij, Emeritus Professor of Medical Oncology at the [Erasmus University Medical Centre] (@erasmus-university-medical-centre), in Rotterdam, who chaired the Soft Tissue and Bone Sarcoma Group of the European Organisation for Research and Treatment of Cancer (EORTC) between 1996 and 1999. Verweij remembers an early meeting in 1999 with Novartis at Newark Airport, in New Jersey. “They discussed the agent and my colleague Allan van Oosterom [EORTC President between 2000 and 2003] was there, and picked that up, and started the discussion with Novartis to develop the agent also for GIST.”

Judson, also involved in the GIST trial, in the UK, remembers them being “in the queue”, because at the time all the imatinib produced by Novartis’s manufacturing facility was being used for the ongoing CML trial, where they were seeing an amazing breakthrough. Despite this, says Verweij, they did manage to interest Novartis in developing the agent for GIST, even though that malignancy was not their primary interest, and GIST was a much rarer cancer than CML.

In March 2000, the Department of Oncology at the Helsinki University Central Hospital, in Finland, where pathologist Heike Joensuu was Medical Director, became the first centre to administer ST1571 to a patient with advanced GIST who had run out of options (Joensuu et al., 2001). “A special licensed clinical trial was put together to enable this patient to be treated with imatinib, and she had a great response,” Judson recalls.

In April 2000, they began to plan parallel studies with Novartis, together with oncologist George Demitri at the Dana Farber Cancer Institute. “We could be very fleet of foot in those times, because regulatory rules that govern trials were much more lax and liberal,” Judson recalls. “Within months, a clinical trial was set up in North America, comparing two different doses of imatinib in patients with GIST, and a simultaneous, very similar, trial was set up in Europe and Australia.” The three-centre European trial at Rotterdam, Leuven and London started with a phase I dose-escalation study of 40 patients, and identified 800mg as the absolute maximum tolerated dose. The trial started in the first week of August.

When the European and US teams met with Novartis in Brussels, in October, to exchange information on the trial, says Verweij, it was already clear the drug was going to make it. “It was very obvious that this drug was a fantastic drug… we decided, at that point in time, to design two studies that were similar,” he says. In addition to the European centres, their study also included patients from Australia. The European phase II trial compared 400mg – half of the established maximum tolerated dose – with the full 800mg dosage (which was similar to the US study), and showed that the two arms were comparable in outcome. All investigators collaborated closely, with weekly teleconferences. In the 11 months of the trial, they recruited 946 patients throughout the world for a disease that was rare – a level of collaboration that Verweij sees as a success in itself.

Verweij adds that the study also included some patients with other types of sarcoma (Verweij et al., 2003). The rationale behind this was that imatinib was known to also target PDGF-receptor tyrosine kinase, and there was increasing evidence that PDGF – a connective tissue cell protein involved in cell division – played a role in sarcomas. Unfortunately, says Verweij, “That study in other sarcomas failed miserably.”

The results for GIST, by contrast, were astounding (Verweij et al. 2004). Verweij says the first patient treated in Europe almost died as a result of the “phenomenal response to the drug,” which led to a massive breakdown of the tumour tissue. “The patient ended up in intensive care, but made it, fortunately, and thereafter benefited for quite a long time from imatinib at a lower dose,’ he recalls.

Similar dramatic responses were being seen in the UK. Judson remembers one patient who had not been doing well before entering the trial. He saw the patient just before taking his Christmas break, and on his return, he was gone. Judson assumed he had died, but his senior registrar informed him that the patient had improved so much that he had been able to join in with Christmas dinner, and had now gone home.

PET scans from the GIST trial at Dana Farber showed radio-labelled glucose uptake was switched off within days of starting imatinib, “So, something really rapid and fundamental was going on,” remembers Judson. “It was just the most exciting thing I've ever been involved in.” Prior to imatinib, doxorubicin had been the standard of care for GIST, but it had been largely ineffective, he says. “Patients with GIST who had metastatic disease had a median life expectancy of 12 to 18 months. Surgery was the only effective treatment; chemotherapy did not work.” With imatinib, the median survival increased to between two and three years. On the basis of those trial results, imatinib was approved for use in GIST patients on both sides of the Atlantic in 2002, only one year after its approval for CML.

“It was a game changer for patients with GIST,” says Verweij, “and I know there are still patients alive that joined those first studies in the year 2000. It's 23 years later now, and they're still doing fairly well, even though they have metastatic GIST.” Of course it is not without side effects. “We principally identified nausea, diarrhoea, skin rash, fatigue, and some problems with marrow,” says Judson, “but in the majority of patients it is incredibly well tolerated.”

What happened next

Imatinib is still recommended as a first-line treatment option for CML, and remains the standard-of-care first-line treatment for GIST. Resistance leading to recurrence within two years is, however, common in GIST patients, and to a lesser extent in those with CML. “Many patients, if not most patients, become resistant to these drugs, and the resistance problems stays with us,” says Matter. To help address this problem, Matter went on to oversee the development of nilotinib (Tasigna), a second Novartis TKI for CML, which also targeted the BCR-ABL protein, and was approved to treat newly diagnosed and imatinib-resistant CML (Blay & Von Mehren, 2011). The drug was designed based on the imatinib structure, and the growing understanding of the molecular mechanism of TKI activity. “This compound was more potent and more selective,” says Matter, and had the ability to circumvent imatinib resistance. It gained approval in Europe and the US in 2007. Since then, a further three TKIs for CML – dasatinib, bosutinib and ponatinib – have come on the market.

Matter argues that, while imatinib was not “a panacea against cancer,” it did open the door to targeted drug therapy. By the start of 2024, the FDA had approved more than 50 TKIs, 90% of them for cancer indications. These included 13 for lung cancers, seven for blood cancers other than CML, and others for certain breast, kidney, liver, thyroid, bladder and colorectal cancers and melanomas. In 2018 the FDA approved the first TKI for treatment of any solid tumour with a specific molecular mutation – larotrectinib for cancers with NTRK gene fusion.

While immunotherapies have overtaken TKIs as the latest generation of cancer therapeutics, Judson says: don’t count them out. “They're still very important.”

References

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Druker, B. J., Talpaz, M., Resta, D. J., et al. (2001). Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med, 344(14), 1031-37.

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Hirota, S., Isozaki, K., Moriyama, Y., et al. (1998). Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science, 279(5350), 577-80.

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Tamaoki, T., Nakano, H. (1990). Potent and Specific Inhibitors of Protein Kinase C of Microbial Origin. Nat Biotechnol, 8, 732–735.

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Verweij, J., Casali, P. G., Zalcberg, J., et al. (2004). Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet, 364(9440), 1127-34.