Targeted therapy in sarcoma treatment

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Published: 20 Jul 2010
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Prof Gary Schwartz -Memorial Sloan-Kettering Cancer Center, New York, USA
Prof Schwartz discusses the use of targeted therapy to treat sarcomas. Imatinib has been shown to reduce recurrence rates and has traditionally been administered daily for a year after surgery. Prof Schwartz speaks about wok that has been done that will help clinicians decide which patients need this treatment and which do not. Some less encouraging results include research investigating the use of IGF-1R inhibitors. Despite initially positive results, this trial has now been shown to be relatively unsuccessful, however, trials are currently underway to find out if this can be overcome by combining IGF-1R inhibitors with rapamycin, a drug that blocks the TOR pathway. Prof Schwartz talks about the results of a phase II trial into palifosfamide, a cytotoxic that has similar effects to ifosfamide but without many of the associated side effects.

ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago

Interview with Professor Gary Schwartz (Memorial Sloan-Kettering Cancer Centre, New York)

Targeted therapy in sarcoma treatment

Today I review the sarcoma highlights at ASCO; every year we review highlights of each of the disciplines and I was the person who reviewed the ASCO highlights. Sarcoma – rare cancer; in the United States 13,000 cases a year makes it an orphan disease. A very complex cancer – in sarcomas there are over fifty different types of cancers. Now sarcomas are different from the classical cancers, more classical cancers are called carcinomas, those are organ cancers – cancers of the lung, the breast, the stomach. Sarcomas are cancers of soft tissue, cancers of muscle, of fat or of bone and that makes it a very rare tumour type. It’s seen in adults and in children.

So this year’s ASCO meeting we reviewed some of the highlights of the last twelve months. Now one of the most common types of sarcoma is called gastrointestinal stromal tumour or GIST. Now GIST is a disease driven by a mutation called C-Kit and this mutation is an activating mutation such that when patients have the mutation it makes the cancer grow. Now we know that when that mutation is present and the cancer grows there are drugs that specifically inhibit this protein called Kit; it’s part of the evolving field in oncology of customised medicine. In fact, the drug is called Imatinib or Gleevec and was first discovered to be effective in another haematological disease called CML in which there is a translocation between two genes, one called BCR and one called ABL. It turned out that Gleevec or Imatinib was not just effective in hitting BCR/ABL but also effective in actually binding and inhibiting this protein or gene called Kit. So over ten years ago this drug was first tested in patients with metastatic GIST tumours and found to be the first new effective therapy ever in this disease. This is a disease for which there were never effective chemotherapies and this drug called Gleevec, basically a diseased patient died within six months, now the patient is living out several years and even patients now almost ten years, even with metastatic cancer. Unheralded in the field of sarcoma and in fact a pivotal study in the field of cancer as a whole, because here is a disease for which there are no proved or beneficial chemotherapies but yet a powerful targeted agent based on the mutation of the patient’s tumour was found to be highly effective. That was the beginning of the evolution or the revolution of targeted therapies we see today.

So now what’s going on that’s new? Several years ago, two years ago at ASCO, the data was presented testing whether this drug would help patients in which the primary tumour was resected. As we know it works in metastatic disease it would also work in patients who’ve had their primary cancer taken out. Now most of these tumours, that are called gastrointestinal tumours, arise from the stomach but also can arise from the small bowel or other parts of the bowel. So the trial that was previously reported was a randomised study of Gleevec 400mg, which was basically one capsule, every day for a year versus a placebo after surgery. What the study showed is that the patients who got the drug had a profound decrease in recurrence compared to no drug at all. In fact, Imatinib therapy after surgical resection of a primary GIST has become standard of care, not just in the US but all over the world.

Now the question is does everybody need a year of Imatinib and also is a year enough of Imatinib? So today’s abstract presentations discuss whether there are subsets of patients who may not need the drug and are there subsets of patients who do really need the drug. So if you look at risk for GIST based on three clinical pathological features: one is the site, stomach, which is the most common, versus other parts of the bowel. Mitosis, that is under the microscope do you see abnormal co-mitotic figures which represents abnormal DNA in the tumour? And finally, size – less than five, greater than five. And using this information we can now create an algorithm of patients who probably do or do not need Imatinib based on size, number of mitoses and site. So a patient, for example, has a tumour arising from the stomach that’s less than 5cm with no mitoses, a low grade tumour, the chance of recurrence even without Imatinib therapy is only 2%. That patient does not need Imatinib therapy. But if you have a big tumour, and this seems rather obvious, with high mitoses that comes from a non-stomach site, the chances of recurrence after Imatinib therapy is probably in the order of 80%. So now we’re beginning to put together algorithms which medical oncologists can begin to use to determine who needs Imatinib, who doesn’t need Imatinib.

What about mutational status? I mentioned the fact that there are mutations, well there’s not just one mutation in Kit, there are actually multiple mutations within different exons. If the patient has an exon 11 mutation those patients do, in fact, quite poorly even without Imatinib therapy and clearly when those patients with Imatinib therapy had exon 11 mutations in the randomised trial, the benefit there was quite dramatic and those patients had a major improvement in recurrence free survival given Imatinib if they had an exon 11 mutation.

Some patients have no mutations, the question was do those patients benefit from Imatinib therapy? And there can be mutations in both Kit and there’s another gene called PDGFRA or Alpha and in patients without any mutations there is no benefit for Imatinib therapy whatsoever.

So now we’re beginning to understand not just how we can identify whether patients need therapy but among those who need it, who really do need it. Can we classify them by pathological features, clinical features and mutational status? The study that was presented by Chris Corless and his group from Oregon and Ron DeMatteo from Memorial Sloan-Kettering for the first time began to address this question – who really needs it?

How long will it be before these results bring about change in clinical practices?

This new study will have an impact immediately on how clinical oncology is done. This is the first time the data has been presented. We’ve known Imatinib therapy has been an effective adjuvant for almost two years now but we haven’t really known who really needs it. Are there clinical features we can identify? Because although Imatinib is not one of the most toxic drugs, clearly you want to avoid unnecessary therapies for patients if they don’t need a drug. Why would a person want to be on a drug, taking a tablet a day, get a rash, get diarrhoea, get an upset stomach, get all the other associated toxicities with the drug if they don’t need it? So we’re trying to make a better assessment of who needs it, not just on clinical features but also using new biology, molecular biology, to look at the tumour, look at the mutations, see which mutations really benefit from the therapy and if there’s a mutation that doesn’t benefit from the therapy not to give the patient the drug or if the mutations don’t exist not to give the patient the drug.

Now there are things that we didn’t address this year at ASCO regarding adjuvant therapy, so the questions we do not know. The study shows a decrease in recurrence free survival, however it doesn’t yet show whether there’s an improvement in overall survival and that data from all these studies is still pending. It doesn’t tell us how long therapy should go on for, so the current studies give a year of Imatinib, the question is “ is maybe two years is better for those patients who need it”; maybe three years is better. And in fact, several clinical trials have just been finished answering that question – one year versus three years, two years versus no therapy. And those studies we hope to see at ASCO in 2011 after this year’s 2010 ASCO presentations.

So that’s GIST and GIST is the most common tumour in sarcoma, about 3,000 cases a year in the United States. Again, a rare disease but 3,000 of the 12,000 total makes it actually the most common sarcoma but shows you the rarity of this cancer. So to do these studies we need to do multi-centre studies, we need to do international studies; and once all the studies are actually combined, European and American, we work together closely with our European colleagues to really test these new drugs in sarcomas in such a rare cancer.

What about other things coming  down the line? One of the future areas, one of the areas that has been of great interest to oncologists in the sarcoma field is new targeted agents. We have Imatinib, a small drug targets Kit, neat idea. You have a gene, it’s mutated, it’s activates, turns on the cancer; block the cancer, turn off the gene with the drug, the cancer dies. GIST - perfect paradigm. We can now begin to apply that for other sarcomas. Remember, there are fifty sarcoma subtypes, all biologically different – a very complex disease.

So it turns out there is a growth factor called IGF1R; it’s a receptor on the cell’s surface, the tumour cell. IGF1R is insulin-like growth factor receptor 1. Now this receptor is stimulated by insulin in the blood and it turns out that certain sarcomas need this receptor to survive; it is an absolute obligatory receptor, essential for tumour cell survival in several sarcoma subtypes, especially in, again, a subtype that is relatively rare, probably more common in kids that adults, called Ewing’s sarcoma. This is a very virulent tumour, it’s highly metastatic and chemotherapy is used but invariably many of these children die of metastatic disease; we see it in adults as well. This IGF1R receptor is actually critical for the growth of these cancers and the idea is could you block the receptor, could you develop a small molecule to bind to it, turn it off, or an antibody to bind to the receptor, to cap it and therefore prevent the growth factor from binding to the receptor and therefore inactivate the receptor because there’s no growth factor binding and the tumour, therefore, will die.

So in the phase I studies, the early studies, there were some amazing, unbelievable responses in some people. In fact, some of the early responses were so dramatic that these people would take their CAT scans and post them on their Facebook website and show people around the world what the responses were. This wasn’t necessarily… the companies weren’t very happy with this, of course, but the patients were ecstatic that they could share their amazing response on a Face page. With the current wave of communication, this is a new thing going on in oncology – patients take their own scans and show the results. Based on that data, the companies then launched these studies and this meeting reported the first results. Now, despite these dramatic, unbelievable results the data in fact was actually disappointing. In one study done by the SAR Group, it’s a national consortium in the United States, response rate was no more than 8 – 10%. Very, very disappointing. There was another study done also with a comparable agent, there were two antibody studies presented, again with another company’s drug, different companies and different antibodies, and in this study also response rate was about 10 – 12%. So despite all of the enthusiasm and all the anticipation this probably is one of the big disappointments of ASCO for sarcoma.

But is there a way forward? Well we try to see the golden lining in anything we do in oncology, I’ve been in this field for twenty years and we have to think of something positive when things come out negative. Unfortunately things often happen negative, though things are changing in cancer therapy. So there may be ways to overcome, or at least enhance the effect of, IGF1R targeting. They’re beginning again to go back to the basic science of IGF1R signalling and it turns out that there are many other pathways that are involved in IGF1R including a pathway called TOR. Now TOR is a pathway downstream of IGF1R and there are drugs that block TOR; they have a number of names, they are all derivatives of a basic drug called Rapamycin and every company has their own they call  by their name, but they’re all very much the same. So one of the presentations today, there is a presentation of a combination of IGF1R inhibitor in combination with an inhibitor of this pathway, TOR. So if IGF1R only partially blocks the pathway can we enhance the effect by blocking parallel pathways so that you get both blockades, IGF1R and TOR, would that be better than IGF1R alone? Is that a pathway forward to really resurrect or continue to develop IGF1R targeted therapies? It looks initially promising. So the phase I data is presented of a small study and it looks very promising. It’s a phase I study, they had significant responses and it’s a prolonged stable disease. We’ll have to see how this plays out and there are some major studies going on, both in Europe and the United States, combining TOR inhibitors with IGF1R inhibitors, taking advantage now of the latest advances in oncological science trying to understand the pathways that can be inhibited with new drugs to enhance the effects of single agent therapy.

So other things we’ve looked at, one of the major drugs in oncology for sarcoma is called Ifosfamide. There are only three or four active oncology drugs in sarcoma. Unlike breast cancer where you have ten to twelve drugs, sarcoma has basically three or four drugs so that’s why there’s such a desperate need for new targeted agents. One of the classic drugs is called Ifosfamide, it’s highly toxic and most oncologists don’t like to use it for that reason. It can cause encephalopathic confusion; it can cause renal failure; it can cause bleeding in the bladder and often requires hospitalisation which makes it a class C drug. So there’s a new drug being developed called Palifosfamide and that data was presented at this meeting as well. Now Palifosfamide has no neurotoxicity; doesn’t cause any bleeding in the bladder. It does affect the white cells comparable to Ifosfamide but some of the more concerning toxicities such as neurotoxicity and the haematuria, the blood in the urine, and the effects in the kidney are less pronounced, in fact in the study that is presented there were really no effects on the bladder or on the brain which makes it a potential new drug. It’s probably, clinically activity-wise, the same as Ifosfamide which is a very inexpensive drug except for the fact that people need to be hospitalised to have it, but this drug has none of the toxicities commonly associated with Ifosfamide and the study showed a combination trial of Ifosfamide plus one of the older drugs, Doxorubicin, versus Doxorubicin alone and the doublet was better than the singlet and there was improvement in median progression free survival. Not clear yet on an overall survival, which often the FDA wants to see, but this is a phase II trial that does give an impetus for the company to go through with the phase III trial to try to prove is this drug going to being a less toxic Ifosfamide and will it become a new drug in the treatment of patients with metastatic sarcoma and give oncologists more of a comfort using a drug that they won’t have to worry about some of the known toxicities of Ifosfamide and in fact tend to shy them away from using it at all.

Is there a phase III trial planned?

The phase III is going to be initiated in the next six months or so and we’ll see. That will take a year or two to come to ASCO. But the phase II data did look encouraging, I think there’s some issues – it could be more expensive or less expensive; expense is going to become a big issue in oncology, both in the US and Europe we’re beginning to deal with the costs of medicine. At one end having a drug that you won’t need to hospitalise patients for can save hospital costs but at the other end of it, Ifosfamide is a very cheap drug, it’s not on patent, basically you can buy generic and it doesn’t cost that much. With a new drug like this coming in, which may see in-patient hospitalisation, it depends how they price it, if it’s going to be astronomical it can offset any in-patient costs. In fact, many of us with Ifosfamide have learnt to give it as an out-patient. So even Ifosfamide, which is considered in-patient chemo can actually be given as an out-patient therapy. So with that background, with out-patient Ifosfamide, with using Mesna, there’s a drug that actually prevents the bleeding in the urine called Mesna which costs pennies; compare that to this new Ifosfamide which, in theory, will not require any in-patient, doesn’t need the Mesna but may give oncologists a more comfort zone because they don’t want to worry about the toxicities. Laying all those things aside, we’ll have to see how it really  plays out and I’m not really sure. It has to be looked at very closely and in the UK I know, especially, the costs of care are critically analysed and there are certain metrics that need to be maintained to get your national health insurance to allow them even to be used in oncology patients. In the US we don’t have quite that rigorous or rigid approach in drug development and approval drug therapies, but clearly the oncology community and the FDA is becoming more cognisant of costs of care and we’ll just have to see how this one plays itself out over the next couple of years and yes, it’s probably going to be a safer Ifosfamide, I think that’s going to definitely be proven to be true. Will it be a less costly Ifosfamide? Well probably not and when you add in all the other costs will it still be a winner overall, and that’s something we’ll have to see.