Παρασκευή, 30 Δεκεμβρίου 2011

NEW DRUGS FOR CML

There are 2 new drugs that I would like to discuss today. Important studies have been done on these drugs, which offer new treatment options for patients with CML in specific scenarios. The first drug is bosutinib. Bosutinib, like dasatinib, is a drug that inhibits Abl and Src tyrosine kinases. In contrast to all of the other tyrosine kinase inhibitors that we have, bosutinib does not inhibit c-kit and the PDGF receptor. So initially, studies looked at using bosutinib as second-line therapy, which led to a study using bosutinib as front-line therapy in CML.
Let me briefly review what has been presented at this meeting. In terms of the second-line use of bosutinib in patients in whom imatinib therapy has already failed and as third-line therapy in patients in whom imatinib therapy and therapy with 1 or 2 of the other tyrosine kinase inhibitors has failed, additional data were presented showing how the mutation profile of patients at the time of prior therapy failure can be predictive of patient response to the next tyrosine kinase inhibitor.[1] Bosutinib has a good profile. It inhibits most of the mutations that we see in the clinic. The obvious exception is T359 and another mutation, V299L. The response is good in all of the mutations that are present in patients whose prior therapy failed and this correlates with major cytogenic responses and complete cytogenetic responses. The overall rate for the total population is approximately 50% of patients with major cytogenetic response and approximately 40% of patients with a complete cytogenetic response. Some of the subsets are very small, but you see responses in all of these different mutations.
In patients in whom bosutinib therapy failed, 2 different mutations were detected at the end of treatment, and these were T359 and V299L. What we learn from this -- and this applies to all tyrosine inhibitors that are being used for second-generation therapy -- is that detection of mutations is predictive of the response and mutations that are not very sensitive to a specific inhibitor may develop during therapy with that inhibitor. That means that we need to monitor our patients closely and when we are changing therapy, we need to look for mutations.

Bosutinib Up Front

The other important study is the use of bosutinib as initial therapy for CML. This was the BELA trial,[2] which was a randomized trial of patients with newly diagnosed disease within 6 months of diagnosis. These patients were randomly assigned to receive either bosutinib or imatinib. The study was very interesting because the primary endpoint was the achievement of compete cytogenetic response at 12 months and the primary endpoint was not met. However, what we saw today were the results of treatment after all patients had been followed for at least 24 months. Major molecular response rate was significantly higher, and more importantly, the rates of transformations, treatment failures, and deaths were all significantly lower. Everything pointed toward a benefit with bosutinib even when the primary endpoint was not met.
Part of the reason that the primary endpoint was not met was toxicity, most commonly diarrhea, although most of it was grade 1 or grade 2. Therefore, many patients were taken off therapy very early in the course of this study and they were not assessed for a cryptogenic response.
In summary, the results are favorable. The patients had better responses and a better rate of transformation, and that is ultimately what we want, that the patients do not transform to an accelerated phase or blast phase. We don't want them to die, of course, so it is a useful drug both in salvage as second-line, as third-line, and certainly as front-line [treatment]. These studies are being evaluated now by regulatory authorities and hopefully there will be new treatment options for these patients.

Ponatinib: Impressive Results

Ponatinib is another important new drug. It is another tyrosine kinase inhibitor, but the important thing about this inhibitor is that, from the preclinical point of view, this drug inhibits the mutation T359. Furthermore, in studies in the laboratory, where you can essentially force leukemia cells to develop resistance to tyrosine kinase inhibitors, the emergence of resistant clones to ponatinib has not been demonstrated; whereas, you can make these resistant clones emerge to dasatinib and erlotinib and even more so to imatinib. That makes it a very attractive option, which has led to the use of ponatinib in phase 1 and phase 2 studies in patients in whom prior therapy with dasatinib or nilotinib has failed.
The results of the phase 2 study called the PACE trial[3] were presented for the very first time at this meeting. These results are very early; the median follow-up was less than 6 months. That means that most patients had been evaluated only once for a cytogenetic response, but the responses are actually quite impressive -- 47% of patients in chronic phase achieved a major cytogenetic response, and most of these responses (nearly 40%) were actually complete cytogenetic responses. At this early stage in the treatment, those are very impressive results.
The responses are a little bit higher in patients who have the mutation T359 than in patients who had other mutations or fewer mutations. Everybody responded well; the differences were small. Ponatinib works in patients with or without a mutation, in patients with a T359 or a different mutation, and in patients who have more advanced stages of the disease (accelerated phase, blast phase). Of course, as you can imagine, in [patients with] more advanced stages of disease, the responses tend to not be as durable. Ponatinib is still an important component because two thirds of these patients had received 3 tyrosine kinase inhibitors or more. That makes it a very powerful drug. Of great importance, ponatinib was very well tolerated, there were no major problems with toxicities (some rashes, some dry skin, very occasionally pancreatitis), [but it was] a very clean drug in terms of safety.
Obviously, these results are early, we need to see them mature and we need to see what happens with longer follow-up, but ponatinib is lining up as a very powerful new drug in the management of patients with CML. At this moment, for patients in whom therapy with dasatinib or nilotinib has failed, where do we take it now? Time will tell. We need studies to see whether it can be moved up to second-line or to first-line, but it has a lot of potential.

The Drugs Keep Coming

It is a very exciting time in CML. We don't seem to be reaching an end to the development of one drug after another. The next one coming is better than the previous one, and this is great news for patients with CML. Evidently, it is critical that we identify patients well. We need to monitor them very closely and use our treatment strategies properly, but we are getting much closer to allowing patients with CML to essentially live a normal life expectancy and not die from this disease.
Thank you very much for joining me in this edition of Medscape Oncology Insights. This is Jorge Cortes reporting from ASH 2011 in San Diego, California. Thank you.

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