Ponatinib: The Real Deal for Refractory CML?

Bruce D. Cheson, MD; Jorge Cortes, MD


December 15, 2010

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Bruce D. Cheson, MD: Hello. I'm Dr. Bruce Cheson, Head of Hematology, Georgetown University Hospital, and Director of Hematology Research for the Lombardi Comprehensive Cancer Center in Washington, DC. I'd like to welcome you to Medscape Oncology Insights on chronic myelogenous leukemia (CML). Today we'll look at a couple of interesting studies presented at American Society of Hematology (ASH) 2010 in Orlando, Florida.

I'm delighted to have with me today Dr. Jorge Cortes, Deputy Chairman of Leukemia at the University of Texas, MD Anderson Cancer Center in Houston. Welcome, Jorge.

Jorge Cortes, MD: Thank you, Bruce.

Ponatinib: Third-Generation TKI

Dr. Cheson: When I was your age, way back then, a patient would come in with CML, and we'd put them on hydroxyurea. The big studies back then were hydroxyurea vs an alkylating agent or something silly, and then we got interferon, and that became the standard, and after that, everybody received a transplant. All of a sudden, we have imatinib and all the other similar drugs. Imatinib appeared in all the newspapers and Time magazine covers as "The Cure for Leukemia." Then we had a parade of new drugs. At this meeting, you present some astounding results on ponatinib. Could you tell us what that is and what the results were?

Dr. Cortes: Yes. They're very interesting results, and as you said, it's the next generation of these tyrosine kinase inhibitors (TKI). Ponatinib is a third-generation TKI, which has the distinct characteristic, as opposed to the other TKIs, of affecting the mutation -- the T315I -- a mutation that is not very common, but we know it's very resistant. None of the drugs that we have now really works in patients who have these mutations. This drug not only can inhibit cells that have this mutation, but it also appears (from preclinical data, anyway) to prevent the emergence of these or any other mutations.

That preclinical work made a very exciting drug for the clinic, so that is what led to this study.[1]This study is a phase 1 study. All of these patients have failed previous therapy with TKIs. Two thirds of these patients have actually failed at least 3 TKIs; these are patients who have gone through one, then another, and then another drug, and they have not responded. The results with ponatinib are very impressive. At least two thirds of patients achieve a major cytogenetic response, and more than half of the patients actually get a complete cytogenetic response. In patients with the T359 mutation, of which only 9 were in chronic phase, all 9 patients responded. These are really unprecedented responses, considering the kind of patients who were included, so it looks like a real drug.

Dr. Cheson: Was this all in chronic phase patients?

Dr. Cortes: No. The results I just described were chronic phase, but there was also a cohort of patients in accelerated and blast phase, and even a few with Philadelphia-positive acute lymphoblatic leukemia (ALL). We also saw very good responses in those patients. Even though the responses were not quite as good, we still had about 25% major cytogenetic responses. Half of them were complete cytogenetic responses. The responses have been durable in that setting; but not as durable in the advanced stages as in the chronic phase. However, I can remember one of my patients with Philadelphia-positive ALL who has been in complete cytogenetic remission for 6 months. At least some patients can go for an extended period of time, so even in that setting, the drug is very useful.

Dr. Cheson: What is the time-to-best response with this?

Dr. Cortes: It evolves little by little. The hematologic response happens very quickly. Within 3 months, you get the hematologic response. You get the cytogenetic responses after a median of 6 months. Typically by 6 months, they may have a minor cytogenetic response, and then over time, that may improve in some of the patients to a major or a complete cytogenetic response.

Dr. Cheson: What are the adverse effects of this drug?

Dr. Cortes: This drug is a pill, so it's easy to administer. Thus far, it's been very well tolerated. What was considered dose-limiting toxicity was pancreatic toxicity, mostly elevation of lipase amylase; occasionally with clinical pancreatitis. Many of these were just transient elevations and the patients were asymptomatic. When we stopped the drug, it resolved. Patients were able to be rechallenged with lower doses, and most of them were able to continue therapy. When the dose exceeded the maximum tolerated dose (60 mg) pancreatitis occurred. There is a little bit of myelosuppression and thrombocytopenia (about 17% of patients, grade 3) but for everything else, toxicity was minimal.

Dr. Cheson: You mentioned that in vitro, there was no emergence of other mutations. Do you think in the clinic, if this drug was used in a large number of patients for a long period of time, you would find that problem?

Dr. Cortes: I'm sure we will. I think that part of what's happening is that as we come with the next generation of better drugs, the leukemia cells learn to survive.

Dr. Cheson: They're smart.

Dr. Cortes: They are not just sitting there waiting to be killed. They find a way to survive, and emerge as something else. We know a lot about mutations, and we may be addressing that issue, but other things will probably emerge. Probably (hopefully) what this will mean is that fewer patients will get to that point or that the patients who do get to that point will be more difficult to manage, because they will have developed the most complicated mechanisms of resistance that we probably don't even understand right now.

Dr. Cheson: If this drug becomes more widely available, would you view it as the next front-line therapy for this disease or would you still use imatinib, bosutinib, nilotinib, etc, first, and save this for patients who either had the mutation documented, developed the mutation, or were resistant to those other drugs? How would you approach these patients?

Dr. Cortes: That's a great question. Obviously, the drug, if it becomes available would initially be for patients who have failed previous therapies. But in a hypothetical scenario where you have all of the options, I do believe that we need to use our best guns first, and if all that we know from preclinical and clinical work continues to be supported by additional data, this drug could be the best front-line option, and you would expect fewer patients to eventually lose their response and relapse. So I think that's where we would like to take this drug eventually.

Of course, we need to demonstrate that all of these things materialize. This is a phase 1 trial. There are still only a few patients, so there's a lot of work to be done, but in a hypothetical situation, yes. That's where I'd like to see the drug.

Dr. Cheson: What do you use first now for these patients?

Dr. Cortes: Good question. I use second-generation TKIs, but I use them mostly in clinical trials. Now these drugs are approved for first-line use in the United States and they're starting to be approved in other countries. On the basis of data, there is good justification for starting with the second-generation TKIs. You get more responses, and you get them faster. So far we seem to be seeing fewer responses.

We have to acknowledge that the way they have been tested is drug vs drug, new drug vs old drug (imatinib). However, we don't use imatinib in isolation. We use imatinib, and in the patients who fail, we effectively salvage many of them with second-generation TKIs. What we really need to understand is what is the best strategy -- starting with the new drug or starting with imatinib -- and then following it with second-generation TKS only and those who need it? That study hasn't been done, and that will be interesting, for it has many implications. We know a lot more about imatinib. It's been around much longer. Having said that, I do start with second-generation TKIs.

Bosutinib vs Imatinib

Dr. Cheson: Are there any other abstracts on CML that really caught your attention at this meeting?

Dr. Cortes: Yes, there are. With respect to what you just asked (what do I use as front-line) a number of abstracts addressed that question. There is follow-up on those initial randomized studies of nilotinib vs imatinib and dasatinib vs imatinib. Essentially, these studies give a little bit more follow-up, but basically confirm everything that we've seen -- higher responses, faster responses, etc.

A similar study is being presented for the first time with a third drug (similar concept -- another second-generation TKI). In this case, it is bosutinib vs imatinib.[2] Bosutinib, at the moment, is not yet approved for any indication. The primary endpoint in this study was the achievement of complete cytogenetic response at 12 months. On intention to treat, this drug did not show a benefit over imatinib. Part of the reason for this was an excess of treatment discontinuations. A lot of patients came off of the study because of toxicity. I'll comment about that in a second.

Molecular response at 12 months, which was a primary endpoint for the nilotinib study, is significantly better for bosutinib vs imatinib. Also, a significantly lower percentage of patients transformed during the period of observation. The median observation at this point is only 14 months, but with a significantly lower rate of transformations and failures. Everything seems to be in the right direction, except the primary endpoint, which was not met. If you consider evaluable patients only, then it was significant.

Dr. Cheson: So it remains to be seen whether the data will be strong enough to get it approved?

Dr. Cortes: Correct. I personally believe that the drug is very good. Part of the problem with these patients coming off is its different toxicity profile. For example, it causes more diarrhea, and it takes a little while to learn how to manage this. I was involved in the phase 1 and phase 2 studies of these drugs, so I saw that at the beginning, but later it became evident that during the initial few weeks, there is a lot of diarrhea, but then it goes away. That is the point when a lot of these patients came off the drug because of toxicity, and I think that is avoidable. We'll have to see, as you said, how these data are interpreted by regulatory authorities.

Role of Transplant in CML

Dr. Cheson: One last question, and it's going to be a real easy one for you. What's the role of transplant in CML?

Dr. Cortes: Oh, it's easy. I think that in the front-line setting, we're not doing transplants anymore. You could make an argument for the very young patients, but even in that setting, most people would still go with a TKI first, but we definitely cannot forget that transplant is a curative strategy in CML and it's a good option. Once a patient starts having problems and fails initial therapy -- certainly, when they fail 2 TKIs, and certainly when they have a T359 mutation -- those patients should be considered for transplant. I would suppose that we would be at least typing these patients early, so that if they meet that criteria, then you're ready to go to transplant if that is indicated.

An interesting scenario would be if we're starting to use these second-generation TKIs as front-line therapy, those failures are probably going to be a little bit more difficult because when they fail imatinib, you do have something to back on. If they fail these drugs, ponatinib may come along, but today, there's not much, so we are probably going to have to consider transplant more in a second-line when our current second-line is first-line.

Dr. Cheson: Are they generally in good enough shape at that point for transplant?

Dr. Cortes: Fortunately, yes. If you're following the patients properly, and doing good monitoring, you'll take the failures by cytogenetic recurrence and all of that, but the patients will be good. So it's a good point that you make because that emphasizes the importance of good, strict monitoring, so that you can identify the patients who are not doing well early. That's when you have your best chance of a good outcome with intervention, whether that is another TKI or transplant.

TKIs: A Cure for CML?

Dr. Cheson: I said it was my last question and it was going to be an easy one. I'm going to ask you an even easier one. Have we cured patients with CML (without transplant) with these new drugs? Are they cured?

Dr. Cortes: To answer that question categorically, it's not possible. If I had to give a categorical answer, I would say no.

However, emerging data suggest that we probably have. There are very intriguing data from French investigators, François Mahon, in a trial that they call STIM [Stop Imatinib].[3] Patients who have been treated with imatinib for a long period of time, who have had negative real time polymerase chain reaction (RT-PCR) levels (by very strict, high sensitivity PCR) sustained for 2 years in a row, were given the option to stop treatment. What they found was that 60% of these patients relapsed. It was just a molecular relapse, and they responded again. However, the intriguing part is that 40% of patients didn't relapse -- the follow-up is still relatively short, but it now extends to a couple of years -- and all the relapses happen in the first 6 months. So then are those 40% of patients cured? Again, follow-up is very short, but it is possible that for a subset of patients, maybe we can think of them as already cured.

Summary and Closing Remarks

Dr. Cheson: That's great news for physicians, and for their patients with CML. I'd like to thank Jorge for joining us today. I've known him since he was a Fellow, and he's come a long way. He's been instrumental in developing a number of these TKIs, and these have resulted in a total change in how we approach patients with CML, and importantly, an improvement in the outcome of these patients. Thank you for joining us today, and I look forward to seeing you again.

Dr. Cortes: My pleasure. Thank you for having me.

Dr. Cheson: This has been Medscape Oncology, focus on CML from the ASH 2010 meeting in Orlando, Florida. Thank you for joining us today.


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