Cortes Highlights Second-Generation TKIs for Frontline Therapy in CML

Jorge Cortes, MD

Jorge Cortes, MD

Studies have shown that patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML) have improved responses with second-generation tyrosine kinase inhibitors (TKIs) compared with first-generation TKIs.

A 5-year analysis of DASISION, a randomized phase III study of dasatinib (Sprycel) versus imatinib (Gleevec) in patients who had not received prior treatment for their chronic-phase CML, showed that dasatinib is a more effective treatment compared with the first-generation TKI imatinib.¹

In the study, 259 patients were given 100 mg of dasatinib orally once a day and 260 patients were given 400 mg of imatinib orally once a day. Cumulative rates of major molecular responses (MMR) and molecular responses with a 4.0- or 4.5-log reduction inBCR-ABL1were significantly higher in the dasatinib arm versus the imatinib arm at the end of 5 years. Of the patients on dasatinib, 84% achievedBCR-ABL1of 10% or less at 3 months, as compared with 64% of the patients receiving imatinib. Fifteen and 19% of patients hadBCR-ABL1mutations identified at discontinuation of dasatinib and imatinib, respectively.

Another randomized phase III study, the ENESTnd trial, focused on nilotinib (Tasigna) at one of 2 doses compared with imatinib in patients with newly diagnosed chronic-phase CML, demonstrating higher response rates with the second-generation agent.²

At 5 years, more than half of the patients in the nilotinib arms (54% with 300 mg twice daily and 52% with 400 mg twice daily) achieved a molecular response 4.5 (MR 4.5) compared with 31% of patients in the imatinib arm. Benefit was seen with the use of nilotinib across all risk groups. Additionally, patients in the nilotinib arms had a lower risk of progression to accelerated/blast phase compared with in the imatinib arm.

Jorge Cortes, MD, who was an investigator in the DASISION trial, sees the future of CML care in earlier treatments. “I think that a lot of the focus now is to see if we should do some interventions early on to try to optimize the number of patients who get to the deepest molecular responses and that would, at some point, be eligible for treatment discontinuation,” he said in an interview withTargeted Oncology.

Cortes, deputy chief and a professor of medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, discussed frontline treatment options for patients with CML withTargeted Oncologyahead of a debate on optimal frontline regimens at the3rd AnnualLive Medical Crossfire: Hematologic Malignancies, hosted by Physicians’ Education Resource.

TARGETED ONCOLOGY:What are some important topics when it comes to therapy for patients with CML?

Cortes:The selection of the initial therapy has become more relevant with the introduction of the generic imatinib. We know that in the randomized studies the second-generation TKIs have a benefit in terms of deeper and faster responses.

But the cost issues become relevant and imatinib is a good drug. So, does it play a role, and should we consider that? If you do treat patients with imatinib, what considerations do you have to have [think about] so that you don't compromise the potential optimal outcome of the patient? Some patients will do well, but others will not, and you have to be able to recognize that early and take appropriate action. I think that that's an important topic of discussion that's become more relevant now: these early measures of success, these early molecular responses—what do they mean clinically and what do you do with those? There's some who think that there may be a need for changing therapy at that point and ones who believes that they are important to keep an eye on in the monitoring of the patients, but they don't necessarily trigger a change in therapy.

Another important topic is the management of patients, of women in particular who are pregnant. In men we don't have much of an issue, by now we've established that conception while on one of these TKI drugs is not a problem for men. But of course, for women the problem is the pregnancy's health and how do you strike a balance between safety for the baby and safety for the mothers so that the baby doesn't get exposed to a drug that could potentially harm their development, but the mother doesn't compromise her potential best outcome from the leukemia point of view. Those are important aspects too, and there's no good consensus on how to manage that. We all have some experience but at least we can speak from that experience and what we know so far.

TARGETED ONCOLOGY:What new frontline therapies have come out recently and how are they improving?

Cortes: The most recent change was the approval of bosutinib, another second-generation [TKI], as frontline therapy. Now we have 3 second-generation TKIs for frontline and imatinib. So, 4 approved [TKIs] for frontline therapy. I think the bulk of the data, if you put all the second-generation data together, they all look consistent with that benefit compared to imatinib. There are some differences which are difficult to reconcile considering that these are similar but not identical studies from one drug to the other, but I do think that it is fair to say that these have become standard.

Some of the important things that are emerging now is, for the dasatinib in particular, the use of lower doses. It's no surprise that the initial results that have emerged from our institution are positive when we consider that with both nilotinib and bosutinib, the dose that we use for frontline is lower than the dose that we use for salvage, so sure enough that's proving to be the same with dasatinib.

I think that a lot of the focus now is to see if we should do some interventions early on to try to optimize the number of patients who get to the deepest molecular responses and that would, at some point, be eligible for treatment discontinuation. There are studies adding ruxolitinib [Jakafi] and adding interferon and other agents. Perhaps one of the most exciting ones is adding venetoclax [Venclexta] with some good pre-clinical data, but there's not enough data yet clinically to assess, but they will come soon. 

TARGETED ONCOLOGY:What are the benefits of using second-generation TKIs over first-generation?

Cortes: There are randomized studies, there's several of them now, and then some sequencing studies independent from the initial studies. They all have confirmed that we have a faster response [with second-generation TKIs]. We get a deeper response. We have fewer transformations and it is more and more important that over time we get more patients with the deepest molecular responses, the MR 4.5 and sustained MR 4.5.

These events, or the frequency of these responses, is not inconsequential. For example, from the ENESTnd study, which has some of the longest follow-up. We know that, for example, 5 years you get to over 50% of patients with an MR 4.5, whereas with imatinib only about 30% of patients. It's a 20 percentage point difference, which is important. The sustained MR 4.5 goes from 40% to 45% versus 20% with imatinib, so I think that those are the things you need to keep in mind. It doesn't improve survival, or it hasn't so far. I think that if we had enough patients and enough follow-up, we would probably see a small benefit, significant but small. But I think we're beyond that now. We've established that other endpoints are important and I think that’s the type of consideration that you, at the very least, have to discuss with the patient—what you're getting with one drug versus the other.

TARGETED ONCOLOGY:What are some challenges that are still unmet in the CML space?

Cortes: I think that I mentioned briefly the challenge of these 2 or 3 occlusive events and these are events that happen with all these drugs, particularly the second- and the third-generation drugs. More with ponatinib [Iclusig] perhaps, but it also happens with nilotinib and dasatinib. Maybe a little bit less with bosutinib and certainly much less with imatinib. It's a challenge because it has to do with the comorbidities that patients have, but a lot of our patients have comorbidities. Some are diabetic, some have hypertension, some smoke. We need to learn more about how to manage these patients so that we give them the benefit of the drugs to try to minimize the risks, because we don't understand the mechanism and we cannot prevent it. I think that's still a big challenge.

The other one that's big is the treatment discontinuation. It's become a reality, no question, and it's a big thing for the patients, but unfortunately today it benefits only about 20% to 25% of the patients because not everybody gets to have the criteria of sustained deep molecular responses, which in my opinion has to be a sustained MR 4.5 for at least 2 years, and ideally 5. And then, of those patients who meet the criteria, about half of them will relapse. So it is great, but it is not a reality for most patients, so how can we improve [that rate]? How can we make more patients eligible and how can we decrease the relapse rate? Either one of those 2 would help us improve the overall impact of this approach, but ideally, we would like to address both. Some combinations studies may help us with that hopefully, but we'll have to wait for some data because right now we do have some leads pre-clinically, some early data in the clinic, but nothing definitive yet. I think that's an important challenge for the future.

TARGETED ONCOLOGY:What do you see coming in the future for CML treatments?

Cortes:I think that the future is still bright for CML. I think that there are some interesting new drugs coming along. Asciminib seems to be a very potent, active drug that'll be very helpful. I think it is important that we haven't addressed much in more advanced stages, blast phase, etc. I think it is important that we continue treating our patients in the best possible way, meaning good monitoring, good management, and that we can continue addressing those unmet needs with clinical trials.

References

1. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial.J Clin Oncol. 2016;34(20):2333-2340. doi: 10.1200/JCO.2015.64.8899.
2. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.Leukemia.2016;30(5):1044-1054. doi: 10.1038/leu.2016.5.