Updated data from a phase II trial of ibrutinib (Imbruvica) in WaldenstrÃ¶mâ€™s Macroglobulinemia (WM) showed a 2-year overall survival (OS) rate of 95% with the BTK inhibitor.
Steven P. Treon, MD
Updated data from a phase II trial of ibrutinib (Imbruvica) in Waldenström’s Macroglobulinemia (WM) showed a 2-year overall survival (OS) rate of 95% with the BTK inhibitor. Initial results from the study supported the approval of ibrutinib in WM earlier this year.
The follow-up data, which were recently published inThe New England Journal of Medicine, also showed an overall response rate (ORR) of 91% (median treatment time, 19.1 months) and a median 2-year progression-free survival (PFS) of 69%.
For expert insight on these new findings,Targeted Oncologyspoke with Steven P. Treon, MD, PhD, first author on the study and director of the Bing Center for Waldenström’s Macroglobulinemia at Dana-Farber Cancer Institute, where the study was conducted.
Targeted Oncology:How significant are these updated results?
Treon:This study was the basis for the FDA approval. What we have learned with this follow-up is that the response rate went up in comparison with the data set that was submitted to the FDA. For the first time, we now have a chance to get a sense of what the PFS and OS impact are for the drug. I think this is particularly exciting given that patients, on average, had two prior therapies; about 40% of them were refractory. Taking into context with other available therapies, this is absolutely remarkable.
How does this compare to other therapies used to treat WM?
When you think about other therapies used with previously exposed patients, the response rates vary for single agents from 30% to 40%. The PFS with many of these agents is usually months up to 2 years, on the highest end. When you are looking at this data in comparison to other therapies, it represents a real advance for patients with WM. This is the first and only approved drug for treating patients with WM.
I think the other remarkable part to the story is how this therapy was discovered to be effective. About 3 years ago, we discovered theMYD88mutation as being a highly prevalent mutation in patients with WM. It is seen in over 90% of patients. Rapidly, we were able to figure outMYD88mutation signals and discovered that BTK was actually one of the key pathways that promoted survival of the tumor cells.
We proceeded to look at ibrutinib, and we were able to receive the first-ever breakthrough designation from the FDA for ibrutinib in WM. That designation had not been previously given to any other cancer. It was really the strong scientific evidence that allowed this fast-track approval. In just under 2 years since being given a breakthrough designation, we received FDA approval for ibrutinib in patients with WM and hopefully an approval will be forthcoming in Europe as well. It is now before the EMA.
What is the long-term impact of ibrutinib as a treatment option for WM?
It is changing the paradigm for how we treat patients. It represents the first targeted therapy for WM as opposed to the hand-me-down therapies that we had to rely on before. Previously, we looked at other related cancers and we would borrow those drugs and see if they worked in WM. This represents the first time we’ve been able to use a therapy that is an on-target therapy for the tumor based on its mutation profile.
This is a safe and very effective way to treat patients with minimal toxicity, and it is in contrast to other therapies used to treat patients with WM that created serious side effects. These include, in some cases, debilitating neuropathy, immune suppression, and also risk for secondary cancers. Ibrutinib represents a new targeted therapy and a safe way of treating patients. It really contrasts itself in terms of efficacy and safety compared to existing therapies.
Are there any concerns or challenges with using ibrutinib for WM that oncologists should be aware of?
There are two main areas that are worth emphasizing. For patients who are on warfarin (Coumadin) or another medication that may be an anticoagulant, the use of ibrutinib should be avoided. The second important concern is that if patients have a history of an arrhythmia, they may see reoccurring atrial fibrillation. This does not mean the drug shouldn’t be used, but patients with a history of arrhythmia should be approached carefully and, if reoccurring atrial fibrillation occurs, they should stop the drug. Once the patient’s rhythm has been restored, they might be able to retry the drug at a lower dose.
Importantly, what we did see in this study is that antibodies that protect against infection, such as IgG and IgA, were not affected by ibrutinib. This is in contrast to other drugs that we used, where IgG and IgA often come down and predispose these patients to an infection. We did not see an infection signal in this study. We did not observe any unexpected infections or incidences of infections.
What are the next steps in studying ibrutinib for the treatment of WM?
In this study, we learned thatMYD88andCXCR4mutations are highly prevalent in WM’s impact outcome. For patients who did not have theMYD88mutation, which represents 5% to 8% of all patients with WM, there was a low response rate to ibrutinib. We are trying to figure out why that is the case, and we are also trying to study those patients genomically to better understand what permits survival of their tumors so we can develop targeted therapy.
One-third of all patients with WM have theCXCR4mutation. This is an interesting mutation because the only cancer that we know of where this occurs, so far, is in WM. It makes the tumor cells less sensitive to ibrutinib, and requires that patients be maintained for longer periods of time on ibrutinib in order to see response. Now, we are trying to use CXCR4 inhibitors along with ibrutinib in order to improve responses in this patient population. We plan on starting a clinical trial, combining a CXCR4 inhibitor with ibrutinib, this year. We received funding from the Leukemia & Lymphoma Society to pursue this study.
Do you think the approval and success shown thus far with ibrutinib will lead the way for other similar therapies for WM?
We think that ibrutinib will open up the doors for other therapies that target the MYD88 pathway. This could include the development of other inhibitors, as well as drugs that can enhance ibrutinib activity. ABT-199, which affects BCL-2, has shown synergistic activity with ibrutinib. We just published a paper on that in theBritish Journal of Haematology.
When a drug is approved for an orphan disease like WM, it also attracts pharmaceutical companies to examine this disease. There is no question that it happened with the approval of ibrutinib. That means there will be more support for clinical trials and the development of new and targeted agents. Just a few years ago, there was very little interest in multiple myeloma. However, when the first drugs were approved, it suddenly opened the door for the development of additional agents. I think this will happen for WM, as well.