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Ibrutinib Nears 100% Two-Year OS Rate in Waldenström's Macroglobulinemia

Laura Panjwani
Published: Thursday, Apr 09, 2015

Dr. Steven Treon

Steven P. Treon, MD, PhD

Updated data from the pivotal 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 in The 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, OncLive spoke 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.

OncLive: How significant are these updated results?

Dr 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 the MYD88 mutation as being a highly prevalent mutation in patients with WM. It is seen in over 90% of patients. Rapidly, we were able to figure out MYD88 mutation 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?


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