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Next-Generation BTK Inhibitors and Why We Need Them

John Pagel Headshot
John Pagel, MD, PhD

Chief of Hematologic Malignancies
Swedish Cancer Institute
Seattle, Washington


John Pagel, MD, PhD, has disclosed that he has received consulting fees from AstraZeneca, Gilead Sciences, and Pharmacyclics.


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Released: October 24, 2019

Treatment of B-cell malignancies, particularly non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), has been revolutionized with the development and approval of the first Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib. Indeed, the addition of ibrutinib to the treatment armamentarium for B cell malignancies has allowed for a paradigm shift away from chemotherapy-based regimens for patients with B-cell malignancies.

Inhibiting BTK in the B-cell signaling cascade stops cell proliferation and induces apoptosis, and oral BTK-targeted agents have proven efficacious for various B-cell malignancies. Ibrutinib was the first BTK inhibitor approved by the FDA to treat some of these indolent hematologic diseases, and has given patients who have failed previous therapies, as well as those who are less fit and cannot tolerate chemotherapy, an unique opportunity to receive important therapy. Now, ibrutinib is approved by the FDA to treat patients with previously treated mantle cell lymphoma (MCL) and marginal zone lymphoma as well as with primary or previously treated CLL/small lymphocytic lymphoma (SLL) and Waldenström macroglobulinemia. Although often considered more tolerable than chemotherapy, ibrutinib does result in specific adverse events (AEs), including myalgias, arthralgias, rash, bruising and, less commonly, serious bleeding, hypertension, or atrial fibrillation. Dose adjustments of ibrutinib can often help alleviate many of these AEs, but some can be dose limiting for individual patients. 

Improving Tolerability With More Selective BTK Inhibitors
Additional BTK inhibitors—with high selectivity for BTK and potentially fewer off-target effects—have been developed to improve on the tolerability. These newer BTK inhibitors may have improved AE profiles that might make them advantageous as new agents in the BTK inhibitor class of drugs. Acalabrutinib is a next-generation BTK inhibitor currently approved by the FDA for patients with MCL who have received at least 1 previous therapy and another next-generation agent on the horizon, zanubrutinib, has been granted FDA priority review for treatment of patients with relapsed/refractory MCL. Clinical trials of these newer BTK inhibitors are also ongoing in other B-cell malignancies.

Data from these clinical trials have suggested that acalabrutinib and zanubrutinib may have unique AE profiles compared with ibrutinib. We await the results from direct head-to-head trials before we know if there is any true differences in BTK inhibitor AE profiles. Two such phase III trials are the phase III ELEVATE R/R trial comparing acalabrutinib with ibrutinib in patients with R/R CLL with either del(17p) or del(11q) and the phase III ALPINE trial with zanubrutinib vs ibrutinib that is ongoing for patients with R/R CLL. The results from these trials will show if there is any differences in safety with these next-generation BTK inhibitors over ibrutinib.

Overcoming Acquired Resistance With Next-Generation BTK Inhibitors
Perhaps the biggest problem with BTK inhibitors employed to date is that patients who relapse most frequently do so because they develop resistance to these BTK inhibitors. This resistance has been attributed to specific mutations, including in BTK at amino acid position 481 (C481X) and a mutation in PLCγ2 downstream from BTK in the B-cell signaling cascade.

Newer BTK inhibitors in development such as LOXO-305, vecabrutinib, and ARQ 531 target both wild-type and C481-mutated BTK. These reversible, non-covalent BTK inhibitors are currently in phase I/II trials in CLL/SLL and/or NHL for patients, including those with resistance to currently available irreversible, covalent BTK inhibitors.

We are hopeful that these novel reversible BTK inhibitors might allow clinicians to keep patients on therapy using BTK inhibition for even longer periods of time and provide patients a clinically meaningful duration of remission that may also translate into a survival benefit.

Potential for Fixed-Duration BTK Inhibitor Therapy
With the impressive efficacy of the currently approved BTK inhibitors, as well as those in late-stage development, the next question becomes: Can we develop treatment regimens including BTK inhibitors that may allow for fixed-duration approaches? The idea of delivering time-limited therapy to patients with novel agents is quite appealing. The current approach being explored is to use these highly potent BTK inhibitors to treat patients for a specific, defined period of time and achieve undetectable minimal residual disease (uMRD). Then, once uMRD is achieved, therapy can likely be stopped and allow the patient can remain off therapy for an extended time.

At relapse, which is common with indolent lymphomas and certainly with CLL, BTK inhibitor–based therapy might be reinitiated to provide additional benefit to patients. This idea of fixed-duration treatment may extend the use of this class of agents and provide a significant clinical benefit for patients. Current studies investigating time limited therapy are on-going.

Join Us for a Symposium on BTK Inhibitors in Orlando This December!
There is currently a lot of excitement about the use of BTK inhibitors along with other new and novel agents for patients with B-cell malignancies. We have just scratched the surface of the optimal use of BTK inhibitors with further research on optimizing dosing schedules to improve the tolerability, overcoming resistance to initial BTK inhibitor therapy, and the potential for combination approaches to provide better outcomes for our patients.

To hear more expert perspectives on the use of BTK inhibitor therapy for hematologic malignancies, please join me and my colleagues Ian W. Flinn, MD, PhD; Jan A. Burger, MD, PhD; and Alexey Danilov, MD, for our upcoming CME-certified symposium at ASH 2019. Click here to register!

Your Thoughts
What are your biggest challenges regarding the use of BTK inhibitors in your practice? Please share your thoughts in the comments box below.

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