No late-phase clinical trial results are available for the Brutonâ€™s tyrosine kinase (BTK) inhibitor ibrutinib, yet a growing body of evidence is showing that not only is targeting BTK a viable strategy, but ibrutinib could change the way in which patients with chronic lymphocytic leukemia (CLL) are managed.
Jennifer Woyach, MD
No late-phase clinical trial results are available for the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, yet a growing body of evidence is showing that not only is targeting BTK a viable strategy, but ibrutinib could change the way in which patients with chronic lymphocytic leukemia (CLL) are managed.
At the 11th International Congress on Targeted Therapies in Cancer, held August 16-17, 2013, in Washington, DC, Jennifer Woyach, MD, assistant professor of Internal Medicine in the Division of Hematology at the Ohio State University Comprehensive Cancer Center in Columbus, described how ibrutinib works and reviewed the data that are currently available on the drug.
BTK is the target of drugs such as ibrutinib, yet it is not mutated like many other targets of small-molecule inhibitors. Instead, Woyach explained, BTK is overexpressed at the transcript level in patients with CLL. BTK is involved in both B-cell activation and B-cell-mediated signaling, and inhibiting this target leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK is also associated with increased tumor cell proliferation and survival in B cell malignancies.
“Even after the drug is metabolized, BTK should still be irreversibly inhibited until new BTK could be generated, which allows the once-a-day dosing, even in the presence of a shorter half-life of the drug,” Woyach said.
Preclinical studies suggested that ibrutinib had the potential to treat CLL, the most prevalent type of adult leukemia. The American Cancer Society estimates that approximately 15,680 new cases of CLL will be diagnosed in 2013 and approximately 4580 people will die from the disease. Woyach explained that the disease is typically treated through chemoimmunotherapy and is incurable outside of an allogeneic stem cell transplant.
In a phase IB/II study, the results of which were published in The New England Journal of Medicine in July, patients who received treatment with either 420 mg or 840 mg of ibrutinib once daily achieved an overall response rate of 71%, with an additional 20% of patients in the 420- mg arm and 15% of patients in the 840-mg arm achieving a partial response with lymphocytosis. After 26 months on the study, the estimated progression-free survival (PFS) rate was 75% and the overall survival rate was 83%.1
However, a further analysis of the data has revealed that not all patients are responding the same. Patients who had deletions of part of the short arm of chromosome 17 (del17p) had an estimated PFS rate at 26 months of 57%, and patients with deletions in chromosome 11 (del11q) had a PFS of 73% in the same time period.
Woyach explained that researchers are not surprised by the lower response rates in patients with del17p because it’s been a phenomenon that has been observed across the board in patients who are treated for CLL. “This does likely indicate a group of patients who has just different disease biology,” Woyach said. “It tends to be one where people need to be treated a little bit earlier in the course of the disease. They develop symptoms more quickly and tend to require multiple courses of therapy.”
Woyach also said that ibrutinib still provides a longer PFS than any existing treatment for patients with del17p, and more research on dosing strategies or combining therapies might help find a way for these patients to respond as well as others in the study.
Additionally, the responses with lymphocytosis that were observed in the trial are also not unexpected. “We think that this is happening because ibrutinib disrupts the homing signal and then disrupts adhesion factors on the CLL cells,” Woyach said. “These cells that initially would be kind of stuck in their microenvironment in the lymph nodes, spleen, potentially the bone marrow, and other niches, as soon as you give ibrutinib, all those homing signals and the adhesion signals go away. Those cells then are free to kind of just go out into the peripheral circulation.”
Woyach said that it is very important to understand that peripheral lymphocytosis is not a sign of relapse, and some groups are going so far as to revise their guidelines to make sure that clinicians who are prescribing ibrutinib or PI3K-delta inhibitors are not concerned about this phenomenon.
It has yet to be determined whether other BTK inhibitors can gain the same kind of traction that ibrutinib has thus far. Woyach said that the only other similar drug with any available data is AVL-292, also known as CC- 292, a more selective BTK inhibitor than ibrutinib. In a study presented at the 18th Annual Congress of the European Hematology Association (EHA), held in Stockholm, Sweden, earlier this year, a study found that among 53 evaluable patients with CLL with at least one lymph node assessment, 24 patients (45%) showed at least a 50% reduction in lymph nodes. The study also found that the overall response rate was 31% in patients who received 750 mg of the drug daily, compared with 66.7% who received 375 mg daily.2
Woyach said that this confirms that selective inhibition of BTK is reasonable, even though the response rates might not have been as high as would have been hoped for through the use of selective inhibition.
“I think that there is a lot of interest in generating more selective BTK inhibitors because we don’t know much about the consequences of the alternative targets of ibrutinib and whether those might contribute to any of the toxicity,” Woyach said. “We also don’t know if those might be contributing to the efficacy of the drug, too, so those are kind of unanswered questions at this point.”