BTK Inhibitor Offers Benefits of Ibrutinib Without Cardio Side Effects

The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, has been improving the survival rates of patients with leukemia and lymphoma since being FDA approved in 2013. Ongoing research and positive patient outcomes have reaffirmed the efficacy of the drug as a cancer treatment.

One major side effect of ibrutinib, however, is cardiovascular damage.

Now, some of the same researchers involved in creating ibrutinib have developed the second-generation cancer drug acalabrutinib. The new BTK inhibitor promises to deliver the same cancer-fighting benefits of its first-generation cousin, but with minimal treatment-limiting side effects.

Data has shown acalabrutinib improves survival rates in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), according to the researchers who developed and tested both BTK inhibitors at The Ohio State University Comprehensive Cancer Center (OSUCCC)—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus.

The OSUCCC—James researchers recently reported data from a clinical trial conducted at 15 cancer centers in the U.S., U.K., and Italy. A total of 134 patients received acalabrutinib, including 132 with CLL and two with small lymphocytic lymphoma. The overall response rate to the treatment was 85 percent and most patients (81%) continued treatment at 19.8 months.

Meanwhile, in a separate analysis led by OSUCCC—James researchers, 610 patients with various blood cancers were treated with acalabrutinib. The average median duration of treatment was 14.2 months. While adverse side effects led to discontinuation of treatment in only 6.1 percent of patients. That compares to 17.3 percent of patients receiving ibrutinib who required discontinuation of therapy due to adverse events.

“It’s very promising that acalabrutinib produces the same response rates that we saw with ibrutinib, but what’s really exciting is that those results seem to deepen with time and also reduce the likelihood of life-impacting side effects like atrial fibrillation,” lead researcher, John C. Byrd, MD, told Oncology Times.

The recently reported data also show the drug is safe and effective in treating multiple blood cancers, not just CLL, Byrd said. “Combined data from seven ongoing clinical trials testing acalabrutinib reported mostly low-grade side effects and excellent cancer control in patients with follicular lymphoma, mantle cell lymphoma, prolymphocytic leukemia, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.”

Rapid Response

FDA granted accelerated approval for acalabrutinib in October 2017 for the treatment of adult patients with MCL who have received one prior therapy. The accelerated approval was based in part on the overall response rate to acalabrutinib, which included 80 percent of patients achieving overall response with 40 percent achieving complete response and 40 percent achieving partial response. By comparison, ibrutinib produced overall response rates of 77 percent, with 33 percent of patients obtaining complete response.

Second-generation acalabrutinib was engineered to overcome the side effects and other treatment challenges identified with ibrutinib, said Byrd, the D. Warren Brown Designated Chair in Leukemia Research and a Distinguished University Professor at Ohio State.

“We found that most patients tolerate [ibrutinib] very well and that it improves survival rates in patients with CLL and MCL. But to understand any resistance to the treatment and overcome any challenges or side effects, we immediately began working on a second-generation drug, acalabrutinib,” he said.

Among the key takeaways from the recent studies of acalabrutinib, Byrd said, is that the results were “very positive in both patients with relapsed disease and patients who had never been treated for CLL, as well as when acalabrutinib was given alone or in combination with other drugs.”

“When acalabrutinib was given in combination with an engineered antibody drug, the response rate was 95 percent in those who had never received treatment, and overall survival in patients with relapsed CLL was 92 percent a year and a half to 2 years after treatment began,” Byrd continued. “When administered alone to CLL and SLL patients, acalabrutinib treatment resulted in an 85 percent response rate and more than 80 percent of patients remained on treatment after 20 months.”

Future research, Byrd said, needs to include finding more ways to treat patients with the new drug.

“The overall response rates to acalabrutinib in these trials begins to show us the potential impact this drug can have on the management of CLL, but there is an urgent need for additional research and to find additional treatment options,” he said.

“We know that this drug is well-tolerated and that its results are durable over time. Now we need to further investigate drug combinations that are going to work for different patients to provide the most effective treatment for their individual cancer.”

Immense Potential

Medical oncologists around the country said they are eager to prescribe acalabrutinib for their patients.

“As ibrutinib is currently indicated in five distinct hematology neoplasm scenarios, the potential for this agent is immense,” said Sean Fischer, MD, Medical Oncologist and Hematologist at Providence Saint John’s Health Center in Santa Monica, Calif.

“Acalabrutinib, in preclinical studies, showed not only higher degrees of selectivity and inhibition of BTK, but also decreased thrombotic risk compared to historical data with ibrutinib suggesting this agent could have best-in-class potential,” he added.

The increase in overall response rates and significant decrease in the number of patients who needed to discontinue treatment due to side effects with acalabrutinib compared to ibrutinib are reasons to consider using the younger BTK inhibitor, Fischer noted.

“Based on this indirect comparison, my bias would be to prescribe acalabrutinib in the appropriate patient population given its efficacy and tolerability compared to similar options for patients with relapsed MCL,” he said. “I have used the agent several times thus far, since its approval, and I hope to gain more experience as the drug’s indications improve, as it is in studies for other indications, such as CLL, SLL, and other low-grade lymphoproliferative disorders.”

Acalabrutinib adds to “an array of multiple, effective novel agents for this disease that have dramatically improved the outcomes of such patients,” said Jack Jacoub, MD, Medical Oncologist and Medical Director of MemorialCare Cancer Institute at Orange Coast Medical Center in Fountain Valley, Calif.

“Initially, I would reserve its use for those who I may be worried about using ibrutinib, the first available BTK inhibitor, such as those patients with a history of arrhythmias, concurrent anticoagulant use, and/or a bleeding diathesis, as preliminary data suggest a low rate of related side effects with acalabrutinib as opposed to ibrutinib,” Jacoub said.

“We have yet to use [acalabrutinib], but we are anticipating clinical trial availability for our patients with this agent that is being studied in many indications,” he added. “Honestly, I would hope it puts a pricing pressure on ibrutinib, proves safer to ibrutinib, and obviously more effective (yet to be determined).”

Chuck Holt is a contributing writer.

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