Brukinsa May Cause Fewer Side Effects Than Other BTK Inhibitors for Patients with B-Cell Malignancies

Targeted drugs known as Bruton’s kinase inhibitors (BTKs) are important treatments for many patients with blood cancers that invade the B immune cells, whose job is to create antibodies that fight infection.

In fact, some large clinical trials indicate that BTK inhibitors should be considered the go-to initial treatment for patients, according to Dr. Ian Flinn, director of lymphoma research and principal investigator at Sarah Cannon Research Institute, and director of the Sarah Cannon Center for Blood Cancer at Tennessee Oncology and TriStar Centennial Medical Center.

But what happens if a patient has to stop taking one of these drugs because it causes intolerable side effects?

A next-generation BTK, Brukinsa (zanubrutinib), may be easier to tolerate for patients who have stopped receiving Imbruvica (ibrutinib) or Calquence (acalabrutinib) because of side effects, Flinn said, and an ongoing clinical trial will test that hypothesis. Flinn presented information about the trial in a poster during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

Brukinsa was approved by the Food and Drug Administration (FDA) in November 2019 as a therapy for previously treated mantle cell lymphoma, a B-cell malignancy.

The phase 2 trial, known as BGB-3111-215, is evaluating the side effect profile of Brukinsa in a broader group of patients with B-cell malignancies who stopped taking Imbruvica or Calquence because of side effects.

The main goal of the study, Flinn told OncLive®, a sister publication of CURE®, is to measure the recurrence and change in severity of treatment-emergent side effects with Brukinsa and compare them with those that arose when the patients received Imbruvica and/or Calquence. Enrollment, which is underway, will take place at 30 community medical centers across the United States.

Investigators plan to enroll approximately 60 patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström macroglobulinemia, mantle cell lymphoma or marginal zone lymphoma whose disease was intolerant of prior BTK inhibition and whose treatment-emergent side effects resolved to mild or lower before they started treatment with Brukinsa.

While Flinn doesn’t think Brukinsa would be an effective treatment for patients whose cancers progressed during treatment with a previous BTK, he believes “there’s good rationale to think that patients who are intolerant to (Imbruvica) or (Calquence) might tolerate (Brukinsa).”

“Zanubrutinib is a specific inhibitor of BTK,” he explained. “It has less inhibition of off-target kinases (meaning it precisely targets and disables the proteins that drive the cancer without affecting others that aren’t involved in the cancer process). As a consequence, the hypothesis is that it will have less of these (side effects), such as arthralgias, atrial fibrillation and bleeding.”

The most common reason patients stop taking Imbruvica, he said, is that they develop arthralgias (joint pain or other aches and pains); this occurs in about 40% of patients. Abnormal heart rhythms and atrial fibrillation occur in up to 15% of patients treated with Imbruvica, and bleeding is another major reason for discontinuation, he said.

In the study, intolerance to a previous BTK is defined as bad joint pain, cardiac arrhythmia or bleeding to the point where a patient’s physician does not think they can remain on the drug, Flinn said. “If the patient has to come off therapy,” he said, “they may be eligible for this trial.”

Once the patient’s side effects subside enough to be considered mild, they can start the study drug, with the goal of testing whether they will develop the same intolerance while taking Brukinsa, Flinn said.

“The hypothesis is that these (side effects) will not reoccur, which will allow patients to continue on “Brukinsa,” he said.

Those interested in participating in the trial can learn more by contacting BeiGene, the pharmaceutical company developing the drug, at clinicaltrials@beigene.com.

There are also other trials in progress that are testing Brukinsa and other BTK inhibitors, Flinn noted.

“The biggest issue we have currently in these diseases is: ‘Which BTK inhibitor is better?’” he said. “There are head-to-head trials comparing (Brukinsa plus Imbruvica) and (Calquence plus Imbruvica) to better understand how the efficacy and (side effect) profiles line up. Many people think that these drugs are fairly similar in their efficacy, but because some patients have to come off treatment — most prominently with (Imbruvica) — that cuts into the efficacy, because patients are no longer on therapy. Perhaps that is where the differences will be (most evident).”

A version of this article originally appeared on OncLive^® as, “Ongoing Trial Evaluates Zanubrutinib in BTK-Intolerant B-Cell Malignancies”.