Nirav N. Shah, MD, MSHP, and Alexey Danilov, MD, PhD, discuss the phase 2 DAYBreak CLL-201 trial evaluating bexobrutideg in relapsed/refractory CLL.
Covalent BTK inhibitors are key therapeutic options in the chronic lymphocytic leukemia (CLL) treatment paradigm, as a monotherapy or in combination with other treatments like BCL2 inhibitors, with the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) also representing a treatment option following a covalent agent. However, upon progressing on a BTK inhibitor, patients with CLL are left with limited options. A novel treatment class, BTK degraders, with agents like bexobrutideg (NX-5948), represents an opportunity to overcome mutations and resistance to BTK inhibitors in CLL.
The ongoing phase 2 DAYBreak CLL-201 trial (NCT07221500) is evaluating bexobrutideg in patients with relapsed or refractory CLL who have previously received a covalent BTK inhibitor, a noncovalent BTK inhibitor, and a BCL2 inhibitor.1
Previous data from the phase 1a/b NX-5948-301 trial (NCT05131022), which were presented at the
Regarding safety, no dose-limiting toxicities were reported during the phase 1 study. Three grade 5 adverse effects were reported, comprising pneumonia, pulmonary embolism, and not otherwise specified, and these were deemed unrelated to bexobrutideg.
“BTK degradation is a completely different way of targeting BTK, [and this] is active against BTK wild-type and BTK resistance mutations. [BTK degradation] really goes after the entire enzyme by using ubiquitination to degrade the entire BTK enzyme and disrupt both the scaffolding and kinase functioning, unlike current BTK inhibitors,” Shah said in an interview with OncLive®.
Shah is an assistant professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin in Milwaukee.
“BTK degraders are very different than BTK inhibitors, which essentially block the ATP binding domain, competing for ATP and blocking the function of the kinase,” Danilov said in another interview with OncLive®. “Instead, BTK degraders result in complete obliteration of the kinase from the cell. Theoretically, all you need is one molecule to reach the cell because once it degrades a molecule of BTK, it enters back into the circulation and can be recycled reused to degrade more BTK molecules.”
Danilov is an associate director for Clinical Services, the Marianne and Gerhard Pinkus Professor of Early clinical Therapeutics, medical director of the Early Phase Therapeutics Program for the Systems Clinical Trials Office, co-director of the Toni Stephenson Lymphoma Center, and a professor in the Division of Lymphoma at City of Hope in Duarte, California.
“When we think about key available classes of drugs, we think of covalent BTK inhibitors like acalabrutinib [Calquence], zanubrutinib [Brukinsa]; noncovalent BTK inhibitors like pirtobrutinib; and a BCL2 inhibitor in venetoclax [Venclexta],” Shah explained. “This is a tough group of patients [to treat]. If they have progressed on all classes of approved options, you really don't have a lot of treatment options available to you. DAYBreak CLL-201 is an opportunity for that patient population to get a drug that can maybe overcome these resistance mutations that may have occurred after exposure to other BTK inhibitors.”
The open-label, multicenter study is enrolling patients at least 18 years of age with relapsed or refractory CLL or small lymphocytic lymphoma per the International Workshop for CLL criteria.1 In addition to receiving prior a covalent BTK inhibitor, a noncovalent BTK inhibitor, and a BCL2 inhibitor, patients need to have an ECOG performance status of 2 or less and adequate organ and bone marrow function.
“The key [aspect of DAYBreak CLL-201’s eligibility criteria] is that patients must have had exposure to both covalent and noncovalent BTK inhibitor,” Danilov said. “They also must have had exposure to BCL2 inhibitor...What we are trying to do is understand how [bexobrutideg] works in patients with triple-refractory or triple-exposed CLL. This is certainly a very high unmet need. There really haven't been any regimens that have been studied in this particular setting.”
If patients have received CAR T-cell therapy or allogeneic/autologous hematopoietic cell transplant within 90 days of enrollment, have known or suspected prolymphocytic leukemia or Richter's transformation, or thromboembolic events within 6 months of treatment, they will not be included in the study.
Patients in the trial will receive once-daily oral doses of bexobrutideg in continuous 28-day cycles until progression.
ORR is the trial’s primary end point, whereas progression-free survival, complete response rate, and ORR with partial response with lymphocytosis serve as secondary end points.
“None of us have a crystal ball into the future, but what I'm hoping that [DAYBreak CLL-201] will show is that [bexobrutideg can be] a new treatment option that will show efficacy in this highly refractory group of patients with CLL,” Shah explained. “I'm not too worried about the safety of [bexobrutideg], because the safety has been well defined in these 142 patients who have been exposed to bexobrutideg [in the phase 1 study]. We're seeing a consistent, well-tolerated drug, and having been an investigator on the original trial, I can tell you from my own patient experience that people have tolerated this drug well.”
In addition to confidence in the efficacy and safety for bexobrutideg in DAYBreak CLL-201, experts are eyeing an accelerated FDA approval.
“What we could potentially expect then is accelerated FDA approval of [bexobrutideg] in this patient population,” Danilov pointed out. “Initially the place will be in a space post covalent noncovalent BTK inhibitor, that's where initially we probably might see the approval.”
“Triple-refractory CLL is just difficult to treat, and we're going to learn a lot about how efficacious this drug is in that clinical setting. If [bexobrutideg] meets the benchmarks like we hope that it does, then it [could become] FDA-approved as another weapon in our arsenal against CLL,” Shah concluded.
