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Chief of Hematologic Malignancies
Swedish Cancer Institute
John Pagel, MD, PhD, has disclosed that he has received consulting fees from AstraZeneca, Gilead Sciences, and Pharmacyclics.
Today, 3 different BTK inhibitors are available for the treatment of mantle cell lymphoma (MCL): ibrutinib, acalabrutinib, and zanubrutinib. All 3 agents are currently approved by the FDA for the treatment of MCL after at least 1 previous line of therapy, and all 3 have demonstrated similar efficacy in clinical trials. In this commentary, I provide an overview of zanubrutinib, which was approved in this setting in November 2019 and is relatively unfamiliar to many clinicians who treat patients with MCL.
Zanubrutinib (previously BGB-3111) is an oral, small-molecule BTK inhibitor with a mechanism of action similar to ibrutinib and acalabrutinib. Zanubrutinib is an irreversible inhibitor that covalently binds to BTK as does ibrutinib and acalabrutinib. BTK signaling in B-cells activates pathways for proliferation, trafficking, chemotaxis, and adhesion. By forming a covalent bond with a cysteine in the BTK active site, zanubrutinib inhibits BTK activity.
Zanubrutinib is approved in MCL at both 320 mg once daily and 160 mg twice daily. The FDA’s accelerated approval was based on results from 2 phase II trials: BGB-3111-AU-003 and BGB-3111-206.
BGB-3111-AU-003 and BGB-3111-206
BGB-3111-AU-003 is an ongoing phase I/II dose-escalation trial of zanubrutinib in patients with B-cell malignancies, including 32 patients with relapsed/refractory MCL. This is an open-label, multicenter trial conducted primarily in Australia, but also in New Zealand, Europe, Asia, and the United States. Patients with a median of 2 previous therapies that did not include a BTK inhibitor were treated with single‑agent zanubrutinib 160 mg twice daily or 320 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was the ORR. Of importance, tumor responses were assessed using the 2014 Lugano classification, which means PET scans were not required.
The phase II BGB-3111-206 study was very similar in that it was also an open‑label, single‑arm trial in patients with previously treated MCL (N = 86). This study was conducted in China with dosing of 160 mg twice daily, and again, ORR was the primary endpoint. An important difference between this study and BGB-3111-AU-003 was that although both used the 2014 Lugano classification, responses in BGB-3111-206 were assessed using PET/CT scans (or CT plus MRI in patients without FDG-avid disease).
In the BGB-3111-AU-003 trial, the median age of patients enrolled was 70 years and included patients as old as 86 years, with approximately one third of patients older than 75 years of age. In this trial, 16% of patients had received a previous autologous stem cell transplant and 31% had high‑risk Mantle Cell Lymphoma International Prognostic Index (MIPI) scores.
In the BGB-3111-206 trial, the median age was 60.5 years. Patients in this trial had been pretreated with various regimens, including rituximab‑ and CHOP‑based regimens in more than 75% of patients and many were refractory to previous therapy; 14% had blastoid variant MCL and 13% had high-risk disease by MIPI scores.
So, despite the fact that both of these trials enrolled patients with relapsed MCL, the study populations were certainly different, as were the criteria for assessing response.
The ORR was exactly the same in both trials: 84%. However, the CR rate of 59% in the Chinese BGB-3111-206 study was more than twice the 22% CR rate in BGB-3111-AU-003. The median duration of remission, however, was almost exactly the same, at approximately 19 months in both studies. The difference in CR rates may be attributed to the use of PET scans as part of the assessment for determining response in BGB-3111-206.
In updated data presented at the 2019 International Conference on Malignant Lymphoma, the median PFS was similar in both trials (19.1 months in BGB-3111-AU-003 and 17.3 months in BGB-3111-206).
Lymph Node Occupancy and Dosing of Zanubrutinib
One potential difference with zanubrutinib compared with other approved BTK inhibitors for relapsed/refractory MCL is that zanubrutinib has outstanding penetration and BTK occupancy in lymph nodes. In fact, more than 94% BTK occupancy has been observed with the approved recommended doses. It is not yet clear how the other BTK inhibitors interact with BTK within the lymphatic tissue or the lymph nodes. Although the data regarding penetration of zanubrutinib into lymph nodes are from studies of twice-daily dosing, it is likely that patients will do very well with once-daily dosing. In my clinical practice, I use 320-mg once-daily dosing for zanubrutinib because it is more convenient than 160-mg twice-daily dosing, particularly for patients who may struggle with twice-daily dosing.
Safety and Tolerability
BTK inhibitors do have unique toxicities that require monitoring and prompt management; understanding and early detection of these adverse events (AEs) can help mitigate the need to discontinue treatment. Zanubrutinib is a very well-tolerated therapy, generally speaking. In these 2 trials that enrolled patients with relapsed/refractory MCL with a median of 2 previous lines of treatment, patients were able to remain on therapy for a prolonged period of time. In fact, 67% of patients in these 2 trials were treated for at least a year and 78% for more than 6 months.
In an analysis of the safety of zanubrutinib in a pooled safety population in MCL (n = 118), the AEs seen in both studies were typical of this class of drugs. Bleeding is the main AE of concern with all 3 BTK inhibitors and appears to be a class effect. Bruising occurred in 14% of patients and hemorrhage was reported in 11% of patients, with 5% experiencing major hemorrhage (grade ≥ 3 or CNS hemorrhage of any grade).
In the pooled analysis, the most common AEs were primarily reversible hematologic events: decreased neutrophil count in 38% of patients (grade ≥ 3 neutropenia: 18%), decreased platelet count in 27% (grade 3 thrombocytopenia in 5%), and decreased WBC in 25% (grade ≥ 3 in 5%). Decreases in hemoglobin were less common at 14% of patients (grade 3 anemia in 8%). Rash was fairly common (36% of patients) and was usually grade 1/2, with no grade 3 rashes reported. Infections were also fairly common, with 39% reporting upper respiratory tract infections (no grade ≥ 3) and pneumonia in 15% (10% grade ≥ 3).
Hypertension was relatively infrequent: 3% reported grade ≥ 3 hypertension, and 12% with any-grade hypertension. Muscle aches and joint pains were relatively uncommon, with only approximately 14% of patients developing any-grade musculoskeletal pain or disorder or connective tissue disorders.
The rate of discontinuation was very low—8%—and the most frequent reason that patients discontinued was pneumonia and lung infection (4%). Although patients may experience atrial fibrillation with this class of therapies, none was seen in any of the patients with relapsed MCL who were treated on the BGB-3111-AU-003 and BGB-3111-206 studies. When looking at other zanubrutinib trials in B-cell malignancies (involving more than 600 patients), AEs are consistent with those seen here, although atrial fibrillation and atrial flutter have been reported in 2% of all patients receiving zanubrutinib and patients with cardiac risk factors, hypertension, or acute infections may be at increased risk for these AEs.
As with other BTK inhibitors, drug–drug interactions with CYP3A inhibitors or inducers can be a concern with zanubrutinib. Clinicians should consult with the patient and his/her pharmacist to determine if there are any concomitant CYP3A inhibitors or inducers being administered, as this might affect the dosing. Zanubrutinib dosing can be adjusted to 80 mg once daily if the patient is also receiving a strong CYP3A inhibitor or 80 mg twice daily if coadministering a moderate CYP3A inhibitor. Zanubrutinib should not be used with concomitant moderate or strong CYP3A inducers.
We now have multiple BTK inhibitors available to treat our patients with MCL (and other B-cell malignancies). Results from the phase I/II BGB-3111-AU-003 and phase II BGB-3111-206 studies led to the accelerated approval of zanubrutinib for relapsed MCL. I am looking forward to seeing additional long-term data and data from randomized phase III investigations to confirm the benefit of zanubrutinib in MCL and in other B-cell malignancies.
For example, a head-to-head comparison of zanubrutinib and ibrutinib is currently being conducted in the phase III ASPEN trial. Although this study was in Waldenström’s macroglobulinemia, not MCL, a recent press release from this trial suggests a comparable rate of CR plus VGPR with these 2 BTK inhibitors and possibly lower rates of serious AEs including atrial fibrillation, major hemorrhage, diarrhea, fatal AEs, and discontinuations due to AEs with zanubrutinib vs ibrutinib. We eagerly await the presentation of data from this study.
What questions do you have about the use of zanubrutinib and other BTK inhibitors in MCL? I encourage you to answer the polling question and join the conversation in the discussion box below.