Zanubrutinib Studies Highlight Efficacy, Tolerability in MZL, CLL, SLL

The treatment appeared to live up to its billing of having fewer off-target effects in studies presented at the American Society of Hematology.

Zanubrutinib, the second-generation Bruton tyrosine kinase (BTK) inhibitor sold as Brukinsa (BeiGene), fared well in a series of studies presented this weekend during the 62nd American Society of Hematology Annual Meeting and Exposition.

Overall, the drug’s selling point—fewer off-target effects—seemed to hold up, as patients are able to stay on the drug for long periods or, as seen in one study, take it successfully after they can’t tolerate other BTK inhibitors. However, serious adverse events (AEs) do occur, and a small number of patients stopped taking the drug across the studies due to side effects.

Results presented Sunday demonstrated effectiveness in patients with marginal zone lymphoma (MZL) and treatment-naïve patients with chronic lymphocytic leukemia or small lympocytic lymphoma (CLL/SLL) with 17p deletion. And results from a phase 2 study presented Monday showed that zanubrutinib was able to maintain or improve clinical outcomes in patients with B-bell malignancies who had stopped taking ibrutinib or acalabrutinib.

Zanubrutinib is FDA-approved in mantle cell lymphoma (MCL) for patients who have received at least 1 prior therapy. Besides MZL and CLL/SLL, it being studied in other blood cancers, including follicular lymphoma, B-cell malignancies and Waldenstrom macroglobulinemia (WM).

The phase 2 results presented Monday were an outgrowth of a phase 2 study in WM, according to Ian Flinn, MD, PhD, of Tennessee Oncology, the senior author on the new study. In the original study patients were randomized to take zanubrutinib or ibrutinib.

“We found that there was much less of the adverse events, such as atrial fibrillation, seen with zanubrutinib than with ibrutinib, and this held true for many of the other adverse events associated with ibrutinib,” Flinn said. “We thought that trying this drug in patients who could no longer take ibrutinib, that maybe we could keep people on therapy with zanubrutinib that could not be on ibrutinib. And that was really the case here.

Arm C, Phase 3 SEQUOIA Trial. Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute, presented follow-up results from the non-randomized “Arm C” of the randomized, open-label phase 3 SEQUOIA trial, which examined zanubrutinib as a monotherapy in treatment-naïve pateints with CLL or SLL with del(17p). As seen in the ASPEN trial for WM, she said, zanubrutinib is “designed to maximize BTK occupancy and minimize off-target inhibition of TEC and EGFR kinases.”

Despite the more favorable safety profile, 5 patients in the study stopped treatment due to AEs, and 2 patients died, including 1 who developed pneumonia related to therapy.

Results reported at ASH 2019 had a follow-up of 10 months, but these new results included 21.9 months of follow-up, and the complete (CR) response rate increased from 1.9% to 6.4% during that time. Progression-free survival at 18 months (PFS) was 90.6% (95% CI, 83.3-94.9), and the overall response rate (ORR) was 94.5%, while the drug’s tolerability remained consistent with what has been reported in previous studies. Overall survival at 18 months was 95.4% (95% CI, 89.3-98.1). PFS at 18 months among patients with unfavorable characteristics included 88% for those with unmutated IGHV and 94% for those with complex karyotype status.

Within the ORR, 6 patients (5.5%) had CRs, 1 (0.9%) had a CR with incomplete bone marrow recovery, 1 (0.9%) had nodular partial response (PR), 94 (86.2%) PRs, and 1 (0.9%) had PR with lymphocytosis. Also, 93.1% maintained response at 12 months, and 87.7% maintained response a6 18 months.

The most common AEs were confusion (20.2%), upper respiratory tract infection (19.3%), diarrhea (17.4%) and nausea (14.7%); less common were back pain, constipation, rash, cough, neutropenia, arthralgia and pneumonia. More than half (52.3%) of patients had an AE of grade 3 or higher, with the most common being neutropenia, pneumonia, falls, and hypertension. More than a third (38.5%) had a serious AE.

Phase 2 MAGNOLIA Trial. Initial results from the single-arm, open-label study showed that zanubrutinib was generally well tolerated among older, high-risk MZL patients who had received at least 1 prior line of an anti-CD20 treatment. The trial’s 68 patients, with an average age of 70 years, had a median of 2 prior treatments; more than 30% had refractory disease and nearly 40% had nodal MZL.

Data were cut off on August 14, 2020. With a median time of 10.7 months, 66 patients were eligible to be evaluated for the drug’s efficacy. Results show:

  • The ORR was 74.2% (95% CI, 62.0-84.2), with 16 complete responses (24.2%), and 33 partial responses (50.0%).
  • The ORR was strong across high-risk subgroups, including patients who were at least 75 years of age, who had an ORR of 88.9%; those with refractory disease, whose ORR was 71.0%, and those with nodal MZL, whose ORR was 84.0%.
  • Median follow-up time for progression-free survival (PFS) was 9.13 months; PFS at 6 months was 80.0%, and 67.0% at 9 months.

Nearly all patients had a treatment-related adverse event (95.6%), with 38.2% having an event of grade 3 or higher. The most common events were neutropenia, diarrhea, pyrexia, thrombocytopenia, anemia and pneumonia. Two patients stopped taking the drug due to treatment related AEs, including 1 patient with a pre-existing cardiovascular condition who suffered a fatal heart attack.

Zanubrutinib after other BTK inhibitors. Mazyar Shadman, MD, PhD, of the Fred Hutchison Cancer Center and the University of Washington in Seattle presented phase 2 results highlighting results for patients who had previously taken ibrutinib or acalabrutinib. A total of 45 patients are enrolled, and 32 patients reached an assessment milestone in time for the data cutoff: 20 with CLL, 5 with SLL, 2 with MCL, and 5 with WM. All but 2 of the patients had taken ibrutinib previously, either as monotherapy or in combination. The median time on a prior BTK inhibitor ranged from 6.41 months for MCL patients to 12.91 months for WM patients, but some were on treatment for less than 2 months.

Researchers reported the following:

  1. Of the 66 ibrutinib intolerant events that occurred with the first BTK inhibitor, 58 did not recur with zanubrutinib.
  2. Of the 25 grade 3 intolerant events that occurred on prior therapy, only 2 recurred on zanubrutinib.
  3. None of the 4 grade 4 events recurred.
  4. 8 intolerant events occurred; 7 were at a lower severity than on the prior therapy, while 1 was the same severity. These were all bleeding events.

No patients have developed disease progression. Clinical assessments show that 44% of the patients are doing as well as they were on prior therapy, while 50% have improved responses. After a median follow-up of 3.5 months, 31 patients remain in the study. The patient no longer in the study is not due to an AE.

References

  1. Brown JR, Robak T, Ghia P, et al. Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Follow-up Results from Arm C of the SEQUOIA (BGB-3111-304) Trial. Presented at the 62nd American Society of Hematology Annual Meeting and Exposition; Virtual, December 5-8, 2020; Abstract 1306.
  2. Opat S, Tedeschi A, Linton K, et al. Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Initial Results of the MAGNOLIA (BGB-3111-214) Trial. Presented at the 62nd American Society of Hematology Annual Meeting and Exposition; Virtual, December 5-8, 2020; Abstract 339.

3. Shadman M, Sharman JP, Levy MY, et al. Phase 2 Study of Zanubrutinib in Patients with Relapsed/Refractory B-Cell Malignancies Intolerant to Ibrutinib/Acalabrutinib. Presented at the 62nd American Society of Hematology Annual Meeting and Exposition; Virtual, December 5-8, 2020; Abstract 2947.

Maggie L. Shaw contributed to this report.