New Phase 2 Results From MAGNOLIA Are Positive for Zanubrutinib

An updated round of results from MAGNOLA involving zanubrutinib in marginal zone lymphoma (MZL) were presented Wednesday at the European Hematology Association (EHA) 2021 Virtual Congress, taking place June 9-17. MAGNOLIA is a single-arm, multicenter phase 2 study of adults with relapsed/refractory marginal zone lymphoma who were previously treated with at least 1 prior line of therapy, including at least 1 CD20-directed regimen.¹

In MAGNOLIA, patients are treated with 160 mg of zanubrutinib twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary end point was the overall response rate (ORR) as determined by an independent review committee. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety.

Results through August 2020 presented at the American Society of Hematology in December showed that patients taking zanubrutinib, a Bruton tyrosine kinase (BTK) inhibitor, seemed to tolerate the drug better than earlier generation BTK inhibitors, which allowed them to stay on the drug. The new round of results presented at EHA, which include data through January 11, 2021, include 68 patients enrolled and treated, with a median age of 70, including 28% who were at least 75 years old.

MZL subtypes seen in the study included 38% of patients with extranodal MZL, 38% nodal, 18% splenic, and 6% indeterminate MZL. Patients in the study had received a median of 2 prior therapies, and 32% had disease that was refractory to their last therapy.

Results presented at EHA showed:

• Patients were exposed to the drug for a median of 59.1 weeks (range, 3.7-84.1). Sixty-six patients could be evaluated for the drug’s efficacy.
• At a median follow-up of 15.5 months (range, 1.6-21.7), investigator-assessed ORR, including complete response (CR) and partial response (PR), was 74%. This included 24 CR, 50% PR, and 17% with stable disease.
• Responses were observed in all subtypes, with an ORR of 68% in extranodal, 84% in nodal, 75% in splenic and 50% in indeterminate subtypes. The CR rate was 36% for extranodal MZL, 20% for nodal, 8% for splenic, and 25% for indeterminate subtype.
• Median DOR and PFS were not reached. At 15 months, PFS was 68%; and the 12-month DOR was 81%.
  
  

Adverse events. Since the last round data cutoff, 2 patients in the study died from COVID-19 pneumonia and 1 patient who had pre-existing coronary artery disease died from a heart attack. Neither case was considered related to zanubrutinib.

Of the 66 patients who could be evaluated, 28 (41%) stopped treatments, including 20 due to disease progression, 1 who withdrew consent, and 3 who required prohibited medications. Four stopped treatment due to adverse events (AEs), including the 2 who had COVID-19 pneumonia, the patient with the heart attack, and 1 due to pyrexia attributed to disease transformation.

The most common (≥10%) treatment-emergent AEs reported were diarrhea (22%), bruising (21%), constipation (15%), pyrexia (13%), abdominal pain (12%), upper respiratory tract infection (12%), back pain (10%), and nausea (10%). Most AEs were grade 1 or 2.

Phase 2 Results in Mantle Cell Lymphoma From Study in China

Long-term data from a phase 2 study in China evaluating zanubrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) were presented Friday during the EHA2021 Virtual Congress. The 86 patients in the study had a median follow-up of 35.3 months, with data cut off in September 2020.²

Patients enrolled in 13 centers in China had a median age of 60.5 years, and 83.7% were considered intermediate-to-high risk based on the International Prognostic Index Score. Most patients had advanced MCL, with 90.7% having stage III or higher; 45.3% had bone marrow involvement and 70.9% had extranodal disease. The median prior lines of therapy was 2, and 52.3% had refractory disease.

Patients in the single-arm study were given 160 mg of zanubrutinib twice a day until disease progression or unacceptable toxicity. Responses were measured every 12 weeks until Week 96, and then every 24 weeks. Investigator assessed ORR rate, PR, DOR, PFS, overall survival (OS), and safety were assessed.

Results were as follows:

• With the median follow-up of 35.3 months, 45.4% of patients were on the study drug and 54.7% had stopped taking it, mostly due to disease progression (43%) or adverse events (9.3%).
• ORR was 83.7%, and 67 patients (77.9%) achieved CR. Median DOR was not reached; 57.3% of the responders were estimated to be event-free—no disease progression or death—at 30 months.
• Median PFS was 33.0 months, and responses were generally consistent across all subgroups analyzed, including the level of prior therapy and refractory status.

Adverse events. Consistent with earlier results, the most treatment-related AEs, which occurred in at least 20% of the patients, were decreased neutrophil count (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), decreased white blood cell count (33.7%), and decreased platelet count (32.6%). Most of these events were grade 1 or 2. The most common grade 3 events were decreased neutrophil count (18.6%) and pneumonia (12.8%).

Most AEs were seen during the initial treatment stage with zanubrutinib, and very few events were reported during the latest follow-up period.

References

1. Opat S, Tedeschi A, Linton K, et al. Phase 2 study of zanubrutinib in patients with relapsed/refractory marginal zone lymphoma (MAGNOLIA). Presented at: EHA 2021 Virtual Congress. Abstract EP783.

2. Song Y, Zhou K, Zou D, et al. Zanubrutinib (ZANU) in patients with relapsed/refractory mantle cell lymphoma (MCL): long-term efficacy and safety results from a phase 2 study. Presented at: EHA 2021 Virtual Congress. Abstract EP789.