Data from an ongoing Phase 1 trial show that BeiGene’s investigational therapy zanubrutinib is highly active in patients with Waldenström’s macroglobulinemia, a rare type of non-Hodgkin lymphoma.
In the trial, 92% of patients responded to treatment and 89% were alive and progression-free after one year.
The findings were recently revealed at the 2018 International Workshop on Waldenström’s Macroglobulinemia (IWWM) in New York City.
Constantine Tam, MD, with the Peter MacCallum Cancer Center in Australia, delivered the presentation, “Improved depth of response with increased follow-up in phase 1 trial of patients with Waldenström macroglobulinemia (WM) treated with oral Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (BGB-3111).”
Zanubrutinib is an inhibitor of the Bruton’s tyrosine kinase (BTK), a protein that B-cells need to thrive and proliferate. By blocking this molecule, zanubrutinib works to kill malignant B-cells and halt lymphoma progression.
Waldenström’s macroglobulinemia is a kind of cancer with features of both non-Hodgkin’s lymphoma and multiple myeloma. It affects two kinds of cells, B-cells and plasma cells — a mature form of B-cells that produce antibodies. Patients often produce large amounts of a certain antibody, called macroglobulin.
Waldenström’s patients often respond well to BTK inhibition, with the first-generation BTK inhibitor Imbruvica (ibrutinib) reducing tumor burden in 73% of patients and keeping 68% of patients alive and without complications or disease progression for more than three years.
Zanubrutinib is thought to be more sensitive to BTK, allowing for lower doses than Imbruvica that will potentially lead to fewer side effects.
The trial (NCT02343120) is testing the safety and efficacy of zanubrutinib in several B-cell cancers.
To date, 77 patients with Waldenström’s macroglobulinemia — both newly diagnosed or those who failed to respond to prior treatments — are enrolled, the presentation shows.
After a median follow-up of 22.5 months, 92% of patients had responded to the treatment, including 41% very good partial responses — meaning at least a 90% reduction in the initial levels of macroglobulin and fewer tumor cells outside the medulla measured by computed tomography (CT) scans. Median time until a response was detected was 85 days.
Waldenström’s patients with an MYD88 mutation are often poor responders to treatment and more likely to experience disease progression. Zanubrutinib reduced tumor burden in 94% of the 54 patients with such mutations. Forty-six percent were very good partial responses.
Patients with a normal MYD88 protein – who normally respond poorly to BTK inhibitors – also showed an 89% response rate, and a 22% very good partial response rate.
“With more than 70 patients with WM now treated, we continue to see a high rate of deep and durable responses across genotypes, including high rates of overall, major, and very good partial responses” Jane Huang, MD, chief medical officer of hematology at BeiGene, said in a press release.
At the time of the analysis, more than half of patients were alive and progression-free. The one-year progression-free survival rate was 89%.
The treatment was reported to be well-tolerated, with most adverse events said to be mild to moderate in severity. The most frequent were damaged small blood vessels in the skin, upper respiratory tract infection, cough, diarrhea, constipation, back pain, and headache.
The Chinese National Medical Products Administration is now reviewing a request to approve zanubrutinib as treatment for relapsed-refractory mantle cell lymphoma in that country; a regulatory filing in the U.S. for Waldenström’s macroglobulinemia patients is planned for next year.
“As we prepare our first U.S. New Drug Application (NDA) filing for zanubrutinib, which we expect to file in the first half of 2019 in patients with Waldenström’s Macroglobulinemia, we are pleased to update data in [these] patients from the Phase 1 trial that will support our filing,” Huang said.
“We are encouraged that additional data on zanubrutinib in patients with WM confirms the initially reported experience, with consistent demonstration of robust activity and good tolerability,” said Tam, director of hematology at St. Vincent’s Hospital and a consultant hematologist at MacCallum center, both in Australia.
The trial is being conducted at sites in Australia, New Zealand, the United States, Italy, and South Korea.
