Zanubrutinib Highly Active in Relapsed/Refractory MCL

Yuqin Song, MD, PhD

The investigational agent zanubrutinib (BGB-3111-206), a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, is highly active in patients with relapsed/refractory mantle cell lymphoma (R/R MCL), said Yuqin Song, MD, PhD, at the 2018 American Society of Hematology meeting. The overall response rate (ORR) in a single-arm, open-label, multicenter, phase II trial was 83.5% and responses appeared to be durable.¹

The 12-month progression-free survival (PFS) in zanubrutinib-treated patients was 90% and the 24-month PFS was 82%. At a median follow-up of 35.9 weeks, the median PFS had not been reached, said Song, chief physician and deputy director of the Lymphoma Department at Peking University Cancer Hospital, Beijing, China.

Data from the phase II trial were included in a new drug application submission in China for zanubrutinib in R/R MCL, she said.

BTK is constitutively activated in MCL and is a key mediator in cell survival. “Zanubrutinib was designed to maximize BTK occupancy to minimize off-target inhibition of TEC and EGFR family kinases,” Song said. “It has been shown to be a highly potent, selective, bioavailable, and irreversible BTK inhibitor with potentially advantageous pharmacokinetic/pharmacodynamic properties.” The high specificity of zanubrutinib allows it to be dosed at a much higher exposure than first- and second-generation BTK inhibitors that also have demonstrated activity in MCL, she said.

Complete and sustained BTK occupancy previously has been observed in paired peripheral bone marrow cells following doses of zanubrutinib as low as 40 mg. At a dose of 160 mg twice daily, the agent has shown 100% median BTK occupancy at trough plasma concentrations, with 94% of patients with various B-cell malignancies having >90% occupancy in lymph nodes.²

The study, conducted in China, enrolled 86 adult patients with MCL who had received 1 to 4 prior treatment regimens. They were treated with 160 mg twice daily of zanubrutinib until disease progression or unacceptable toxicity. The primary endpoint was ORR by independent review committee using positron emission tomography-based imaging according to the Lugano classification.

Data cutoff was March 27, 2018. At that time, 21 patients were off treatment, 13 due to progressive disease and 6 because of adverse events. One patient was discontinued at the investigator’s discretion 1 month after starting zanubrutinib and 1 patient who achieved a complete response withdrew consent.

A total of 85 patients was evaluable for efficacy. Of the 71 patients with an ORR, the best ORR was a complete response in 50 (58.8%), partial response in 21 (24.7%), and stable disease in 2 (2.4%). Five patients discontinued treatment prior to the first disease assessment and 1 had no evidence of measurable disease at baseline. “The responses achieved by zanubrutinib treatment appear durable although we need a longer follow-up time to confirm,” Song said.

The treatment benefit of zanubrutinib was consistent across subgroups, including patients with and without the blastoid variant form of MCL, those with and without bulky disease, and those treated with <3 or 3 or more prior lines. The response rate among the patients with the blastoid variant was 75% (9 of 12).

“Zanubrutinib tolerability was generally consistent with previous reports of zanubritinib treatment in patients with various B-cell malignancies,” Song said.

A total of 28 patients (32.6%) had a grade 3 treatment-emergent adverse event (TEAE) regardless of causality. Six patients (7.0%) discontinued zanubrutinib because of a TEAE. There were 4 deaths; 1 in the setting of infection, 1 due to pneumonia, 1 due to cerebral hemorrhage, and 1 because of a traffic accident. TEAEs of special interest included diarrhea (10.5%), hypertension (8.1%), and petechiae/purpura/contusion (4.7%).

The most frequent TEAEs included decreased neutrophil count (31.4%), upper respiratory tract infection (29.1%), rash (29.1%), decreased platelet count (22.1%), and decreased white blood cell (WBC) count (17.4%). Grade ≥3 TEAEs reported in at least 2 patients included decreased neutrophil count (11.6%), lung infection (5.8%), anemia (4.7%), and decreased WBC count (3.5%).

With respect to the performance of BTK inhibitors as a whole, investigators noted that distinctive AEs were observed in this trial: diarrhea was observed in 9 patients (10.5%), all grade 1/2 events. A major hemorrhage was observed in 1 patient (1.2%) with a blastoid variant of MCL who had intra-parenchymal central nervous system bleeding. There were no cases of atrial fibrillation or atrial flutter.

In July, zanubrutinib was granted Fast Track Designation by the FDA for the treatment of patients with Waldenström macroglobulinemia.

References

1. Song Y, Zhou K, Zou D, et al. Safety and activity of the investigational Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) in patients with mantle cell lymphoma from a phase 2 trial. Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego. Abstract 148.
2. BeiGene. Update on BTK inhibitor zanubrutinib (BGB-3111) and the Clinical Development Program. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017.

<<< 2018 ASH Annual Meeting

Median patient age was 60.5 years. Disease status was refractory in 52.3% and relapsed in 47.7%. Seventy-eight (90.7%) patients had stage III/IV disease and 72 (83.7%) were intermediate or high risk by the Mantle Cell Lymphoma International Prognostic Index Combined Biologic Index. Seven patients (8.1%) had bulky disease >10 cm and 37 (43%) had disease >5 cm. Patients received a median of 2 prior lines of therapy. Twelve patients (14%) had the blastoid variant of MCL.