Zanubrutinib, a highly specific and irreversible next-generation Bruton’s tyrosine kinase (BTK) inhibitor, exhibited excellent activity in a single-arm, open-label multicenter phase 2 clinical trial of patients with relapsed or refractory mantle-cell lymphoma (MCL). Early study results were reported at ASH 2018.
At 12 months, the overall response rate (the study’s end point) was 83.5%, and the responses appeared to be durable, reported lead investigator Yuqin Song, MD, PhD, Department of Lymphoma, Peking University Cancer Hospital & Institute (Beijing Cancer Hospital), China.
“Zanubrutinib was designed to maximize BTK occupancy to minimize off-target inhibition of Tec and EGFR family kinases,” Dr Song said.
“It has been shown to be a highly potent, selective, bioavailable, and irreversible BTK inhibitor, with potentially advantageous pharmacokinetic and pharmacodynamic properties,” he noted.
Among responding patients, at 24 weeks after initial response, the event-free rate was 90%, and the progression-free survival (PFS) was 82%. At a median follow-up of 35.9 weeks, the median PFS had not been reached, Dr Song said.
The high specificity of zanubrutinib allows it to be dosed at a much higher level than first- and second-generation BTK inhibitors, according to Dr Song.
High Response Rate
The study was conducted in China and enrolled 86 adults (median age, 60.5 years) with relapsed or refractory MCL. Enrolled patients had received 1 to 4 previous lines of therapy, with a median of 2 treatments. At study entry, patients received zanubrutinib 160 mg twice daily until disease progression or unacceptable adverse events.
The proportion of patients with relapsed or refractory disease was similar (47.7% vs 52.3%). The majority (90.7%) of patients had stage III or stage IV disease, and 83.7% had intermediate- or high-risk disease, based on the Mantle Cell Lymphoma International Prognostic Index Combined Biologic Index. Overall, 37 (43%) patients had a tumor size >5 cm, and 7 (8.1%) patients had bulky tumors (>10 cm). Of the 86 enrolled patients, 12 (14%) had the blastoid variant of MCL, a variant that affects 10% to 15% of all MCL cases and is difficult to diagnose based on morphology alone (molecular studies can aid the diagnosis).
Of the 85 patients who were evaluated for efficacy, 71 (83.5%) patients had a response to zanubrutinib therapy; of these, 50 (58.8%) patients had a complete response, 21 (24.7%) patients had a partial response, and 2 (2.4%) patients had stable disease. The response rate among the patients with the blastoid variant of MCL was 75% (9 of 12).
“The responses achieved by zanubrutinib treatment appear durable, although we need a longer follow-up time to confirm,” Dr Song emphasized.
Treatment benefit was consistent across subgroups, including patients with and without the blastoid variant form of MCL, those with and without bulky tumors, and those who received treatment with fewer than or more than 3 previous lines of therapy.
Zanubrutinib Safety Profile
As of the data cutoff point on March 27, 2018, a total of 21 patients were off treatment: 13 patients because of progressive disease, 6 because of adverse events, 1 per the investigator’s discretion, and 1 patient who achieved a complete response but later withdrew consent.
Grade ≥3 treatment-emergent adverse events were reported in 28 (32.6%) patients, including reduced neutrophil count (11.6%), lung infection (5.8%), anemia (4.7%), and decreased white blood cell count (3.5%).
Treatment-emergent events of special interest included diarrhea (10.5%), hypertension (8.1%), and petechiae/purpura/contusion (4.7%). Decreased neutrophil count (31.4%), upper respiratory tract infection (29.1%), rash (29.1%), decreased platelet count (22.1%), and decreased white blood cell count (17.4%) constituted the most common events.
Of the 4 deaths that occurred during the study, 1 resulted from infection, 1 was a result of pneumonia, and 1 was caused by cerebral hemorrhage. The other patient died in a traffic accident.