Blood cancers

Early promise with zanubrutinib in mantle cell lymphoma

Zanubrutinib is well tolerated and has demonstrated activity in patients with relapsed or refractory mantle cell lymphoma (MCL).

A study, published in Blood Advances, reported the safety and efficacy of the BTK inhibitor in the subgroup of patients with R/R MCL enrolled in an ongoing study of zanubrutinib in various B-cell malignancies.

The phase 1/2 study, conducted in six countries including Australia and New Zealand, enrolled 37 patients to receive either 160 mg zanubrutinib twice daily or 320 mg once daily.

Most had already received rituximab-containing regimen as a prior line of therapy.

The study found eight patients (25%) discontinued treatment due to adverse events of which three (9.4%) – pneumonia; cerebral infarction in the context of atrial flutter; and cardiac failure in the context of known ischaemic heart disease and baseline cardiomyopathy – were fatal.

Only one of the eight discontinuations – a grade 3 peripheral oedema – was considered to be related to zanubrutinib.

Almost all patients reported an adverse event of any grade (96.9%) including diarrhoea (43.8%), contusion (37.5%), constipation (31.3%), and upper respiratory tract infection (31.3%).

More than half of patients (59.4%) reported a grade ≥3 adverse event such as anaemia (12.5%), neutropenia (9.4%), pneumonia (9.4%), and myalgia (9.4%).

The study found an objective response was recorded in most (91%) patients by investigator assessment and 84% by independent review committee (IRC). Almost a third (31%) of patients achieved a complete response (CR) according to investigator assessment and 25% by IRC.

The median time to response was 2.8 months and median time to CR was 5.5 months.

The investigators said treatment benefit was consistent across subgroups, including very elderly patients and those with high MCL International Prognostic Index (MIPI) risk scores or refractory disease.

“The percentage of patients still responding to treatment at 6 months and 12 months was 83.3% and 78.7%, respectively,” they said.

The median PFS was 21.1 months.

The study found no discernible difference in response between the two dosing regimens which they said may provide some flexibility for patients and help improve adherence to therapy.

“Viewed in the context of the poor outcomes associated with R/R MCL and currently available treatment options, the benefit-risk profile for zanubrutinib is favourable, suggesting that it offers a promising treatment option for patients with R/R MCL,” the study authors concluded.

Almost a third (31.3%) of patients discontinued treatment due to progressive disease.

Professor Judith Trotman, from Concord Repatriation Hospital and the University of Sydney, told the limbic that responses were often high but not usually durable in the RR MCL setting.

“This is why it’s considered more an aggressive rather than indolent lymphoma. A median PFS of 21 months to zanubrutinib alone is excellent in this context but clearly we now need to be thinking about synergistic combinations.”

She added that zanubrutinib was very safe as demonstrated by mostly mild AEs and only one requiring treatment discontinuation.

“The phase 3 trial in CLL compared to ibrutinib confirmed this favourable safety profile, especially lower cardiovascular toxicity and diarrhoea.’

Disclosure: The study was supported by research funding from BeiGene

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