Data Support Once-Daily Dosing of Zanubrutinib for MCL

A summary of data published in Leukemia & Lymphoma supports the recommended 320 mg daily dose of the approved indication for zanubrutinib in patients with mantle cell lymphoma (MCL).

Zanubrutinib (Brukinsa) is a second-generation irreversible Bruton’s tyrosine kinase (BTK) inhibitor that was granted accelerated FDA approval for adult patients with relapsed or refractory (R/R) MCL who had received at least 1 prior therapy.

“Zanubrutinib was designed to overcome some of the limitations associated with the first-generation BTK inhibitor, ibrutinib. Zanubrutinib is more selective than ibrutinib, minimizing binding with off-target kinases,” researchers explained.

Dose selection of cancer therapies to optimize efficacy can be challenging, while selection between 320-mg once daily (QD) or 160-mg twice daily (BID) dosing for oral targeted cancer therapies is frequently discussed during clinical development.

To better understand outcomes of dose regimens of zanubrutinib in patients with MCL, investigators assessed data from a single-arm, open-label multicenter phase 2 study in which patients were treated with zanubrutinib 160 mg BID until disease progression or unacceptable toxicity. They also assessed data from an additional multicenter phase 1, first-in-human study of the drug administered at starting doses of 40 mg, 80 mg, 160 mg, or 320 mg QD or 160 mg BID in patients with B-cell malignancies.

A total of 86 patients were enrolled in the phase 2 study and 37 in the phase 1 study (of which 32 were treated at the recommended phase 2 dose of either 320 mg QD [n = 18] or 160 mg BID [ n= 14]).

Supportive data from 3 additional studies were also included. In these trials, zanubrutinib was administered as a monotherapy.

Analyses revealed:

• As the pharmacokinetic (PK) profile of zanubrutinib is linear from 40- to 320-mg doses, simulations showed the same steady-state area under the plasma concentration-time curve from time 0 to 24h (AUC0-24,ss) estimate of 2042ng h/mL following both 160 mg BID and 320 mg QD dosing
• The geometric mean zanubrutinib maximum plasma concentration at steady-state (Cmax,ss) was 264 (42%) ng/mL following the 160 mg BID dose and was 513 (41.8%) ng/mL following the 320 mg QD dose
• For both dosing regimens, median BTK occupancy in peripheral blood mononuclear cells (PBMCs) was 100% across all time points, including those at Ctrough (pre-dose samples prior to dosing on week 2, day 1) when zanubrutinib plasma concentrations had dropped to almost undetectable levels
• Zanubrutinib has exposure coverage above inhibitory concentration (IC50) during the entire dose interval for both BID and QD dosing schedules.
• Both objective response rate and duration of response were similar for the 160-mg BID and 320-mg QD dosing regimens
• There were no remarkable differences in safety and tolerability profiles between 160-mg BID (N = 278) and 320-mg QD (N = 95) dosing regimens based on the safety dataset

Overall, data showed “that similar plasma exposure and BTK inhibition were achieved, and differences in trough concentration and maximum plasma concentration between the 2 regimens are unlikely to have a meaningful impact on efficacy and safety endpoints,” authors wrote.

Despite previous research indicating median BTK occupancy in lymph nodes was numerically lower at the 320 mg QD dose than at the 160 mg BID dose (94% vs 100%), the current analysis show that observed difference is unlikely to have a meaningful clinical impact.

“An oral dose of the 320-mg QD dosage regimen in addition to the 160-mg BID dose may provide patients and caregivers with additional dosing flexibility and the potential for increased drug adherence,” researchers explained. This may be of particular importance in older patients, as the median patient age in trials of zanubrutinib is around 65.

By simplifying the regimen of oral dosing, patients may improve medication adherence and concurrently maintain overall dose intensity.

“This report provides a case for a totality-of-evidence approach to bridge clinical findings related to BID and QD dosing regimens, supporting the recommendation of a 320-mg total daily dose,” authors concluded.

Reference

Ou YC, Tang Z, Novotny W, et al. Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma. Leuk Lymphoma. Published online June 23, 2021. doi:10.1080/10428194.2021.1929961