BRUKINSA Capsule Ref.[49875] Active ingredients: Zanubrutinib

BTK Occupancy in PBMCs and Lymph Nodes

The median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at 100% over 24 hours at a total daily dose of 320 mg in patients with B-cell malignancies. The median steady-state BTK occupancy in lymph nodes was 94% to 100% following the approved recommended dosage.

Cardiac Electrophysiology

At the approved recommended doses (160 mg twice daily or 320 mg once daily), there were no clinically relevant effects on the QTc interval. The effect of BRUKINSA on the QTc interval above the therapeutic exposure has not been evaluated.

Zanubrutinib maximum plasma concentration (C_max) and area under the plasma drug concentration over time curve (AUC) increase proportionally over a dosage range from 40 mg to 320 mg (0.13 to 1 time the recommended total daily dose). Limited systemic accumulation of zanubrutinib was observed following repeated administration.

The geometric mean (CV) zanubrutinib steady-state daily AUC is 2,099 (42) ng∙h/mL following 160 mg twice daily and 1,917 (59%) ng∙h/mL following 320 mg once daily. The geometric mean (CV) zanubrutinib steady-state C_max is 295 (55) ng/mL following 160 mg twice daily and 537 (55%) ng/mL following 320 mg once daily.

Absorption

The median t_max of zanubrutinib is 2 hours.

Effect of Food

No clinically significant differences in zanubrutinib AUC or C_max were observed following administration of a high-fat meal (approximately 1,000 calories with 50% of total caloric content from fat) in healthy subjects.

Distribution

The geometric mean (CV) apparent volume of distribution (Vz/F) of zanubrutinib is 537 (73) L. The plasma protein binding of zanubrutinib is approximately 94% and the blood-to-plasma ratio is 0.7 to 0.8.

Elimination

The mean half-life (t_½) of zanubrutinib is approximately 2 to 4 hours following a single oral zanubrutinib dose of 160 mg or 320 mg. The geometric mean (CV) apparent oral clearance (CL/F) of zanubrutinib is 128 (58) L/h.

Metabolism

Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A.

Excretion

Following a single radiolabeled zanubrutinib dose of 320 mg to healthy subjects, approximately 87% of the dose was recovered in feces (38% unchanged) and 8% in urine (less than 1% unchanged).

Specific Populations

No clinically significant differences in the pharmacokinetics of zanubrutinib were observed based on age (19 to 90 years), sex, race (Asian, Caucasian, and Other), body weight (36 to 144 kg) or mild, moderate or severe renal impairment (creatinine clearance [CLcr] ≥15 mL/min as estimated by Cockcroft-Gault). The effect of dialysis on zanubrutinib pharmacokinetics is unknown.

Hepatic Impairment

The total AUC of zanubrutinib increased by 11% in subjects with mild hepatic impairment (Child-Pugh class A), by 21% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 60% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. The unbound AUC of zanubrutinib increased by 23% in subjects with mild hepatic impairment (Child-Pugh class A), by 43% in subjects with moderate hepatic impairment (Child-Pugh class B) and by 194% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

CYP3A Inhibitors: Co-administration of multiple doses of CYP3A inhibitors increases zanubrutinib C_max and AUC (Table 10).

Table 10. Observed or Predicted Increase in Zanubrutinib Exposure After Co-Administration of CYP3A Inhibitors:

CYP3A Inducers: Co-administration of multiple doses of rifampin (strong CYP3A inducer) decreased the zanubrutinib C_max by 92% and AUC by 93%.

Co-administration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib C_max by 58% and AUC by 60%.

CYP3A Substrates: Co-administration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) C_max by 30% and AUC by 47%.

CYP2C19 Substrates: Co-administration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) C_max by 20% and AUC by 36%.

Other CYP Substrates: No clinically significant differences were observed with warfarin (CYP2C9 substrate) pharmacokinetics when co-administered with zanubrutinib.

Transporter Systems: Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) C_max by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when co-administered with zanubrutinib.

Gastric Acid Reducing Agents: No clinically significant differences in zanubrutinib pharmacokinetics were observed when co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists).

In Vitro Studies

CYP Enzymes: Zanubrutinib is an inducer of CYP2B6 and CYP2C8.

Transporter Systems: Zanubrutinib is likely to be a substrate of P-gp. Zanubrutinib is not a substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1 or OATP1B3.

Carcinogenicity studies have not been conducted with zanubrutinib.

Zanubrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.

A combined male and female fertility and early embryonic development study was conducted in rats at oral zanubrutinib doses of 30 to 300 mg/kg/day. Male rats were dosed 4 weeks prior to mating and through mating and female rats were dosed 2 weeks prior to mating and to gestation day 7. No effect on male or female fertility was noted but at the highest dose tested, morphological abnormalities in sperm and increased post-implantation loss were noted. The high dose of 300 mg/kg/day is approximately 10 times the human recommended dose, based on body surface area.

14.1 Mantle Cell Lymphoma

The efficacy of BRUKINSA was assessed in BGB-3111-206 [NCT03206970], a Phase 2, open-label, multicenter, single-arm trial of 86 previously treated patients with MCL who had received at least one prior therapy. BRUKINSA was given orally at a dose of 160 mg twice daily until disease progression or unacceptable toxicity.

The median age of patients was 60.5 years (range: 34 to 75) and the majority were male (78%). The median time since diagnosis to study entry was 30 months (range: 3 to 102) and the median number of prior therapies was 2 (range: 1 to 4). The most common prior regimens were CHOP-based (91%) followed by rituximab-based (74%). The majority of patients had extranodal involvement (71%) and refractory disease (52%). Blastoid variant of MCL was present in 14% of patients. The MIPI score was low in 58%, intermediate in 29%, and high risk in 13%.

The efficacy of BRUKINSA was also assessed in BGB-3111-AU-003 [NCT02343120], a Phase 1/2, open-label, dose-escalation, global, multicenter, single-arm trial of B-cell malignancies including 32 previously treated MCL patients treated with BRUKINSA. BRUKINSA was given orally at doses of 160 mg twice daily or 320 mg daily. The median age of patients with previously treated MCL was 70 years (range: 42 to 86) and 38% of patients were ≥ 75 years old. Most patients were male (69%) and Caucasian (78%). The MIPI score was low in 28%, intermediate in 41%, and high risk in 31%.

Tumor response was according to the 2014 Lugano Classification for both studies, and the primary efficacy endpoint was overall response rate as assessed by an Independent Review Committee.

Table 11. Efficacy Results in Patients with MCL by Independent Review Committee:

ORR: overall response rate, CR: complete response, PR: partial response, DoR: duration of response, CI: confidence interval, NE: not estimable.
^* FDG-PET scans were not required for response assessment.

14.2 Waldenström’s Macroglobulinemia

The efficacy of BRUKINSA was evaluated in ASPEN [NCT03053440], a randomized, active control, open-label trial, comparing BRUKINSA and ibrutinib in patients with MYD88 L265P mutation (MYD88^MUT) WM. Patients in Cohort 1 (n=201) were randomized 1:1 to receive BRUKINSA 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. Randomization was stratified by number of prior therapies (0 versus 1-3 versus >3) and CXCR4 status (presence or absence of a WHIM-like mutation as measured by Sanger assay).

The major efficacy outcome was the response rate defined as PR or better as assessed by IRC based on standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM)-6 criteria. An additional efficacy outcome measure was duration of response (DOR).

The median age was 70 years (range: 38 to 90) and 68% were male. Of those enrolled, 2% were Asian, 91% were White and 7% were of unknown race. ECOG performance status of 0 or 1 was present in 93% patients at baseline and 7% had a baseline ECOG performance status of 2. A total of 82% had relapsed/refractory disease with 85% having received prior alkylating agents and 91% prior anti-CD20 therapy. The median number of prior therapies in those with relapsed/refractory disease was 1 (range: 1 to 8). A total of 91 (45%) patients had International Prognostic Scoring System (IPSS) high WM.

The study did not meet statistical significance for the pre-specified efficacy outcome of superior CR+VGPR as assessed by IRC, tested first in patients with R/R disease in ASPEN.

Table 12 shows the response rates in ASPEN based on IRC assessment.

Table 12. Response Rate and Duration of Response Based on IRC Assessment in ASPEN:

^* IWWM-6 criteria (Owen et al, 2013) require complete resolution of extramedullary disease (EMD) if present at baseline for VGPR to be assessed.
^† Modified IWWM-6 criteria (Treon, 2015) require a reduction in EMD if present at baseline for VGPR to be assessed.
^‡ 2-sided Clopper-Pearson 95% confidence interval.
^§ Estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley.

ASPEN Cohort 2

Cohort 2 enrolled patients with MYD88 wildtype (MYD88^WT) or MYD88 mutation unknown WM (N = 26 and 2, respectively) and received BRUKINSA 160 mg twice daily. The median age was 72 years (range: 39 to 87) with 43% >75 years, 50% were male, 96% were White and 4% were not reported (unknown race). 86% patients had a baseline ECOG performance status 0 or 1 and 14% had a baseline performance status of 2. Twenty-three of the 28 patients in Cohort 2 had relapsed or refractory disease.

In Cohort 2, response (CR+VGPR+PR) as assessed by IRC using IWWM-6 or modified IWWM-6 was seen in 50% (13 out of 26 response evaluable patients; 95% CI: 29.9, 70.1).

14.3 Marginal Zone Lymphoma

The efficacy of BRUKINSA was assessed in Study BGB-3111-214 [NCT03846427], an open-label, multicenter, single-arm trial that evaluated 66 patients with MZL who received at least one prior anti-CD20-based therapy. BRUKINSA was given orally at a dosage of 160 mg twice daily until disease progression or unacceptable toxicity. The median age was 70 years (range: 37 to 85); 55% were male; 38% had extranodal MZL, 38% nodal, 18% splenic and 6% had unknown subtype. The median number of prior systemic therapies was 2 (range: 1 to 6), with 27% having 3 or more lines of systemic therapy; 88% had prior rituximab-based chemotherapy; 32% had refractory disease at study entry.

The efficacy of BRUKINSA was also assessed in BGB-3111-AU-003 [NCT02343120], an open-label, multicenter, single-arm trial that included 20 patients with previously treated MZL (45% having extranodal MZL, 25% nodal, 30% splenic). BRUKINSA was given orally at dosages of 160 mg twice daily or 320 mg once daily. The median age was 70 years (range: 52 to 85); 50% were male. The median number of prior systemic therapies was 2 (range: 1 to 5), with 20% having 3 or more lines of systemic therapy; 95% had prior rituximab-based chemotherapy.

Efficacy was based on overall response rate (ORR) and duration of response as assessed by an Independent Review Committee (IRC) using 2014 Lugano criteria (Table 13).

Table 13. Efficacy Results per IRC in Patients with MZL:

ORR: overall response rate, CR: complete response, PR: partial response, DoR: duration of response, CI: confidence interval, NE: not estimable
^* Per 2014 CT-based Lugano criteria. FDG-PET scans were not considered for this response assessment.
^† Based on Kaplan-Meier estimation. Estimated median follow-up for DoR was 8.3 months for Study BGB-3111-214 and 31.4 months for Study BGB-3111-AU-003.

In study BGB-3111-214, ORR prioritizing PET-CT when available (55 patients, with the remainder assessed by CT scan) was 67% (95% CI: 54, 78) with a CR rate of 26%.